TY - JOUR AB - The use of artificial intelligence (AI) to improve the diagnosis, assessment and treatment of people with diabetes has the potential to drive a paradigm shift in diabetes care, both minimising treatment inertia and optimising clinical outcomes. This is a significant opportunity, given the predicted increase in the burden of diabetes over the next 20 years. However, there are concerns that regulatory processes for development and implementation of AI-driven technologies are not adequate for systems that may adapt to new data and change from their original performance characteristics as evaluated. The European Diabetes Forum (EUDF) convened a working group to review and investigate the unmet needs around implementation of AI technology in diabetes care. The working group developed the framework and focus of the accompanying analysis through a series of virtual and face-to-face meetings, including email conversations. The working group examined the key objectives for good diabetes care in the context of current and predicted AI-driven clinical decision support systems (AI-CDSS), including the outcomes for people with diabetes, the goals for personalised medicine and the implications for guideline-driven diabetes services and healthcare professionals. The process covered the needs of primary care healthcare professionals, who will shoulder the majority of diabetes care. The challenge of developing regulatory concepts and processes that are sufficiently robust to be AI inclusive was considered as central to the outcomes. Based on the available evidence, the EUDF working group believes that AI-CDSS will deliver benefits for people with diabetes, although there are clear challenges to moving AI-CDSS into the practical clinical space. To encourage debate on how this can be achieved safely and effectively, at the conclusion of the process a series of 14 recommendations was agreed using a nominal group technique and Delphi methodology, which are discussed in context in this article. AU - Bajramagic, M.* AU - Battelino, T.* AU - Cos, X.* AU - Cote, M.L.* AU - Cui, N.* AU - Forbes, A.* AU - Galderisi, A.* AU - Heinemann, L.* AU - Hussain, S.* AU - Imbert, J.* AU - Holm Jönsson, C.* AU - Joubert, M.* AU - Lalic, N.M.* AU - Phillip, M.* AU - Schwarz, P.E. AU - Torbeyns, B.* AU - Wake, D.J.* AU - Zakrzewska, K.* AU - Del Prato, S.* C1 - 76054 C2 - 58368 TI - Artificial intelligence-driven clinical decision support systems to assist healthcare professionals and people with diabetes in Europe at the point of care: a Delphi-based consensus roadmap. JO - Diabetologia PY - 2025 SN - 0012-186X ER - TY - JOUR AB - Early detection of type 1 diabetes, in its presymptomatic stage, offers significant clinical advantages, including treatment that can delay disease onset. Current screening focuses on identifying islet autoantibody positivity, with proposed optimal testing at ages 2, 6 and 10 years potentially achieving up to 80% sensitivity. However, challenges arise from participation rates and costs associated with multiple screenings. Genetic pre-screening has been suggested as a complementary strategy to target high-risk individuals prior to autoantibody testing, but its real-world benefits remain uncertain. Broad genetic selection strategies, based on family history, HLA typing or polygenic risk scores, can identify subsets of the population at elevated risk. However, these approaches face issues like low recall rates, socioeconomic biases and limited applicability across diverse ancestries. Additionally, the cost-effectiveness and infrastructure requirements of integrating genetic testing into routine healthcare remain significant hurdles. The combined use of genetic and autoantibody testing could improve predictive value, especially with innovations like point-of-care genetic testing. Yet, the ultimate success of any screening programme depends less on specific strategies and more on maximising public and healthcare-provider engagement, ensuring high participation, and addressing socioeconomic and demographic disparities. Digital-health infrastructure may play a crucial role in improving recall rates and maintaining follow-up adherence. In conclusion, while repeated islet autoantibody screening remains the most effective standalone approach, conducting genetic screening prior to islet autoantibody testing may be practical in certain contexts, provided that sufficient resources and equitable strategies are employed. Public engagement and robust infrastructure are essential to realising the full potential of early type 1 diabetes detection programmes. AU - Bonifacio, E.* AU - Coelho, R.* AU - Ewald, D.A.* AU - Gemulla, G.* AU - Hubmann, M.* AU - Jarosz-Chobot, P.* AU - Kohls, M. AU - Kordonouri, O.* AU - Lampasona, V.* AU - Narendran, P.* AU - Pociot, F.* AU - Šumník, Z.* AU - Szypowska, A.* AU - Zapardiel-Gonzalo, J. AU - Ziegler, A.-G. C1 - 73718 C2 - 57187 SP - 1101-1107 TI - The efficacy of islet autoantibody screening with or without genetic pre-screening strategies for the identification of presymptomatic type 1 diabetes. JO - Diabetologia VL - 68 IS - 6 PY - 2025 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: Despite continued interest in precision diagnostics and type 2 diabetes subtypes, the challenge of uncertainty in the classification of individuals into subtypes remains. This study introduces a novel method for quantifying and accounting for classification uncertainty in type 2 diabetes subtypes. METHODS: Building on recommendations from the ADA/EASD Precision Medicine in Diabetes Initiative, we quantified classification uncertainty using the normalised relative entropy (NRE), computed from distances to cluster centroids. A lower NRE value indicates greater uncertainty in an individual's cluster assignment. We examined the NRE in a cohort of 859 individuals with recent-onset type 2 diabetes from the prospective, observational German Diabetes Study (GDS) and compared it across previously identified diabetes subtypes, defined by age, BMI, HbA1c, HOMA-IR and HOMA-B. Predicted 10 year CVD risk (SCORE2-Diabetes) of the subtypes was evaluated with and without accounting for classification uncertainty. RESULTS: Individuals with mild age-related diabetes (n=395) and mild obesity-related diabetes (n=316) had a median NRE of 0.155 (95% CI 0.142, 0.177) and 0.119 (95% CI 0.107, 0.131), respectively. By contrast, individuals with severe insulin-resistant diabetes (n=130) and severe insulin-deficient diabetes (n=18) had a lower median NRE of 0.086 (95% CI 0.075, 0.108) and 0.082 (95% CI 0.071, 0.109), respectively. After weighting individuals by classification certainty, the proportion of variation in SCORE2-Diabetes explained by the subtypes (R2) increased from 17.4% (95% CI 12.8, 23.0) to 31.5% (95% CI 26.4, 37.1). The predicted 10 year CVD risk of the mild age-related diabetes subtype increased from 10.3% (95% CI 9.8, 10.7) to 11.6% (95% CI 11.2, 12.0). CONCLUSIONS/INTERPRETATION: The NRE provides a means to quantify and compare individual classification uncertainty in type 2 diabetes subtypes. Classification uncertainty varied between subtypes and individuals with type 2 diabetes, and accounting for it improved the ability of the subtypes to predict 10 year CVD risk. AU - Mori, T.* AU - Zaharia, O.P.* AU - Straßburger, K.* AU - Dennis, J.M.* AU - Mai, K.* AU - Kabisch, S.* AU - Bornstein, S.* AU - Szendroedi, J.* AU - Blüher, M. AU - Meyhöfer, S.* AU - Seissler, J.* AU - Birkenfeld, A.L.* AU - Stefan, N.* AU - Roden, M.* AU - Wagner, R.* AU - Kuß, O.* C1 - 75244 C2 - 57876 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - 2139-2150 TI - Recognising, quantifying and accounting for classification uncertainty in type 2 diabetes subtypes. JO - Diabetologia VL - 68 IS - 10 PB - Springer PY - 2025 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: Type 1 diabetes manifests after irreversible beta cell damage, highlighting the crucial need for markers of the presymptomatic phase to enable early and effective interventions. Current efforts to identify molecular markers of disease-triggering events lack resolution and convenience. Analysing frequently self-collected dried blood spots (DBS) could enable the detection of early disease-predictive markers and facilitate tailored interventions. Here, we present a novel strategy for monitoring transient molecular changes induced by environmental triggers that enable timely disease interception. METHODS: Whole blood (10 μl) was sampled regularly (every 1-5 days) from adult NOD mice infected with Coxsackievirus B3 (CVB3) or treated with vehicle alone. Blood samples (5 μl) were dried on filter discs. DBS samples were analysed by proximity extension assay. Generalised additive models were used to assess linear and non-linear relationships between protein levels and the number of days post infection (p.i.). A multi-layer perceptron (MLP) classifier was developed to predict infection status. CVB3-infected SOCS-1-transgenic (tg) mice were treated with immune- or non-immune sera on days 2 and 3 p.i., followed by monitoring of diabetes development. RESULTS: Frequent blood sampling and longitudinal measurement of the blood proteome revealed transient molecular changes in virus-infected animals that would have been missed with less frequent sampling. The MLP classifier predicted infection status after day 2 p.i. with over 90% accuracy. Treatment with immune sera on day 2 p.i. prevented diabetes development in all (100%) of CVB3-infected SOCS-1-tg NOD mice while five out of eight (62.5%) of the CVB3-infected controls treated with non-immune sera developed diabetes. CONCLUSIONS/INTERPRETATION: Our study demonstrates the utility of frequently collected DBS samples to monitor dynamic proteome changes induced by an environmental trigger during the presymptomatic phase of type 1 diabetes. This approach enables disease interception and can be translated into human initiatives, offering a new method for early detection and intervention in type 1 diabetes. DATA AND CODE AVAILABILITY: Additional data available at https://doi.org/10.17044/scilifelab.27368322 . Additional visualisations are presented in the Shiny app interface https://mouse-dbs-profiling.serve.scilifelab.se/ . AU - Parajuli, A.* AU - Bendes, A.* AU - Byvald, F.* AU - Stone, V.M.* AU - Ringqvist, E.E.* AU - Butrym, M.* AU - Angelis, E. AU - Kipper, S.* AU - Bauer, S. AU - Roxhed, N.* AU - Schwenk, J.M.* AU - Flodstrom-Tullberg, M.* C1 - 75305 C2 - 57932 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - 2277-2289 TI - Frequent longitudinal blood microsampling and proteome monitoring identify disease markers and enable timely intervention in a mouse model of type 1 diabetes. JO - Diabetologia VL - 68 IS - 10 PB - Springer PY - 2025 SN - 0012-186X ER - TY - JOUR AU - Phillip, M.* AU - Achenbach, P. AU - Addala, A.* AU - Albanese-O'Neill, A.* AU - Battelino, T.* AU - Bell, K.J.* AU - Besser, R.E.J.* AU - Bonifacio, E. AU - Colhoun, H.M.* AU - Couper, J.J.* AU - Craig, M.E.* AU - Danne, T.* AU - de Beaufort, C.* AU - Dovc, K.* AU - Dutta, S.* AU - Ebekozien, O.* AU - Elding Larsson, H.* AU - Frohnert, B.I.* AU - Gallagher, M.P.* AU - Greenbaum, C.J.* AU - Griffin, K.J.* AU - Hagopian, W.* AU - Haller, M.J.* AU - Hendriks, E.* AU - Holt, R.I.G.* AU - Ismail, H.M.* AU - Jacobsen, L.M.* AU - Kolb, L.E.* AU - Kordonouri, O.* AU - Lange, K.* AU - Lash, R.W.* AU - Lernmark, Å.* AU - Libman, I.M.* AU - Lundgren, M.* AU - Maahs, D.M.* AU - Marcovecchio, M.L.* AU - Mathieu, C.* AU - Oron, T.* AU - Patil, S.P.* AU - Rewers, M.J.* AU - Rich, S.S.* AU - Schatz, D.A.* AU - Schulman-Rosenbaum, R.* AU - Simmons, K.M.* AU - Sims, E.K.* AU - Skyler, J.S.* AU - Speake, C.* AU - Steck, A.K.* AU - Tonyushkina, K.N.* AU - Veijola, R.* AU - Wentworth, J.M.* AU - Wherrett, D.K.* AU - Wood, J.R.* AU - Ziegler, A.-G. AU - Dimeglio, L.A.* C1 - 73372 C2 - 57028 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - 892–895 TI - Considerations for more actionable consensus guidance for monitoring individuals with islet autoantibody-positive pre-stage 3 type 1 diabetes. Reply to Mallone R [letter]. JO - Diabetologia VL - 68 PB - Springer PY - 2025 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: Previous pathology studies have associated enterovirus infections with type 1 diabetes by examining the enterovirus capsid protein 1 (VP1) in autopsy pancreases obtained near diabetes diagnosis. The Network for Pancreatic Organ Donors with Diabetes (nPOD) has since obtained pancreases from organ donors with type 1 diabetes (with broad age and disease duration) and donors with disease-associated autoantibodies (AAbs), the latter representing preclinical disease. Two accompanying manuscripts from the nPOD-Virus Group report primary data from a coordinated analysis of multiple enterovirus indices. We aimed to comprehensively assess the association of multiple enterovirus markers with type 1 diabetes. METHODS: The nPOD-Virus Group examined pancreases from 197 donors, recovered between 2007 and 2019, classified into five groups: donors with type 1 diabetes, with residual insulin-containing islets (T1D-ICI group, n=41) or with only insulin-deficient islets (T1D-IDI, n=42); donors without diabetes who are AAb-negative (ND, n=83); and rare donors without diabetes expressing a single AAb (AAb+, n=22) or multiple AAbs (AAb++, n=9). We assessed the overall association of multiple indicators of enterovirus infection, case-by-case and between donor groups, as well as assay agreement and reproducibility, using various statistical methods. We examined data from 645 assays performed across 197 nPOD donors. RESULTS: Detection of enterovirus indices by independent laboratories had high reproducibility, using both enterovirus-targeted and unbiased methods. T1D-ICI donors had significantly higher (p<0.001) proportions of positive assay outcomes (58.4%) vs T1D-IDI (10.3%), ND (17.8%) and AAb-positive donors (AAb+ 24.6%; AAb++ 35.0%). Head-to-head comparisons revealed increased proportions of donors positive in two independent assays among T1D-ICI vs ND donors (VP1/HLA class I [HLA-I], p<0.0001; VP1/enterovirus-specific RT-PCR (EV-PCR), p=0.076; EV-PCR/HLA-I, p=0.016; proteomics/HLA-I, p<0.0001; VP1/proteomics, p=0.06). Among 110 donors examined for three markers (VP1, EV-PCR and HLA-I), 83.3% of T1D-ICI donors were positive in two or more assays vs 0% of ND (p<0.001), 26.7% of AAb+ (p=0.006), 28.6% of AAb++ (p=0.023) and 0% of T1D-IDI (p<0.001) donors. CONCLUSIONS/INTERPRETATION: The nPOD-Virus Group conducted, to date, the largest and most comprehensive analysis of multiple indices of pancreatic enterovirus infections in type 1 diabetes; these were more prevalent in T1D-ICI and AAb++ donors than in other groups. Their preferential detection of these indices in donors with residual beta cells and autoimmunity implicates enterovirus infections across disease progression stages and supports a contribution to beta cell loss, directly or indirectly, even after diagnosis. The relatively small number of infected cells and the low amount of viral RNA support the existence of non-acute, low level, possibly persistent enterovirus infections in the pancreas. AU - Richardson, S.J.* AU - Rodriguez-Calvo, T. AU - Laiho, J.E.* AU - Kaddis, J.S.* AU - Nyalwidhe, J.O.* AU - Kusmartseva, I.* AU - Morfopoulou, S.* AU - Petrosino, J.F.* AU - Plagnol, V.* AU - Maedler, K.* AU - Morris, M.A.* AU - Nadler, J.L.* AU - Atkinson, M.A.* AU - von Herrath, M.* AU - Lloyd, R.E.* AU - Hyöty, H.* AU - Morgan, N.G.* AU - Pugliese, A.* C1 - 73680 C2 - 57170 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - 1226-1241 TI - Joint analysis of the nPOD-Virus Group data: The association of enterovirus with type 1 diabetes is supported by multiple markers of infection in pancreas tissue. JO - Diabetologia VL - 68 IS - 6 PB - Springer PY - 2025 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: Earlier studies of pancreases from donors with type 1 diabetes demonstrated enteroviral capsid protein VP1 in beta cells. In the context of a multidisciplinary approach undertaken by the nPOD-Virus group, we assessed VP1 positivity in pancreas and other tissues (spleen, duodenum and pancreatic lymph nodes) from 188 organ donors, including donors with type 1 diabetes and donors expressing autoantibody risk markers. We also investigated whether VP1 positivity is linked to the hyperexpression of HLA class I (HLA-I) molecules in islet cells. METHODS: Organ donor tissues were collected by the Network for Pancreatic Organ Donors with Diabetes (nPOD) from donors without diabetes (ND, n=76), donors expressing a single or multiple diabetes-associated autoantibodies (AAb+, n=20; AAb++, n=9) and donors with type 1 diabetes with residual insulin-containing islets (T1D-ICIs, n=41) or only insulin-deficient islets (T1D-IDIs, n=42). VP1 was assessed using immunohistochemistry (IHC) and HLA-I using IHC and immunofluorescence, in two independent laboratories. We determined assay concordance across laboratories and overall occurrence of positive assays, on a case-by-case basis and between donor groups. RESULTS: Islet cell VP1 positivity was detected in most T1D-ICI donors (77.5%) vs only 38.2% of ND donors (p<0.001). VP1 positivity was associated with HLA-I hyperexpression. Of those donors assessed for HLA-I and VP1, 73.7% had both VP1 immunopositivity and HLA-I hyperexpression (p<0.001 vs ND). Moreover, VP1+ cells were detected at higher frequency in donors with HLA-I hyperexpression (p<0.001 vs normal HLA-I). Among VP1+ donors, the proportion with HLA-I hyperexpression was significantly higher in the AAb++ and T1D-ICI groups (94.9%, p<0.001 vs ND); this was not restricted to individuals with recent-onset diabetes. Critically, for all donor groups combined, HLA-I hyperexpression occurred more frequently in VP1+ compared with VP1- donors (45.8% vs 16%, p<0.001). CONCLUSIONS/INTERPRETATION: We report the most extensive analysis to date of VP1 and HLA-I in pancreases from donors with preclinical and diagnosed type 1 diabetes. We find an association of VP1 with residual beta cells after diagnosis and demonstrate VP1 positivity during the autoantibody-positive preclinical stage. For the first time, we show that VP1 positivity and HLA-I hyperexpression in islet cells are both present during the preclinical stage. While the study of tissues does not allow us to demonstrate causality, our data support the hypothesis that enterovirus infections may occur throughout the natural history of type 1 diabetes and may be one of multiple mechanisms driving islet cell HLA-I hyperexpression. AU - Rodriguez-Calvo, T. AU - Laiho, J.E.* AU - Oikarinen, M.* AU - Akhbari, P.* AU - Flaxman, C.* AU - Worthington, T.* AU - Apaolaza Gallegos, S.P. AU - Kaddis, J.S.* AU - Kusmartseva, I.* AU - Tauriainen, S.* AU - Campbell-Thompson, M.* AU - Atkinson, M.A.* AU - von Herrath, M.* AU - Hyöty, H.* AU - Morgan, N.G.* AU - Pugliese, A.* AU - Richardson, S.J.* C1 - 73679 C2 - 57169 SP - 1197-1210 TI - Enterovirus VP1 protein and HLA class I hyperexpression in pancreatic islet cells of organ donors with type 1 diabetes. JO - Diabetologia VL - 68 IS - 6 PY - 2025 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: Unimolecular peptides targeting the receptors for glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon (GCG) have been shown to improve glycaemic management in both mice and humans. Yet the identity of the downstream signalling events mediated by these peptides remain to be elucidated. Here, we aimed to assess the mechanisms by which a validated peptide triagonist for GLP-1/GIP/GCG receptors (IUB447) stimulates insulin secretion in murine pancreatic islets. METHODS: Islets were isolated from wild-type (WT), Gipr-knockout (Gipr-/-), Gcgr-knockout (Gcgr-/-), Glp-1r (also known as Glp1r)/Gipr double-knockout and Trpm5-knockout (Trpm5-/-) mice, followed by assessment of beta cell function and insulin secretion in response to mono- and multi-agonist administration. Metabolic phenotypes of WT and Trpm5-/- mice under chow and high-fat diets were investigated following triagonist application. RESULTS: The triagonist promoted glucose-stimulated insulin secretion (GSIS) to a greater degree than co-administration of conventional mono-agonists in WT mouse islets. The triagonist-induced increase in GSIS was unchanged in the absence of either Gipr or Gcgr. However, the triagonist failed to enhance insulin secretion in islets lacking both Glp-1r and Gipr and upon treatment with the GLP-1 receptor-specific antagonist exendin-3 (9-39). Similarly, the specific blocking of Gαq signalling with YM254890 or transient receptor potential melastatin 5 (TRPM5) with triphenylphosphine oxide (TPPO) suppressed the triagonist-induced enhancement of GSIS. In vivo assessment of high-fat-fed Trpm5-/- mice demonstrated the absence of triagonist-induced therapeutic effects on glycaemic management. CONCLUSIONS/INTERPRETATION: Triagonist-induced augmentation of GSIS is primarily mediated through its interaction with the GLP-1 receptor and subsequent activation of the Gαq-TRPM5 signalling pathway. Given that Gαq is a key player in the amplification of GSIS, particularly under diabetic conditions, these findings highlight a GLP-1 receptor-centric pharmacological profile that underlies the potent effects of this multi-receptor agonist. AU - Schreier, P.C.F.* AU - Beyerle, P.* AU - Boulassel, S.* AU - Beck, A.* AU - Novikoff, A. AU - Reinach, P.S.* AU - Boekhoff, I.* AU - Breit, A.* AU - Neuberger, A.* AU - Müller, T.D. AU - Cebrian Serrano, A. AU - Gudermann, T.* AU - Khajavi, N.* C1 - 75525 C2 - 58025 CY - One New York Plaza, Suite 4600, New York, Ny, United States TI - GLP-1/GIP/GCG receptor triagonist (IUB447) enhances insulin secretion via GLP-1 receptor and Gαq signalling pathway in mice. JO - Diabetologia PB - Springer PY - 2025 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: Despite playing critical roles in the pathophysiology of type 2 diabetes and other metabolic disorders, the molecular mechanisms underlying circulating adipokine levels remain poorly understood. By identifying genomic regions involved in the regulation of adipokine levels and adipokine-mediated disease risk, we can improve our understanding of type 2 diabetes pathogenesis and inter-individual differences in metabolic risk. METHODS: We conducted an epigenome-wide meta-analysis of associations between serum adiponectin (n=2791) and leptin (n=3661) and leukocyte DNA methylation at over 400,000 CpG sites across five European cohorts. The resulting methylation signatures were followed up using functional genomics, integrative analyses and causal inference methods. RESULTS: Our findings revealed robust associations with adiponectin at 73 CpGs and leptin at 211 CpGs. Many of the identified sites were also associated with risk factors for the metabolic syndrome and located in enhancers close to relevant transcription factor binding sites. Integrative analyses additionally linked 35 of the adiponectin-associated CpGs to the expression of 46 genes, and 100 of the leptin-associated CpGs to the expression of 151 genes, with implicated genes enriched for lipid transport (e.g. ABCG1), metabolism (e.g. CPT1A) and biosynthesis (e.g. DHCR24). Bidirectional two-sample Mendelian randomisation further identified two specific CpG sites as plausible drivers of both adiponectin levels and metabolic health: one annotated to ADIPOQ, the gene encoding adiponectin; and another linked to the expression of SREBF1, an established modifier of type 2 diabetes risk known to exert its effects via adiponectin. CONCLUSIONS/INTERPRETATION: Taken together, these large-scale and integrative analyses uncovered links between adipokines and widespread, yet functionally specific, differences in regulation of genes with a central role in type 2 diabetes and its risk factors. AU - Sinke, L.* AU - Delerue, T. AU - Wilson, R. AU - Lu, X.* AU - Xia, Y.* AU - Costeira, R.* AU - Nasr, M.K.* AU - Beekman, M.* AU - Franke, L.* AU - Zhernakova, A.* AU - Fu, J.* AU - Gieger, C. AU - Herder, C.* AU - Koenig, W.* AU - Peters, A. AU - Ordovas, J.M.* AU - Dörr, M.* AU - Grabe, H.J.* AU - Nauck, M.* AU - Bell, J.T.* AU - Teumer, A.* AU - Snieder, H.* AU - Waldenberger, M. AU - Slagboom, P.E.* AU - Heijmans, B.T.* C1 - 75736 C2 - 57980 CY - One New York Plaza, Suite 4600, New York, Ny, United States TI - DNA methylation of genes involved in lipid metabolism drives adiponectin levels and metabolic disease. JO - Diabetologia PB - Springer PY - 2025 SN - 0012-186X ER - TY - JOUR AU - Zapardiel-Gonzalo, J. AU - Ziegler, A.-G. AU - Bonifacio, E.* C1 - 74073 C2 - 57325 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - 1352–1354 TI - The genetic architecture of type 1 diabetes over time: How well can we rely on past data to predict the future? JO - Diabetologia VL - 68 PB - Springer PY - 2025 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: Islet prohormone-processing enzymes convert peptide hormone precursors to mature hormones. Defective beta cell prohormone processing and the release of incompletely processed peptide hormones are observed prior to the onset of diabetes, yet molecular mechanisms underlying impaired prohormone processing during the development of diabetes remains largely unknown. Previous studies have shown that prohormone convertase 1/3 (PC1/3) protein and mRNA expression levels are reduced in whole islets from donors with type 1 diabetes, although whether PC1/3-mediated prohormone processing in alpha and beta cells is disrupted in type 1 diabetes remained to be explored. Herein, we aimed to analyse the expression of PC1/3 in islets from non-diabetic donors, autoantibody-positive donors and donors diagnosed with type 1 diabetes or type 2 diabetes. METHODS: Immunostaining and high-dimensional image analysis were performed on pancreatic sections from a cross-sectional cohort of 54 donors obtained from the Network for Pancreatic Organ Donors with Diabetes (nPOD) repository, to evaluate PC1/3 expression patterns in islet alpha, beta and delta cells at different stages of diabetes. RESULTS: Alpha and beta cell morphology were altered in donors with type 1 diabetes, including decreased alpha and beta cell size. As expected, the insulin-positive and PC1/3-positive areas in the islets were both reduced, and this was accompanied by a reduced percentage of PC1/3-positive and insulin-positive/PC1/3-positive cells in islets. PC1/3 and insulin co-localisation was also reduced. The glucagon-positive area, as well as the percentage of glucagon-positive and glucagon-positive/PC1/3-positive cells in islets, was increased. PC1/3 and glucagon co-localisation was also increased in donors with type 1 diabetes. The somatostatin-positive cell area and somatostatin staining intensity were elevated in islets from donors with recent-onset type 1 diabetes. CONCLUSIONS/INTERPRETATION: Our high-resolution histomorphological analysis of human pancreatic islets from donors with and without diabetes has uncovered details of the cellular origin of islet prohormone peptide processing defects. Reduced beta cell PC1/3 and increased alpha cell PC1/3 in islets from donors with type 1 diabetes pinpointed the functional deterioration of beta cells and the concomitant potential increase in PC1/3 usage for prohormone processing in alpha cells during the pathogenesis of type 1 diabetes. Our finding of PC1/3 loss in beta cells may inform the discovery of new prohormone biomarkers as indicators of beta cell dysfunction, and the finding of elevated PC1/3 expression in alpha cells may encourage the design of therapeutic targets via leveraging alpha cell adaptation in diabetes. AU - Apaolaza Gallegos, S.P. AU - Chen, Y.C.* AU - Grewal, K.* AU - Lurz, Y.* AU - Boulassel, S. AU - Verchere, C.B.* AU - Rodriguez-Calvo, T. C1 - 72016 C2 - 56345 CY - One New York Plaza, Suite 4600, New York, Ny, United States TI - Quantitative analysis of islet prohormone convertase 1/3 expression in human pancreas donors with diabetes. JO - Diabetologia PB - Springer PY - 2024 SN - 0012-186X ER - TY - JOUR AB - The graphical abstract (available at https://doi.org/10.1007/s00125-023-06053-9) included a typographical error (‘insulin-dependent insulin secretion’, rather than ‘glucose-dependent insulin secretion’). The online version has been corrected. (Figure presented.). AU - Blüher, M. AU - Rosenstock, J.* AU - Hoefler, J.* AU - Manuel, R.* AU - Hennige, A.M.* C1 - 69988 C2 - 55352 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - 758-758 TI - Correction to: Dose-response effects on HbA1c and bodyweight reduction of survodutide, a dual glucagon/GLP-1 receptor agonist, compared with placebo and open-label semaglutide in people with type 2 diabetes: A randomised clinical trial. JO - Diabetologia VL - 67 IS - 4 PB - Springer PY - 2024 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: The aim of this work was to understand the role of non-beta cells in pancreatic islets at early stages of type 2 diabetes pathogenesis. METHODS: Specific clustering was employed to single-cell transcriptome data from islet cells of obese mouse strains differing in their diabetes susceptibility (diabetes-resistant B6.V.Lepob/ob [OB] and diabetes-susceptible New Zealand Obese [NZO] mice) on a diabetogenic diet. RESULTS: Refined clustering analysis revealed several heterogeneous subpopulations for alpha cells, delta cells and macrophages, of which 133 mapped to human diabetes genes identified by genome-wide association studies. Importantly, a similar non-beta cell heterogeneity was found in a dataset of human islets from donors at different stages of type 2 diabetes. The predominant alpha cell cluster in NZO mice displayed signs of cellular stress and lower mitochondrial capacity (97 differentially expressed genes [DEGs]), whereas delta cells from these mice exhibited higher expression levels of maturation marker genes (Hhex and Sst) but lower somatostatin secretion than OB mice (184 DEGs). Furthermore, a cluster of macrophages was almost twice as abundant in islets of OB mice, and displayed extensive cell-cell communication with beta cells of OB mice. Treatment of beta cells with IL-15, predicted to be released by macrophages, activated signal transducer and activator of transcription (STAT3), which may mediate anti-apoptotic effects. Similar to mice, humans without diabetes possess a greater number of macrophages than those with prediabetes (39 mmol/mol [5.7%] < HbA1c < 46 mmol/mol [6.4%]) and diabetes. CONCLUSIONS/INTERPRETATION: Our study indicates that the transcriptional heterogeneity of non-beta cells has an impact on intra-islet crosstalk and participates in beta cell (dys)function. DATA AVAILABILITY: scRNA-seq data from the previous study are available in gene expression omnibus under gene accession number GSE159211 ( https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE159211 ). AU - Gottmann, P.* AU - Speckmann, T.* AU - Stadion, M.* AU - Chawla, P.* AU - Saurenbach, J.* AU - Ninov, N.* AU - Lickert, H. AU - Schürmann, A.* C1 - 72326 C2 - 56597 CY - One New York Plaza, Suite 4600, New York, Ny, United States TI - Transcriptomic heterogeneity of non-beta islet cells is associated with type 2 diabetes development in mouse models. JO - Diabetologia PB - Springer PY - 2024 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: The aim of this study was to determine whether BMI in early childhood was affected by the COVID-19 pandemic and containment measures, and whether it was associated with the risk for islet autoimmunity. METHODS: Between February 2018 and May 2023, data on BMI and islet autoimmunity were collected from 1050 children enrolled in the Primary Oral Insulin Trial, aged from 4.0 months to 5.5 years of age. The start of the COVID-19 pandemic was defined as 18 March 2020, and a stringency index was used to assess the stringency of containment measures. Islet autoimmunity was defined as either the development of persistent confirmed multiple islet autoantibodies, or the development of one or more islet autoantibodies and type 1 diabetes. Multivariate linear mixed-effect, linear and logistic regression methods were applied to assess the effect of the COVID-19 pandemic and the stringency index on early-childhood BMI measurements (BMI as a time-varying variable, BMI at 9 months of age and overweight risk at 9 months of age), and Cox proportional hazard models were used to assess the effect of BMI measurements on islet autoimmunity risk. RESULTS: The COVID-19 pandemic was associated with increased time-varying BMI (β = 0.39; 95% CI 0.30, 0.47) and overweight risk at 9 months (β = 0.44; 95% CI 0.03, 0.84). During the COVID-19 pandemic, a higher stringency index was positively associated with time-varying BMI (β = 0.02; 95% CI 0.00, 0.04 per 10 units increase), BMI at 9 months (β = 0.13; 95% CI 0.01, 0.25) and overweight risk at 9 months (β = 0.23; 95% CI 0.03, 0.43). A higher age-corrected BMI and overweight risk at 9 months were associated with increased risk for developing islet autoimmunity up to 5.5 years of age (HR 1.16; 95% CI 1.01, 1.32 and HR 1.68, 95% CI 1.00, 2.82, respectively). CONCLUSIONS/INTERPRETATION: Early-childhood BMI increased during the COVID-19 pandemic, and was influenced by the level of restrictions during the pandemic. Controlling for the COVID-19 pandemic, elevated BMI during early childhood was associated with increased risk for childhood islet autoimmunity in children with genetic susceptibility to type 1 diabetes. AU - Hummel, S. AU - Rosenberger, S. AU - von dem Berge, T.* AU - Besser, R.E.J.* AU - Casteels, K.* AU - Hommel, A. AU - Kordonouri, O.* AU - Elding Larsson, H.* AU - Lundgren, M.* AU - Marcus, B.A.* AU - Oltarzewski, M.* AU - Rochtus, A.* AU - Szypowska, A.* AU - Todd, J.A.* AU - Weiss, A. AU - Winkler, C. AU - Bonifacio, E. AU - Ziegler, A.-G. C1 - 69755 C2 - 55255 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - 670-678 TI - Early-childhood body mass index and its association with the COVID-19 pandemic, containment measures and islet autoimmunity in children with increased risk for type 1 diabetes. JO - Diabetologia VL - 67 IS - 4 PB - Springer PY - 2024 SN - 0012-186X ER - TY - JOUR AU - Jumpertz von Schwartzenberg, R. AU - Vazquez Arreola, E.* AU - Sandforth, A. AU - Hanson, R.L.* AU - Birkenfeld, A.L. C1 - 70729 C2 - 55864 CY - One New York Plaza, Suite 4600, New York, Ny, United States TI - Role of weight loss-induced prediabetes remission in the prevention of type 2 diabetes: Time to improve diabetes prevention. JO - Diabetologia PB - Springer PY - 2024 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: Quantitative sensory testing (QST) allows the identification of individuals with rapid progression of diabetic sensorimotor polyneuropathy (DSPN) based on certain sensory phenotypes. Hence, the aim of this study was to investigate the relationship of these phenotypes with the structural integrity of the sciatic nerve among individuals with type 2 diabetes. METHODS: Seventy-six individuals with type 2 diabetes took part in this cross-sectional study and underwent QST of the right foot and high-resolution magnetic resonance neurography including diffusion tensor imaging of the right distal sciatic nerve to determine the sciatic nerve fractional anisotropy (FA) and cross-sectional area (CSA), both of which serve as markers of structural integrity of peripheral nerves. Participants were then assigned to four sensory phenotypes (participants with type 2 diabetes and healthy sensory profile [HSP], thermal hyperalgesia [TH], mechanical hyperalgesia [MH], sensory loss [SL]) by a standardised sorting algorithm based on QST. RESULTS: Objective neurological deficits showed a gradual increase across HSP, TH, MH and SL groups, being higher in MH compared with HSP and in SL compared with HSP and TH. The number of participants categorised as HSP, TH, MH and SL was 16, 24, 17 and 19, respectively. There was a gradual decrease of the sciatic nerve's FA (HSP 0.444, TH 0.437, MH 0.395, SL 0.382; p=0.005) and increase of CSA (HSP 21.7, TH 21.5, MH 25.9, SL 25.8 mm2; p=0.011) across the four phenotypes. Further, MH and SL were associated with a lower sciatic FA (MH unstandardised regression coefficient [B]=-0.048 [95% CI -0.091, -0.006], p=0.027; SL B=-0.062 [95% CI -0.103, -0.020], p=0.004) and CSA (MH β=4.3 [95% CI 0.5, 8.0], p=0.028; SL B=4.0 [95% CI 0.4, 7.7], p=0.032) in a multivariable regression analysis. The sciatic FA correlated negatively with the sciatic CSA (r=-0.35, p=0.002) and markers of microvascular damage (high-sensitivity troponin T, urine albumin/creatinine ratio). CONCLUSIONS/INTERPRETATION: The most severe sensory phenotypes of DSPN (MH and SL) showed diminishing sciatic nerve structural integrity indexed by lower FA, likely representing progressive axonal loss, as well as increasing CSA of the sciatic nerve, which cannot be detected in individuals with TH. Individuals with type 2 diabetes may experience a predefined cascade of nerve fibre damage in the course of the disease, from healthy to TH, to MH and finally SL, while structural changes in the proximal nerve seem to precede the sensory loss of peripheral nerves and indicate potential targets for the prevention of end-stage DSPN. TRIAL REGISTRATION: ClinicalTrials.gov NCT03022721. AU - Mooshage, C.M.* AU - Tsilingiris, D. AU - Schimpfle, L.* AU - Seebauer, L.* AU - Eldesouky, O.* AU - Aziz-Safaie, T.* AU - Hohmann, A.* AU - Herzig, S. AU - Szendroedi, J.* AU - Nawroth, P.* AU - Heiland, S.* AU - Bendszus, M.* AU - Kurz, F.T.* AU - Kopf, S.* AU - Jende, J.M.E.* AU - Kender, Z.* C1 - 68896 C2 - 53749 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - 275-289 TI - A diminished sciatic nerve structural integrity is associated with distinct peripheral sensory phenotypes in individuals with type 2 diabetes. JO - Diabetologia VL - 67 IS - 2 PB - Springer PY - 2024 SN - 0012-186X ER - TY - JOUR AB - Unfortunately, the affiliation for Linda A. DiMeglio was incorrect in this paper. The original article has been corrected. AU - Phillip, M.* AU - Achenbach, P. AU - Addala, A.* AU - Albanese-O'Neill, A.* AU - Battelino, T.* AU - Bell, K.J.* AU - Besser, R.E.J.* AU - Bonifacio, E. AU - Colhoun, H.M.* AU - Couper, J.J.* AU - Craig, M.E.* AU - Danne, T.* AU - de Beaufort, C.* AU - Dovc, K.* AU - Driscoll, K.A.* AU - Dutta, S.* AU - Ebekozien, O.* AU - Larsson, H.E.* AU - Feiten, D.J.* AU - Frohnert, B.I.* AU - Gabbay, R.A.* AU - Gallagher, M.P.* AU - Greenbaum, C.J.* AU - Griffin, K.J.* AU - Hagopian, W.* AU - Haller, M.J.* AU - Hendrieckx, C.* AU - Hendriks, E.* AU - Holt, R.I.G.* AU - Hughes, L.* AU - Ismail, H.M.* AU - Jacobsen, L.M.* AU - Johnson, S.B.* AU - Kolb, L.E.* AU - Kordonouri, O.* AU - Lange, K.* AU - Lash, R.W.* AU - Lernmark, Å.* AU - Libman, I.M.* AU - Lundgren, M.* AU - Maahs, D.M.* AU - Marcovecchio, M.L.* AU - Mathieu, C.* AU - Miller, K.M.* AU - O'Donnell, H.K.* AU - Oron, T.* AU - Patil, S.P.* AU - Pop-Busui, R.* AU - Rewers, M.J.* AU - Rich, S.S.* AU - Schatz, D.A.* AU - Schulman-Rosenbaum, R.* AU - Simmons, K.M.* AU - Sims, E.K.* AU - Skyler, J.S.* AU - Smith, L.B.* AU - Speake, C.* AU - Steck, A.K.* AU - Thomas, N.P.B.* AU - Tonyushkina, K.N.* AU - Veijola, R.* AU - Wentworth, J.M.* AU - Wherrett, D.K.* AU - Wood, J.R.* AU - Ziegler, A.-G. AU - Dimeglio, L.A.* C1 - 71619 C2 - 56314 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - 2012–2014 TI - Correction to: Consensus guidance for monitoring individuals with islet autoantibody‑positive pre‑stage 3 type 1 diabetes. JO - Diabetologia VL - 67 PB - Springer PY - 2024 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: As the prevalence of insulin resistance and glucose intolerance is increasing throughout the world, diabetes-induced eye diseases are a global health burden. We aim to identify distinct optical bands which are closely related to insulin and glucose metabolism, using non-invasive, high-resolution spectral domain optical coherence tomography (SD-OCT) in a large, population-based dataset. METHODS: The LIFE-Adult-Study randomly selected 10,000 participants from the population registry of Leipzig, Germany. Cross-sectional, standardised phenotyping included the assessment of various metabolic risk markers and ocular imaging, such as SD-OCT-derived thicknesses of ten optical bands of the retina. Global and Early Treatment Diabetic Retinopathy Study (ETDRS) subfield-specific optical retinal layer thicknesses were investigated in 7384 healthy eyes of 7384 participants from the LIFE-Adult-Study stratified by normal glucose tolerance, prediabetes (impaired fasting glucose and/or impaired glucose tolerance and/or HbA1c 5.7-6.4% [39-47 mmol/mol]) and diabetes. The association of optical retinal band characteristics with different indices of glucose tolerance (e.g. fasting glucose, area under the glucose curve), insulin resistance (e.g. HOMA2-IR, triglyceride glucose index), or insulin sensitivity (e.g. estimated glucose disposal rate [eGDR], Stumvoll metabolic clearance rate) was determined using multivariable linear regression analyses for the individual markers adjusted for age, sex and refraction. Various sensitivity analyses were performed to validate the observed findings. RESULTS: In the study cohort, nine out of ten optical bands of the retina showed significant sex- and glucose tolerance-dependent differences in band thicknesses. Multivariable linear regression analyses revealed a significant, independent, and inverse association between markers of glucose intolerance and insulin resistance (e.g. HOMA2-IR) with the thickness of the optical bands representing the anatomical retinal outer nuclear layer (ONL, standardised β=-0.096; p<0.001 for HOMA2-IR) and myoid zone (MZ; β=-0.096; p<0.001 for HOMA2-IR) of the photoreceptors. Conversely, markers of insulin sensitivity (e.g. eGDR) positively and independently associated with ONL (β=0.090; p<0.001 for eGDR) and MZ (β=0.133; p<0.001 for eGDR) band thicknesses. These global associations were confirmed in ETDRS subfield-specific analyses. Sensitivity analyses further validated our findings when physical activity, neuroanatomical cell/tissue types and ETDRS subfield categories were investigated after stratifying the cohort by glucose homeostasis. CONCLUSIONS/INTERPRETATION: An impaired glucose homeostasis associates with a thinning of the optical bands of retinal ONL and photoreceptor MZ. Changes in ONL and MZ thicknesses might predict early metabolic retinal alterations in diabetes. AU - Rauscher, F.G.* AU - Elze, T.* AU - Francke, M.* AU - Martinez-Perez, M.E.* AU - Li, Y.* AU - Wirkner, K.* AU - Tönjes, A.* AU - Engel, C.* AU - Thiery, J.* AU - Blüher, M. AU - Stumvoll, M.* AU - Kirsten, T.* AU - Loeffler, M.* AU - Ebert, T.* AU - Wang, M.* C1 - 70090 C2 - 55414 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - 928-939 TI - Glucose tolerance and insulin resistance/sensitivity associate with retinal layer characteristics: The LIFE-Adult-Study. JO - Diabetologia VL - 67 IS - 5 PB - Springer PY - 2024 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: Type 2 diabetes is a chronic condition that is caused by hyperglycaemia. Our aim was to characterise the metabolomics to find their association with the glycaemic spectrum and find a causal relationship between metabolites and type 2 diabetes. METHODS: As part of the Innovative Medicines Initiative - Diabetes Research on Patient Stratification (IMI-DIRECT) consortium, 3000 plasma samples were measured with the Biocrates AbsoluteIDQ p150 Kit and Metabolon analytics. A total of 911 metabolites (132 targeted metabolomics, 779 untargeted metabolomics) passed the quality control. Multivariable linear and logistic regression analysis estimates were calculated from the concentration/peak areas of each metabolite as an explanatory variable and the glycaemic status as a dependent variable. This analysis was adjusted for age, sex, BMI, study centre in the basic model, and additionally for alcohol, smoking, BP, fasting HDL-cholesterol and fasting triacylglycerol in the full model. Statistical significance was Bonferroni corrected throughout. Beyond associations, we investigated the mediation effect and causal effects for which causal mediation test and two-sample Mendelian randomisation (2SMR) methods were used, respectively. RESULTS: In the targeted metabolomics, we observed four (15), 34 (99) and 50 (108) metabolites (number of metabolites observed in untargeted metabolomics appear in parentheses) that were significantly different when comparing normal glucose regulation vs impaired glucose regulation/prediabetes, normal glucose regulation vs type 2 diabetes, and impaired glucose regulation vs type 2 diabetes, respectively. Significant metabolites were mainly branched-chain amino acids (BCAAs), with some derivatised BCAAs, lipids, xenobiotics and a few unknowns. Metabolites such as lysophosphatidylcholine a C17:0, sum of hexoses, amino acids from BCAA metabolism (including leucine, isoleucine, valine, N-lactoylvaline, N-lactoylleucine and formiminoglutamate) and lactate, as well as an unknown metabolite (X-24295), were associated with HbA1c progression rate and were significant mediators of type 2 diabetes from baseline to 18 and 48 months of follow-up. 2SMR was used to estimate the causal effect of an exposure on an outcome using summary statistics from UK Biobank genome-wide association studies. We found that type 2 diabetes had a causal effect on the levels of three metabolites (hexose, glutamate and caproate [fatty acid (FA) 6:0]), whereas lipids such as specific phosphatidylcholines (PCs) (namely PC aa C36:2, PC aa C36:5, PC ae C36:3 and PC ae C34:3) as well as the two n-3 fatty acids stearidonate (18:4n3) and docosapentaenoate (22:5n3) potentially had a causal role in the development of type 2 diabetes. CONCLUSIONS/INTERPRETATION: Our findings identify known BCAAs and lipids, along with novel N-lactoyl-amino acid metabolites, significantly associated with prediabetes and diabetes, that mediate the effect of diabetes from baseline to follow-up (18 and 48 months). Causal inference using genetic variants shows the role of lipid metabolism and n-3 fatty acids as being causal for metabolite-to-type 2 diabetes whereas the sum of hexoses is causal for type 2 diabetes-to-metabolite. Identified metabolite markers are useful for stratifying individuals based on their risk progression and should enable targeted interventions. AU - Sharma, S. AU - Dong, Q. AU - Haid, M. AU - Adam, J. AU - Bizzotto, R.* AU - Fernandez-Tajes, J.J.* AU - Jones, A.G.* AU - Tura, A.* AU - Artati, A. AU - Prehn, C. AU - Kastenmüller, G. AU - Koivula, R.W.* AU - Franks, P.W.* AU - Walker, M.* AU - Forgie, I.M.* AU - Giordano, G.N.* AU - Pavo, I.* AU - Ruetten, H.* AU - Dermitzakis, M.* AU - McCarthy, M.I.* AU - Pedersen, O.* AU - Schwenk, J.M.* AU - Tsirigos, K.D.* AU - De Masi, F.* AU - Brunak, S.* AU - Viñuela, A.* AU - Mari, A.* AU - McDonald, T.J.* AU - Kokkola, T.* AU - Adamski, J. AU - Pearson, E.R.* AU - Grallert, H. C1 - 71883 C2 - 56243 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - 2804-2818 TI - Role of human plasma metabolites in prediabetes and type 2 diabetes from the IMI-DIRECT study. JO - Diabetologia VL - 67 PB - Springer PY - 2024 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: Delivery by Caesarean section continues to rise globally and has been associated with the risk of developing type 1 diabetes and the rate of progression from pre-symptomatic stage 1 or 2 type 1 diabetes to symptomatic stage 3 disease. The aim of this study was to examine the association between Caesarean delivery and progression to stage 3 type 1 diabetes in children with pre-symptomatic early-stage type 1 diabetes. METHODS: Caesarean section was examined in 8135 children from the TEDDY study who had an increased genetic risk for type 1 diabetes and were followed from birth for the development of islet autoantibodies and type 1 diabetes. RESULTS: The likelihood of delivery by Caesarean section was higher in children born to mothers with type 1 diabetes (adjusted OR 4.61, 95% CI 3.60, 5.90, p<0.0001), in non-singleton births (adjusted OR 4.35, 95% CI 3.21, 5.88, p<0.0001), in premature births (adjusted OR 1.91, 95% CI 1.53, 2.39, p<0.0001), in children born in the USA (adjusted OR 2.71, 95% CI 2.43, 3.02, p<0.0001) and in children born to older mothers (age group >28-33 years: adjusted OR 1.19, 95% CI 1.04, 1.35, p=0.01; age group >33 years: adjusted OR 1.80, 95% CI 1.58, 2.06, p<0.0001). Caesarean section was not associated with an increased risk of developing pre-symptomatic early-stage type 1 diabetes (risk by age 10 years 5.7% [95% CI 4.6%, 6.7%] for Caesarean delivery vs 6.6% [95% CI 6.0%, 7.3%] for vaginal delivery, p=0.07). Delivery by Caesarean section was associated with a modestly increased rate of progression to stage 3 type 1 diabetes in children who had developed multiple islet autoantibody-positive pre-symptomatic early-stage type 1 diabetes (adjusted HR 1.36, 95% CI 1.03, 1.79, p=0.02). No interaction was observed between Caesarean section and non-HLA SNPs conferring susceptibility for type 1 diabetes. CONCLUSIONS/INTERPRETATION: Caesarean section increased the rate of progression to stage 3 type 1 diabetes in children with pre-symptomatic early-stage type 1 diabetes. DATA AVAILABILITY: Data from the TEDDY study ( https://doi.org/10.58020/y3jk-x087 ) reported here will be made available for request at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Central Repository (NIDDK-CR) Resources for Research (R4R) ( https://repository.niddk.nih.gov/ ). AU - Singh, T. AU - Weiss, A. AU - Vehik, K.* AU - Krischer, J.* AU - Rewers, M.* AU - Toppari, J.* AU - Lernmark, Å.* AU - Hagopian, W.* AU - Akolkar, B.* AU - Bonifacio, E. AU - Ziegler, A.-G. AU - Winkler, C. C1 - 70783 C2 - 55891 CY - One New York Plaza, Suite 4600, New York, Ny, United States TI - Caesarean section and risk of type 1 diabetes. JO - Diabetologia PB - Springer PY - 2024 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: Rodent pancreas development has been described in great detail. On the other hand, there are still gaps in our understanding of the developmental trajectories of pancreatic cells during human ontogenesis. Here, our aim was to map the spatial and chronological dynamics of human pancreatic cell differentiation and proliferation by using 3D imaging of cleared human embryonic and fetal pancreases. METHODS: We combined tissue clearing with light-sheet fluorescence imaging in human embryonic and fetal pancreases during the first trimester of pregnancy. In addition, we validated an explant culture system enabling in vitro proliferation of pancreatic progenitors to determine the mitogenic effect of candidate molecules. RESULTS: We detected the first insulin-positive cells as early as five post-conceptional weeks, two weeks earlier than previously observed. We observed few insulin-positive clusters at five post-conceptional weeks (mean ± SD 9.25±5.65) with a sharp increase to 11 post-conceptional weeks (4307±152.34). We identified a central niche as the location of onset of the earliest insulin cell production and detected extra-pancreatic loci within the adjacent developing gut. Conversely, proliferating pancreatic progenitors were located in the periphery of the epithelium, suggesting the existence of two separated pancreatic niches for differentiation and proliferation. Additionally, we observed that the proliferation ratio of progenitors ranged between 20% and 30%, while for insulin-positive cells it was 1%. We next unveiled a mitogenic effect of the platelet-derived growth factor AA isoform (PDGFAA) in progenitors acting through the pancreatic mesenchyme by increasing threefold the number of proliferating progenitors. CONCLUSIONS/INTERPRETATION: This work presents a first 3D atlas of the human developing pancreas, charting both endocrine and proliferating cells across early development. AU - Villalba, A.* AU - Gitton, Y.* AU - Inoue, M.* AU - Aiello, V.* AU - Blain, R.* AU - Toupin, M.* AU - Mazaud-Guittot, S.* AU - Rachdi, L.* AU - Semb, H. AU - Chedotal, A.* AU - Scharfmann, R.* C1 - 70541 C2 - 55655 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - 1066-1078 TI - A 3D atlas of the human developing pancreas to explore progenitor proliferation and differentiation. JO - Diabetologia VL - 67 IS - 6 PB - Springer PY - 2024 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: Insulitis is not present in all islets, and it is elusive in humans. Although earlier studies focused on islets that fulfilled certain criteria (e.g. ≥15 CD45+ cells or ≥6 CD3+ cells), there is a fundamental lack of understanding of the infiltration dynamics in terms of its magnitude (i.e. how much) and extent (i.e. where). Here, we aimed to perform an in-depth characterisation of T cell infiltration by investigating islets with moderate (1-5 CD3+ cells) and high (≥6 CD3+ cells) infiltration in individuals with and without type 1 diabetes. METHODS: Pancreatic tissue sections from 15 non-diabetic, eight double autoantibody-positive and ten type 1 diabetic (0-2 years of disease duration) organ donors were obtained from the Network for Pancreatic Organ Donors with Diabetes, and stained for insulin, glucagon, CD3 and CD8 by immunofluorescence. T cell infiltration was quantified in a total of 8661 islets using the software QuPath. The percentage of infiltrated islets and islet T cell density were calculated. To help standardise the analysis of T cell infiltration, we used cell density data to develop a new T cell density threshold capable of differentiating non-diabetic and type 1 diabetic donors. RESULTS: Our analysis revealed that 17.1% of islets in non-diabetic donors, 33% of islets in autoantibody-positive and 32.5% of islets in type 1 diabetic donors were infiltrated by 1 to 5 CD3+ cells. Islets infiltrated by ≥6 CD3+ cells were rare in non-diabetic donors (0.4%) but could be found in autoantibody-positive (4.5%) and type 1 diabetic donors (8.2%). CD8+ and CD8- populations followed similar patterns. Likewise, T cell density was significantly higher in the islets of autoantibody-positive donors (55.4 CD3+ cells/mm2) and type 1 diabetic donors (74.8 CD3+ cells/mm2) compared with non-diabetic individuals (17.3 CD3+ cells/mm2), which was accompanied by higher exocrine T cell density in type 1 diabetic individuals. Furthermore, we showed that the analysis of a minimum of 30 islets and the use of a reference mean value for T cell density of 30 CD3+ cells/mm2 (the 30-30 rule) can differentiate between non-diabetic and type 1 diabetic donors with high specificity and sensitivity. In addition, it can classify autoantibody-positive individuals as non-diabetic or type 1 diabetic-like. CONCLUSIONS/INTERPRETATION: Our data indicates that the proportion of infiltrated islets and T cell density change dramatically during the course of type 1 diabetes, and these changes can be already observed in double autoantibody-positive individuals. This suggests that, as disease progresses, T cell infiltration extends throughout the pancreas, reaching the islets and exocrine compartment. While it predominantly targets insulin-containing islets, large accumulations of cells are rare. Our study fulfils the need to further understand T cell infiltration, not only after diagnosis but also in individuals with diabetes-related autoantibodies. Furthermore, the development and application of new analytical tools based on T cell infiltration, like the 30-30 rule, will allow us to correlate islet infiltration with demographic and clinical variables with the aim of identifying individuals at the very early stages of the disease. AU - Apaolaza Gallegos, S.P. AU - Balcacean, D. AU - Zapardiel-Gonzalo, J. AU - Rodriguez-Calvo, T. C1 - 67751 C2 - 54061 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - 1129-1141 TI - The extent and magnitude of islet T cell infiltration as powerful tools to define the progression to type 1 diabetes. JO - Diabetologia VL - 66 IS - 6 PB - Springer PY - 2023 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: The aim of this study was to assess the dose-response effects of the subcutaneous glucagon receptor/glucagon-like peptide-1 receptor dual agonist survodutide (BI 456906) on HbA1c levels and bodyweight reduction. METHODS: This Phase II, multicentre, randomised, double-blind, parallel-group, placebo-controlled study, conducted in clinical research centres, assessed survodutide in participants aged 18-75 years with type 2 diabetes, an HbA1c level of 53-86 mmol/mol (7.0-10.0%) and a BMI of 25-50 kg/m2 on a background of metformin therapy. Participants were randomised via interactive response technology to receive survodutide (up to 0.3, 0.9, 1.8 or 2.7 mg once weekly [qw; dose group (DG) 1-4, respectively] or 1.2 or 1.8 mg twice weekly [DG 5 and 6, respectively]), placebo or semaglutide (up to 1.0 mg qw). Participants and all those involved in the trial conduct/analysis were blinded; the semaglutide arm was open-label. The primary endpoint was absolute change from baseline in HbA1c after 16 weeks' treatment. The key secondary endpoint was relative change from baseline in bodyweight after 16 weeks' treatment. RESULTS: A total of 413 participants were randomised (DG1, n=50; DG2, n=50; DG3, n=52; DG4, n=50; DG5, n=51; DG6, n=50; semaglutide, n=50; placebo, n=60). The full analysis set comprised 411 treated participants (DG6, n=49; placebo, n=59). Adjusted mean (95% CI) HbA1c decreased from baseline (mean ± SD 64.7±9.2 mmol/mol [8.07±0.84%] after 16 weeks' treatment: DG1 (n=41), -9.92 mmol/mol (-12.27, -7.56; -0.91% [-1.12, -0.69]); DG2 (n=46), -15.95 mmol/mol (-18.27, -13.63; -1.46% [-1.67, -1.25]); DG3 (n=36), -18.72 mmol/mol (-21.15, -16.29; -1.71% [-1.94, -1.49]); DG4 (n=33), -17.01 mmol/mol (-19.59, -14.43; -1.56% [-1.79, -1.32]); DG5 (n=44), -17.84 mmol/mol (-20.18, -15.51; -1.63% [-1.85, -1.42]); DG6 (n=36), -18.38 mmol/mol (-20.90, -15.87; -1.68% [-1.91, -1.45]). The mean reduction in HbA1c was similar with low-dose survodutide (DG2: -15.95 mmol/mol [-1.46%]; n=46) and semaglutide (-16.07 mmol/mol [-1.47%]; n=45). Mean (95% CI) bodyweight decreased dose-dependently up to -8.7% (-10.1, -7.3; DG6, n=37); survodutide ≥1.8 mg qw produced greater bodyweight reductions than semaglutide (-5.3% [-6.6, -4.1]; n=45). Adverse events (AEs) were reported for 77.8% of survodutide-treated participants (mainly gastrointestinal), 52.5% receiving placebo and 52.0% receiving semaglutide. CONCLUSIONS/INTERPRETATION: Survodutide reduced HbA1c levels and bodyweight after 16 weeks' treatment in participants with type 2 diabetes. Dose-related gastrointestinal AEs could be mitigated with slower dose escalations. TRIAL REGISTRATION: ClinicalTrials.gov NCT04153929 and EudraCT 2019-002390-60. FUNDING: Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany. AU - Blüher, M. AU - Rosenstock, J.* AU - Hoefler, J.* AU - Manuel, R.* AU - Hennige, A.M.* C1 - 68973 C2 - 53791 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - 13 TI - Dose-response effects on HbA1c and bodyweight reduction of survodutide, a dual glucagon/GLP-1 receptor agonist, compared with placebo and open-label semaglutide in people with type 2 diabetes: A randomised clinical trial. JO - Diabetologia PB - Springer PY - 2023 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: Glucagon receptor (GCGR) antagonism ameliorates hyperglycaemia and promotes beta cell regeneration in mouse models of type 2 diabetes. However, the underlying mechanisms remain unclear. The present study aimed to investigate the mechanism of beta cell regeneration induced by GCGR antagonism in mice. METHODS: The db/db mice and high-fat diet (HFD)+streptozotocin (STZ)-induced mice with type 2 diabetes were treated with antagonistic GCGR monoclonal antibody (mAb), and the metabolic variables and islet cell quantification were evaluated. Plasma cytokine array and liver RNA sequencing data were used to screen possible mediators, including fibroblast growth factor 21 (FGF21). ELISA, quantitative RT-PCR and western blot were applied to verify FGF21 change. Blockage of FGF21 signalling by FGF21-neutralising antibody (nAb) was used to clarify whether FGF21 was involved in the effects of GCGR mAb on the expression of beta cell identity-related genes under plasma-conditional culture and hepatocyte co-culture conditions. FGF21 nAb-treated db/db mice, systemic Fgf21-knockout (Fgf21-/-) diabetic mice and hepatocyte-specific Fgf21-knockout (Fgf21Hep-/-) diabetic mice were used to reveal the involvement of FGF21 in beta cell regeneration. A BrdU tracing study was used to analyse beta cell proliferation in diabetic mice treated with GCGR mAb. RESULTS: GCGR mAb treatment improved blood glucose control, and increased islet number (db/db 1.6±0.1 vs 0.8±0.1 per mm2, p<0.001; HFD+STZ 1.2±0.1 vs 0.5±0.1 per mm2, p<0.01) and area (db/db 2.5±0.2 vs 1.2±0.2%, p<0.001; HFD+STZ 1.0±0.1 vs 0.3±0.1%, p<0.01) in diabetic mice. The plasma cytokine array and liver RNA sequencing data showed that FGF21 levels in plasma and liver were upregulated by GCGR antagonism. The GCGR mAb induced upregulation of plasma FGF21 levels (db/db 661.5±40.0 vs 466.2±55.7 pg/ml, p<0.05; HFD+STZ 877.0±106.8 vs 445.5±54.0 pg/ml, p<0.05) and the liver levels of Fgf21 mRNA (db/db 3.2±0.5 vs 1.8±0.1, p<0.05; HFD+STZ 2.0±0.3 vs 1.0±0.2, p<0.05) and protein (db/db 2.0±0.2 vs 1.4±0.1, p<0.05; HFD+STZ 1.6±0.1 vs 1.0±0.1, p<0.01). Exposure to plasma or hepatocytes from the GCGR mAb-treated mice upregulated the mRNA levels of characteristic genes associated with beta cell identity in cultured mouse islets and a beta cell line, and blockage of FGF21 activity by an FGF21 nAb diminished this upregulation. Notably, the effects of increased beta cell number induced by GCGR mAb were attenuated in FGF21 nAb-treated db/db mice, Fgf21-/- diabetic mice and Fgf21Hep-/- diabetic mice. Moreover, GCGR mAb treatment enhanced beta cell proliferation in the two groups of diabetic mice, and this effect was weakened in Fgf21-/- and Fgf21Hep-/- mice. CONCLUSIONS/INTERPRETATION: Our findings demonstrate that liver-derived FGF21 is involved in the GCGR antagonism-induced beta cell regeneration in a mouse model of type 2 diabetes. AU - Cui, X.* AU - Feng, J. AU - Wei, T.* AU - Zhang, L.* AU - Lang, S.* AU - Yang, K.Q.* AU - Yang, J.* AU - Liu, J.* AU - Sterr, M. AU - Lickert, H. AU - Wei, R.* AU - Hong, T.* C1 - 66611 C2 - 53244 SP - 535-550 TI - Pancreatic alpha cell glucagon-liver FGF21 axis regulates beta cell regeneration in a mouse model of type 2 diabetes. JO - Diabetologia VL - 66 IS - 3 PY - 2023 SN - 0012-186X ER - TY - JOUR AB - Aims/hypothesis: The aim of this study was to estimate the long-term health and economic consequences of improved risk factor control in German adults with type 2 diabetes. Methods: We used the UK Prospective Diabetes Study Outcomes Model 2 to project the patient-level health outcomes and healthcare costs of people with type 2 diabetes in Germany over 5, 10 and 30 years. We parameterised the model using the best available data on population characteristics, healthcare costs and health-related quality of life from German studies. The modelled scenarios were: (1) a permanent reduction of HbA1c by 5.5 mmol/mol (0.5%), of systolic BP (SBP) by 10 mmHg, or of LDL-cholesterol by 0.26 mmol/l in all patients, and (2) achievement of guideline care recommendations for HbA1c (≤53 mmol/mol [7%]), SBP (≤140 mmHg) or LDL-cholesterol (≤2.6 mmol/l) in patients who do not meet the recommendations. We calculated nationwide estimates using age- and sex-specific quality-adjusted life year (QALY) and cost estimates, type 2 diabetes prevalence and population size. Results: Over 10 years, a permanent reduction of HbA1c by 5.5 mmol/mol (0.5%), SBP by 10 mmHg or LDL-cholesterol by 0.26 mmol/l led to per-person savings in healthcare expenditures of €121, €238 and €34, and 0.01, 0.02 and 0.015 QALYs gained, respectively. Achieving guideline care recommendations for HbA1c, SBP or LDL-cholesterol could reduce healthcare expenditure by €451, €507 and €327 and gained 0.03, 0.05 and 0.06 additional QALYs in individuals who did not meet the recommendations. Nationally, achieving guideline care recommendations for HbA1c, SBP and LDL-cholesterol could reduce healthcare costs by over €1.9 billion. Conclusions/interpretation: Sustained improvements in HbA1c, SBP and LDL-cholesterol control among diabetes patients in Germany can lead to substantial health benefits and reduce healthcare expenditures. Graphical Abstract: [Figure not available: see fulltext.]. AU - Fan, M. AU - Stephan, A.-J. AU - Emmert-Fees, K. AU - Peters, A. AU - Laxy, M. C1 - 68453 C2 - 54640 SP - 1693-1704 TI - Health and economic impact of improved glucose, blood pressure and lipid control among German adults with type 2 diabetes: A modelling study. JO - Diabetologia VL - 66 IS - 9 PY - 2023 SN - 0012-186X ER - TY - JOUR AU - Hummel, S. AU - Friedl, N. AU - Winkler, C. AU - Ziegler, A.-G. AU - Achenbach, P. C1 - 68262 C2 - 54784 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - 2389-2390 TI - Presymptomatic type 1 diabetes and disease severity at onset. Reply to Schneider J, Gemulla G, Kiess W et al [letter]. JO - Diabetologia VL - 66 IS - 12 PB - Springer PY - 2023 SN - 0012-186X ER - TY - JOUR AB - Aims/hypothesis: We aimed to determine whether disease severity was reduced at onset of clinical (stage 3) type 1 diabetes in children previously diagnosed with presymptomatic type 1 diabetes in a population-based screening programme for islet autoantibodies. Methods: Clinical data obtained at diagnosis of stage 3 type 1 diabetes were evaluated in 128 children previously diagnosed with presymptomatic early-stage type 1 diabetes between 2015 and 2022 in the Fr1da study and compared with data from 736 children diagnosed with incident type 1 diabetes between 2009 and 2018 at a similar age in the DiMelli study without prior screening. Results: At the diagnosis of stage 3 type 1 diabetes, children with a prior early-stage diagnosis had lower median HbA1c (51 mmol/mol vs 91 mmol/mol [6.8% vs 10.5%], p<0.001), lower median fasting glucose (5.3 mmol/l vs 7.2 mmol/l, p<0.05) and higher median fasting C-peptide (0.21 nmol/l vs 0.10 nmol/l, p<0.001) compared with children without previous early-stage diagnosis. Fewer participants with prior early-stage diagnosis had ketonuria (22.2% vs 78.4%, p<0.001) or required insulin treatment (72.3% vs 98.1%, p<0.05) and only 2.5% presented with diabetic ketoacidosis at diagnosis of stage 3 type 1 diabetes. Outcomes in children with a prior early-stage diagnosis were not associated with a family history of type 1 diabetes or diagnosis during the COVID-19 pandemic. A milder clinical presentation was observed in children who participated in education and monitoring after early-stage diagnosis. Conclusions/interpretation: Diagnosis of presymptomatic type 1 diabetes in children followed by education and monitoring improved clinical presentation at the onset of stage 3 type 1 diabetes. Graphical Abstract: [Figure not available: see fulltext.]. AU - Hummel, S. AU - Carl, J. AU - Friedl, N. AU - Winkler, C. AU - Kick, K.* AU - Stock, J. AU - Reinmüller, F.* AU - Ramminger, C. AU - Schmidt, J.* AU - Lwowsky, D.* AU - Braig, S.* AU - Dunstheimer, D.* AU - Ermer, U.* AU - Gerstl, E.M.* AU - Weber, L.* AU - Nellen-Hellmuth, N.* AU - Brämswig, S.* AU - Sindichakis, M.* AU - Tretter, S.* AU - Lorrmann, A.* AU - Bonifacio, E. AU - Ziegler, A.-G. AU - Achenbach, P. C1 - 68519 C2 - 54680 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - 1633-1642 TI - Children diagnosed with presymptomatic type 1 diabetes through public health screening have milder diabetes at clinical manifestation. JO - Diabetologia VL - 66 IS - 9 PB - Springer PY - 2023 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: Characterisation of genetic variation that influences the response to glucose-lowering medications is instrumental to precision medicine for treatment of type 2 diabetes. The Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH) examined the acute response to metformin and glipizide in order to identify new pharmacogenetic associations for the response to common glucose-lowering medications in individuals at risk of type 2 diabetes. METHODS: One thousand participants at risk for type 2 diabetes from diverse ancestries underwent sequential glipizide and metformin challenges. A genome-wide association study was performed using the Illumina Multi-Ethnic Genotyping Array. Imputation was performed with the TOPMed reference panel. Multiple linear regression using an additive model tested for association between genetic variants and primary endpoints of drug response. In a more focused analysis, we evaluated the influence of 804 unique type 2 diabetes- and glycaemic trait-associated variants on SUGAR-MGH outcomes and performed colocalisation analyses to identify shared genetic signals. RESULTS: Five genome-wide significant variants were associated with metformin or glipizide response. The strongest association was between an African ancestry-specific variant (minor allele frequency [MAFAfr]=0.0283) at rs149403252 and lower fasting glucose at Visit 2 following metformin (p=1.9×10-9); carriers were found to have a 0.94 mmol/l larger decrease in fasting glucose. rs111770298, another African ancestry-specific variant (MAFAfr=0.0536), was associated with a reduced response to metformin (p=2.4×10-8), where carriers had a 0.29 mmol/l increase in fasting glucose compared with non-carriers, who experienced a 0.15 mmol/l decrease. This finding was validated in the Diabetes Prevention Program, where rs111770298 was associated with a worse glycaemic response to metformin: heterozygous carriers had an increase in HbA1c of 0.08% and non-carriers had an HbA1c increase of 0.01% after 1 year of treatment (p=3.3×10-3). We also identified associations between type 2 diabetes-associated variants and glycaemic response, including the type 2 diabetes-protective C allele of rs703972 near ZMIZ1 and increased levels of active glucagon-like peptide 1 (GLP-1) (p=1.6×10-5), supporting the role of alterations in incretin levels in type 2 diabetes pathophysiology. CONCLUSIONS/INTERPRETATION: We present a well-phenotyped, densely genotyped, multi-ancestry resource to study gene-drug interactions, uncover novel variation associated with response to common glucose-lowering medications and provide insight into mechanisms of action of type 2 diabetes-related variation. DATA AVAILABILITY: The complete summary statistics from this study are available at the Common Metabolic Diseases Knowledge Portal ( https://hugeamp.org ) and the GWAS Catalog ( www.ebi.ac.uk/gwas/ , accession IDs: GCST90269867 to GCST90269899). AU - Li, J.H.* AU - Brenner, L.N.* AU - Kaur, V.* AU - Figueroa, K.* AU - Schroeder, P.* AU - Huerta-Chagoya, A.* AU - Udler, M.S.* AU - Leong, A.* AU - MAGIC Investigators (Grallert, H. AU - Zeggini, E. AU - Peters, A. AU - Schwarz, P.E.) C1 - 70143 C2 - 55023 SP - 1260-1272 TI - Genome-wide association analysis identifies ancestry-specific genetic variation associated with acute response to metformin and glipizide in SUGAR-MGH. JO - Diabetologia VL - 66 IS - 7 PY - 2023 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: After birth, the neonatal islets gradually acquire glucose-responsive insulin secretion, a process that is subjected to maternal imprinting. Although NEFA are major components of breastmilk and insulin secretagogues, their role for functional maturation of neonatal beta cells is still unclear. NEFA are the endogenous ligands of fatty acid receptor 1 (FFA1, encoded by Ffar1 in mice), a Gq-coupled receptor with stimulatory effect on insulin secretion. This study investigates the role of FFA1 in neonatal beta cell function and in the adaptation of offspring beta cells to parental high-fat feeding. METHODS: Wild-type (WT) and Ffar1-/- mice were fed high-fat (HFD) or chow diet (CD) for 8 weeks before mating, and during gestation and lactation. Blood variables, pancreas weight and insulin content were assessed in 1-, 6-, 11- and 26-day old (P1-P26) offspring. Beta cell mass and proliferation were determined in P1-P26 pancreatic tissue sections. FFA1/Gq dependence of insulin secretion was evaluated in isolated islets and INS-1E cells using pharmacological inhibitors and siRNA strategy. Transcriptome analysis was conducted in isolated islets. RESULTS: Blood glucose levels were higher in CD-fed Ffar1-/- P6-offspring compared with CD-fed WT P6-offspring. Accordingly, glucose-stimulated insulin secretion (GSIS) and its potentiation by palmitate were impaired in CD Ffar1-/- P6-islets. In CD WT P6-islets, insulin secretion was stimulated four- to fivefold by glucose and five- and sixfold over GSIS by palmitate and exendin-4, respectively. Although parental HFD increased blood glucose in WT P6-offspring, it did not change insulin secretion from WT P6-islets. In contrast, parental HFD abolished glucose responsiveness (i.e. GSIS) in Ffar1-/- P6-islets. Inhibition of Gq by FR900359 or YM-254890 in WT P6-islets mimicked the effect of Ffar1 deletion, i.e. suppression of GSIS and of palmitate-augmented GSIS. The blockage of Gi/o by pertussis toxin (PTX) enhanced (100-fold) GSIS in WT P6-islets and rendered Ffar1-/- P6-islets glucose responsive, suggesting constitutive activation of Gi/o. In WT P6-islets, FR900359 cancelled 90% of PTX-mediated stimulation, while in Ffar1-/- P6-islets it completely abolished PTX-elevated GSIS. The secretory defect of Ffar1-/- P6-islets did not originate from insufficient beta cells, since beta cell mass increased with the offspring's age irrespective of genotype and diet. In spite of that, in the breastfed offspring (i.e. P1-P11) beta cell proliferation and pancreatic insulin content had a genotype- and diet-driven dynamic. Under CD, the highest proliferation rate was reached by the Ffar1-/- P6 offspring (3.95% vs 1.88% in WT P6), whose islets also showed increased mRNA levels of genes (e.g. Fos, Egr1, Jun) typically high in immature beta cells. Although parental HFD increased beta cell proliferation in both WT (4.48%) and Ffar1-/- (5.19%) P11 offspring, only the WT offspring significantly increased their pancreatic insulin content upon parental HFD (5.18 µg under CD to 16.93 µg under HFD). CONCLUSIONS/INTERPRETATION: FFA1 promotes glucose-responsive insulin secretion and functional maturation of newborn islets and is required for adaptive offspring insulin secretion in the face of metabolic challenge, such as parental HFD. AU - Lorza-Gil, E. AU - Kaiser, G. AU - Carlein, C.* AU - Hoffmann, M.D.A.* AU - König, G.M.* AU - Haug, S.* AU - Prates Roma, L.* AU - Rexen Ulven, E.* AU - Ulven, T.* AU - Kostenis, E.* AU - Birkenfeld, A.L. AU - Häring, H.U.* AU - Ullrich, S. AU - Gerst, F. C1 - 67907 C2 - 54385 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - 1501-1515 TI - Glucose-stimulated insulin secretion depends on FFA1 and Gq in neonatal mouse islets. JO - Diabetologia VL - 66 IS - 8 PB - Springer PY - 2023 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: This study aimed to elucidate the aetiological role of plasma proteins in glucose metabolism and type 2 diabetes development. METHODS: We measured 233 proteins at baseline in 1653 participants from the Cooperative Health Research in the Region of Augsburg (KORA) S4 cohort study (median follow-up time: 13.5 years). We used logistic regression in the cross-sectional analysis (n=1300), and Cox regression accounting for interval-censored data in the longitudinal analysis (n=1143). We further applied two-level growth models to investigate associations with repeatedly measured traits (fasting glucose, 2 h glucose, fasting insulin, HOMA-B, HOMA-IR, HbA1c), and two-sample Mendelian randomisation analysis to investigate causal associations. Moreover, we built prediction models using priority-Lasso on top of Framingham-Offspring Risk Score components and evaluated the prediction accuracy through AUC. RESULTS: We identified 14, 24 and four proteins associated with prevalent prediabetes (i.e. impaired glucose tolerance and/or impaired fasting glucose), prevalent newly diagnosed type 2 diabetes and incident type 2 diabetes, respectively (28 overlapping proteins). Of these, IL-17D, IL-18 receptor 1, carbonic anhydrase-5A, IL-1 receptor type 2 (IL-1RT2) and matrix extracellular phosphoglycoprotein were novel candidates. IGF binding protein 2 (IGFBP2), lipoprotein lipase (LPL) and paraoxonase 3 (PON3) were inversely associated while fibroblast growth factor 21 was positively associated with incident type 2 diabetes. LPL was longitudinally linked with change in glucose-related traits, while IGFBP2 and PON3 were linked with changes in both insulin- and glucose-related traits. Mendelian randomisation analysis suggested causal effects of LPL on type 2 diabetes and fasting insulin. The simultaneous addition of 12 priority-Lasso-selected biomarkers (IGFBP2, IL-18, IL-17D, complement component C1q receptor, V-set and immunoglobulin domain-containing protein 2, IL-1RT2, LPL, CUB domain-containing protein 1, vascular endothelial growth factor D, PON3, C-C motif chemokine 4 and tartrate-resistant acid phosphatase type 5) significantly improved the predictive performance (ΔAUC 0.0219; 95% CI 0.0052, 0.0624). CONCLUSIONS/INTERPRETATION: We identified new candidates involved in the development of derangements in glucose metabolism and type 2 diabetes and confirmed previously reported proteins. Our findings underscore the importance of proteins in the pathogenesis of type 2 diabetes and the identified putative proteins can function as potential pharmacological targets for diabetes treatment and prevention. AU - Luo, H. AU - Bauer, A. AU - Nano, J. AU - Petrera, A. AU - Rathmann, W.* AU - Herder, C.* AU - Hauck, S.M. AU - Sun, B.B.* AU - Hoyer, A.* AU - Peters, A. AU - Thorand, B. C1 - 67826 C2 - 54304 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - 1655-1668 TI - Associations of plasma proteomics with type 2 diabetes and related traits: Results from the longitudinal KORA S4/F4/FF4 Study. JO - Diabetologia VL - 66 IS - 9 PB - Springer PY - 2023 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: Although insulin resistance often leads to type 2 diabetes mellitus, its early stages are often unrecognised, thus reducing the probability of successful prevention and intervention. Moreover, treatment efficacy is affected by the genetics of the individual. We used gene expression profiles from a cross-sectional study to identify potential candidate genes for the prediction of diabetes risk and intervention response. METHODS: Using a multivariate regression model, we linked gene expression profiles of human skeletal muscle and intermuscular adipose tissue (IMAT) to fasting glucose levels and glucose infusion rate. Based on the expression patterns of the top predictive genes, we characterised and compared individual gene expression with clinical classifications using k-nearest neighbour clustering. The predictive potential of the candidate genes identified was validated using muscle gene expression data from a longitudinal intervention study. RESULTS: We found that genes with a strong association with clinical measures clustered into three distinct expression patterns. Their predictive values for insulin resistance varied substantially between skeletal muscle and IMAT. Moreover, we discovered that individual gene expression-based classifications may differ from classifications based predominantly on clinical variables, indicating that participant stratification may be imprecise if only clinical variables are used for classification. Of the 15 top candidate genes, ST3GAL2, AASS, ARF1 and the transcription factor SIN3A are novel candidates for predicting a refined diabetes risk and intervention response. CONCLUSION/INTERPRETATION: Our results confirm that disease progression and successful intervention depend on individual gene expression states. We anticipate that our findings may lead to a better understanding and prediction of individual diabetes risk and may help to develop individualised intervention strategies. AU - Lutter, D. AU - Sachs, S. AU - Walter, M.C. AU - Kerege, A.* AU - Perreault, L.* AU - Kahn, D.E.* AU - Wolide, A.D. AU - Kleinert, M. AU - Bergman, B.C.* AU - Hofmann, S.M. C1 - 67470 C2 - 54125 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - 873-883 TI - Skeletal muscle and intermuscular adipose tissue gene expression profiling identifies new biomarkers with prognostic significance for insulin resistance progression and intervention response. JO - Diabetologia VL - 66 IS - 5 PB - Springer PY - 2023 SN - 0012-186X ER - TY - JOUR AB - Aims/hypothesis: The Islet Autoantibody Standardization Program (IASP) aims to improve the performance of immunoassays measuring autoantibodies in type 1 diabetes and the concordance of results across laboratories. IASP organises international workshops distributing anonymised serum samples to participating laboratories and centralises the collection and analysis of results. In this report, we describe the results of assays measuring IAA submitted to the IASP 2018 and 2020 workshops. Methods: The IASP distributed uniquely coded sera from individuals with new-onset type 1 diabetes, multiple islet autoantibody-positive individuals, and diabetes-free blood donors in both 2018 and 2020. Serial dilutions of the anti-insulin mouse monoclonal antibody HUI-018 were also included. Sensitivity, specificity, area under the receiver operating characteristic curve (ROC-AUC), partial ROC-AUC at 95% specificity (pAUC95) and concordance of qualitative/quantitative results were compared across assays. Results: Results from 45 IAA assays of seven different formats and from 37 IAA assays of six different formats were submitted to the IASP in 2018 and 2020, respectively. The median ROC-AUC was 0.736 (IQR 0.617–0.803) and 0.790 (IQR 0.730–0.836), while the median pAUC95 was 0.016 (IQR 0.004–0.021) and 0.023 (IQR 0.014–0.026) in the 2018 and 2020 workshops, respectively. Assays largely differed in AUC (IASP 2018 range 0.232–0.874; IASP 2020 range 0.379–0.924) and pAUC95 (IASP 2018 and IASP 2020 range 0–0.032). Conclusions/interpretation: Assay formats submitted to this study showed heterogeneous performance. Despite the high variability across laboratories, the in-house radiobinding assay (RBA) remains the gold standard for IAA measurement. However, novel non-radioactive IAA immunoassays showed a good performance and, if further improved, might be considered valid alternatives to RBAs. Graphical abstract: [Figure not available: see fulltext.] AU - Marzinotto, I.* AU - Pittman, D.L.* AU - Williams, A.J.K.* AU - Long, A.E.* AU - Achenbach, P. AU - Schlosser, M.* AU - Akolkar, B.* AU - Winter, W.E.* AU - Lampasona, V.* C1 - 67428 C2 - 54146 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - 897-912 TI - Islet Autoantibody Standardization Program: Interlaboratory comparison of insulin autoantibody assay performance in 2018 and 2020 workshops. JO - Diabetologia VL - 66 IS - 5 PB - Springer PY - 2023 SN - 0012-186X ER - TY - JOUR AB - Incretin hormones (glucose-dependent insulinotropic polypeptide [GIP] and glucagon-like peptide-1 [GLP-1]) play a role in the pathophysiology of type 2 diabetes. Along with their derivatives they have shown therapeutic success in type 2 diabetes, with the potential for further improvements in glycaemic, cardiorenal and body weight-related outcomes. In type 2 diabetes, the incretin effect (greater insulin secretory response after oral glucose than with 'isoglycaemic' i.v. glucose, i.e. with an identical glycaemic stimulus) is markedly reduced or absent. This appears to be because of a reduced ability of GIP to stimulate insulin secretion, related either to an overall impairment of beta cell function or to specific defects in the GIP signalling pathway. It is likely that a reduced incretin effect impacts on postprandial glycaemic excursions and, thus, may play a role in the deterioration of glycaemic control. In contrast, the insulinotropic potency of GLP-1 appears to be much less impaired, such that exogenous GLP-1 can stimulate insulin secretion, suppress glucagon secretion and reduce plasma glucose concentrations in the fasting and postprandial states. This has led to the development of incretin-based glucose-lowering medications (selective GLP-1 receptor agonists or, more recently, co-agonists, e.g. that stimulate GIP and GLP-1 receptors). Tirzepatide (a GIP/GLP-1 receptor co-agonist), for example, reduces HbA1c and body weight in individuals with type 2 diabetes more effectively than selective GLP-1 receptor agonists (e.g. semaglutide). The mechanisms by which GIP receptor agonism may contribute to better glycaemic control and weight loss after long-term exposure to tirzepatide are a matter of active research and may change the pessimistic view that developed after the disappointing lack of insulinotropic activity in people with type 2 diabetes when exposed to GIP in short-term experiments. Future medications that stimulate incretin hormone and other receptors simultaneously may have the potential to further increase the ability to control plasma glucose concentrations and induce weight loss. AU - Nauck, M.A.* AU - Müller, T.D. C1 - 68123 C2 - 54601 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - 1780-1795 TI - Incretin hormones and type 2 diabetes. JO - Diabetologia VL - 66 IS - 10 PB - Springer PY - 2023 SN - 0012-186X ER - TY - JOUR AB - Glucagon-like peptide-1 (GLP-1) receptor agonists are established pharmaceutical therapies for the treatment of type 2 diabetes and obesity. They mimic the action of GLP-1 to reduce glucose levels through stimulation of insulin secretion and inhibition of glucagon secretion. They also reduce body weight by inducing satiety through central actions. The GLP-1 receptor agonists used clinically are based on exendin-4 and native GLP-1 and are available as formulations for daily or weekly s.c. or oral administration. GLP-1 receptor agonism is also achieved by inhibitors of dipeptidyl peptidase-4 (DPP-4), which prevent the inactivation of GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), thereby prolonging their raised levels after meal ingestion. Other developments in GLP-1 receptor agonism include the formation of small orally available agonists and compounds with the potential to pharmaceutically stimulate GLP-1 secretion from the gut. In addition, GLP-1/glucagon and GLP-1/GIP dual receptor agonists and GLP-1/GIP/glucagon triple receptor agonists have shown the potential to reduce blood glucose levels and body weight through their effects on islets and peripheral tissues, improving beta cell function and stimulating energy expenditure. This review summarises developments in gut hormone-based therapies and presents the future outlook for their use in type 2 diabetes and obesity. AU - Tschöp, M.H. AU - Nogueiras, R.* AU - Ahrén, B.* C1 - 67825 C2 - 54303 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - 1796-1808 TI - Gut hormone-based pharmacology: Novel formulations and future possibilities for metabolic disease therapy. JO - Diabetologia VL - 66 IS - 10 PB - Springer PY - 2023 SN - 0012-186X ER - TY - JOUR AB - The peptide hormone glucagon, discovered in late 1922, is secreted from pancreatic alpha cells and is an essential regulator of metabolic homeostasis. This review summarises experiences since the discovery of glucagon regarding basic and clinical aspects of this hormone and speculations on the future directions for glucagon biology and glucagon-based therapies. The review was based on the international glucagon conference, entitled ‘A hundred years with glucagon and a hundred more’, held in Copenhagen, Denmark, in November 2022. The scientific and therapeutic focus of glucagon biology has mainly been related to its role in diabetes. In type 1 diabetes, the glucose-raising properties of glucagon have been leveraged to therapeutically restore hypoglycaemia. The hyperglucagonaemia evident in type 2 diabetes has been proposed to contribute to hyperglycaemia, raising questions regarding underlying mechanism and the importance of this in the pathogenesis of diabetes. Mimicry experiments of glucagon signalling have fuelled the development of several pharmacological compounds including glucagon receptor (GCGR) antagonists, GCGR agonists and, more recently, dual and triple receptor agonists combining glucagon and incretin hormone receptor agonism. From these studies and from earlier observations in extreme cases of either glucagon deficiency or excess secretion, the physiological role of glucagon has expanded to also involve hepatic protein and lipid metabolism. The interplay between the pancreas and the liver, known as the liver–alpha cell axis, reflects the importance of glucagon for glucose, amino acid and lipid metabolism. In individuals with diabetes and fatty liver diseases, glucagon’s hepatic actions may be partly impaired resulting in elevated levels of glucagonotropic amino acids, dyslipidaemia and hyperglucagonaemia, reflecting a new, so far largely unexplored pathophysiological phenomenon termed ‘glucagon resistance’. Importantly, the hyperglucagonaemia as part of glucagon resistance may result in increased hepatic glucose production and hyperglycaemia. Emerging glucagon-based therapies show a beneficial impact on weight loss and fatty liver diseases and this has sparked a renewed interest in glucagon biology to enable further pharmacological pursuits. Graphical Abstract: [Figure not available: see fulltext.] AU - Wewer Albrechtsen, N.J.* AU - Holst, J.J.* AU - Cherrington, A.D.* AU - Finan, B.* AU - Gluud, L.L.* AU - Dean, E.D.* AU - Campbell, J.E.* AU - Bloom, S.R.* AU - Tan, T.M.M.* AU - Knop, F.K.* AU - Müller, T.D. C1 - 68468 C2 - 54657 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - 1378-1394 TI - 100 years of glucagon and 100 more. JO - Diabetologia VL - 66 IS - 8 PB - Springer PY - 2023 SN - 0012-186X ER - TY - JOUR AB - 'The clock to type 1 diabetes has started when islet antibodies are first detected', commented George Eisenbarth with regard to the pathogenesis of type 1 diabetes. This review focuses on 'starting the clock', i.e. the initiation of pre-symptomatic islet autoimmunity/the first appearance of islet autoantibodies. In particular, this review addresses why susceptibility to developing islet autoimmunity is greatest in the first 2 years of life and why beta cells are a frequent target of the immune system during this fertile period. A concept for the development of beta cell autoimmunity in childhood is discussed and three factors are highlighted that contribute to this early predisposition: (1) high beta cell activity and potential vulnerability to stress; (2) high rates of and first exposures to infection; and (3) a heightened immune response, with a propensity for T helper type 1 (Th1) immunity. Arguments are presented that beta cell injury, accompanied by activation of an inflammatory immune response, precedes the initiation of autoimmunity. Finally, the implications for strategies aimed at primary prevention for a world without type 1 diabetes are discussed. AU - Ziegler, A.-G. C1 - 67891 C2 - 54369 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - 1169-1178 TI - The countdown to type 1 diabetes: when, how and why does the clock start? JO - Diabetologia VL - 66 IS - 7 PB - Springer PY - 2023 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: Type 2 diabetes is a complex metabolic disease with increasing prevalence worldwide. Improving the prediction of incident type 2 diabetes using epigenetic markers could help tailor prevention efforts to those at the highest risk. The aim of this study was to identify predictive methylation markers for incident type 2 diabetes by combining epigenome-wide association study (EWAS) results from five prospective European cohorts. METHODS: We conducted a meta-analysis of EWASs in blood collected 7-10 years prior to type 2 diabetes diagnosis. DNA methylation was measured with Illumina Infinium Methylation arrays. A total of 1250 cases and 1950 controls from five longitudinal cohorts were included: Doetinchem, ESTHER, KORA1, KORA2 and EPIC-Norfolk. Associations between DNA methylation and incident type 2 diabetes were examined using robust linear regression with adjustment for potential confounders. Inverse-variance fixed-effects meta-analysis of cohort-level individual CpG EWAS estimates was performed using METAL. The methylGSA R package was used for gene set enrichment analysis. Confirmation of genome-wide significant CpG sites was performed in a cohort of Indian Asians (LOLIPOP, UK). RESULTS: The meta-analysis identified 76 CpG sites that were differentially methylated in individuals with incident type 2 diabetes compared with control individuals (p values <1.1 × 10-7). Sixty-four out of 76 (84.2%) CpG sites were confirmed by directionally consistent effects and p values <0.05 in an independent cohort of Indian Asians. However, on adjustment for baseline BMI only four CpG sites remained genome-wide significant, and addition of the 76 CpG methylation risk score to a prediction model including established predictors of type 2 diabetes (age, sex, BMI and HbA1c) showed no improvement (AUC 0.757 vs 0.753). Gene set enrichment analysis of the full epigenome-wide results clearly showed enrichment of processes linked to insulin signalling, lipid homeostasis and inflammation. CONCLUSIONS/INTERPRETATION: By combining results from five European cohorts, and thus significantly increasing study sample size, we identified 76 CpG sites associated with incident type 2 diabetes. Replication of 64 CpGs in an independent cohort of Indian Asians suggests that the association between DNA methylation levels and incident type 2 diabetes is robust and independent of ethnicity. Our data also indicate that BMI partly explains the association between DNA methylation and incident type 2 diabetes. Further studies are required to elucidate the underlying biological mechanisms and to determine potential causal roles of the differentially methylated CpG sites in type 2 diabetes development. AU - Fraszczyk, E.* AU - Spijkerman, A.M.W.* AU - Zhang, Y.* AU - Brandmaier, S. AU - Day, F.R.* AU - Zhou, L.* AU - Wackers, P.* AU - Dollé, M.E.T.* AU - Bloks, V.W.* AU - Gao, X.* AU - Gieger, C. AU - Kooner, J.* AU - Kriebel, J. AU - Picavet, H.S.J.* AU - Rathmann, W. AU - Schöttker, B.* AU - Loh, M.* AU - Verschuren, W.M.M.* AU - van Vliet-Ostaptchouk, J.V.* AU - Wareham, N.J.* AU - Chambers, J.C.* AU - Ong, K.K.* AU - Grallert, H. AU - Brenner, H.* AU - Luijten, M.* AU - Snieder, H.* C1 - 64362 C2 - 51921 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - 763-776 TI - Epigenome-wide association study of incident type 2 diabetes: A meta-analysis of five prospective European cohorts. JO - Diabetologia VL - 65 IS - 5 PB - Springer PY - 2022 SN - 0012-186X ER - TY - JOUR AB - Aims/hypothesis: No established blood-based biomarker exists to monitor diabetic sensorimotor polyneuropathy (DSPN) and evaluate treatment response. The neurofilament light chain (NFL), a blood biomarker of neuroaxonal damage in several neurodegenerative diseases, represents a potential biomarker for DSPN. We hypothesised that higher serum NFL levels are associated with prevalent DSPN and nerve dysfunction in individuals recently diagnosed with diabetes. Methods: This cross-sectional study included 423 adults with type 1 and type 2 diabetes and known diabetes duration of less than 1 year from the prospective observational German Diabetes Study cohort. NFL was measured in serum samples of fasting participants in a multiplex approach using proximity extension assay technology. DSPN was assessed by neurological examination, nerve conduction studies and quantitative sensory testing. Associations of serum NFL with DSPN (defined according to the Toronto Consensus criteria) were estimated using Poisson regression, while multivariable linear and quantile regression models were used to assess associations with nerve function measures. In exploratory analyses, other biomarkers in the multiplex panel were also analysed similarly to NFL. Results: DSPN was found in 16% of the study sample. Serum NFL levels increased with age. After adjustment for age, sex, waist circumference, height, HbA1c, known diabetes duration, diabetes type, cholesterol, eGFR, hypertension, CVD, use of lipid-lowering drugs and use of non-steroidal anti-inflammatory drugs, higher serum NFL levels were associated with DSPN (RR [95% CI] per 1-normalised protein expression increase, 1.92 [1.50, 2.45], p<0.0001), slower motor (all p<0.0001) and sensory (all p≤0.03) nerve conduction velocities, lower sural sensory nerve action potential (p=0.0004) and higher thermal detection threshold to warm stimuli (p=0.023 and p=0.004 for hand and foot, respectively). There was no evidence for associations between other neurological biomarkers and DSPN or nerve function measures. Conclusions/interpretation: Our findings in individuals recently diagnosed with diabetes provide new evidence associating higher serum NFL levels with DSPN and peripheral nerve dysfunction. The present study advocates NFL as a potential biomarker for DSPN. Graphical abstract: [Figure not available: see fulltext.] AU - Maalmi, H.* AU - Strom, A.* AU - Petrera, A. AU - Hauck, S.M. AU - Strassburger, K.* AU - Kuss, O.* AU - Zaharia, O.P.* AU - Bönhof, G.J.* AU - Rathmann, W.* AU - Trenkamp, S.* AU - Burkart, V.* AU - Szendroedi, J. AU - Ziegler, D.* AU - Roden, M.* AU - Herder, C.* C1 - 66936 C2 - 53357 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - 579-589 TI - Serum neurofilament light chain: A novel biomarker for early diabetic sensorimotor polyneuropathy. JO - Diabetologia VL - 66 IS - 3 PB - Springer PY - 2022 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: Attenuated counterregulation after recurrent hypoglycaemia is a major complication of diabetes treatment. As there is previous evidence for the relevance of sleep in metabolic control, we assessed the acute contribution of sleep to the counterregulatory adaptation to recurrent hypoglycaemia. METHODS: Within a balanced crossover design, 15 healthy, normal-weight male participants aged 18-35 years underwent three hyperinsulinaemic-hypoglycaemic clamps with a glucose nadir of 2.5 mmol/l, under two experimental conditions, sleep and sleep deprivation. Participants were exposed to two hypoglycaemic episodes, followed by a third hypoglycaemic clamp after one night of regular 8 h sleep vs sleep deprivation. The counterregulatory response of relevant hormones (glucagon, growth hormone [GH], ACTH, cortisol, adrenaline [epinephrine] and noradrenaline [norepinephrine]) was measured, and autonomic and neuroglycopenic symptoms were assessed. RESULTS: Sleep deprivation compared with sleep dampened the adaptation to recurrent hypoglycaemia for adrenaline (p=0.004), and this pattern also emerged in an overall analysis including adrenaline, GH and glucagon (p=0.064). After regular sleep, the counterregulatory responses of adrenaline (p=0.005), GH (p=0.029) and glucagon (p=0.009) were attenuated during the 3rd clamp compared with the 1st clamp, but were preserved after sleep deprivation (all p>0.225). Neuroglycopenic and autonomic symptoms during the 3rd clamp compared with the 1st clamp were likewise reduced after sleep (p=0.005 and p=0.019, respectively). In sleep deprivation, neuroglycopenic symptoms increased (p=0.014) and autonomic symptoms were unchanged (p=0.859). CONCLUSIONS/INTERPRETATION: The counterregulatory adaptation to recurrent hypoglycaemia is compromised by sleep deprivation between hypoglycaemic episodes, indicating that sleep is essential for the formation of a neurometabolic memory, and may be a potential target of interventions to treat hypoglycaemia unawareness syndrome. AU - Meyhöfer, S.* AU - Dembinski, K.* AU - Schultes, B.* AU - Born, J. AU - Wilms, B.* AU - Lehnert, H.* AU - Hallschmid, M. AU - Meyhöfer, S.M.* C1 - 64890 C2 - 51979 SP - 1212-1221 TI - Sleep deprivation prevents counterregulatory adaptation to recurrent hypoglycaemia. JO - Diabetologia VL - 65 IS - 7 PY - 2022 SN - 0012-186X ER - TY - JOUR AB - The authors regret that funding details for M. Le Marois were omitted. The original article has been corrected. AU - Morgenstern, J.* AU - Groener, J.B.* AU - Jende, J.M.E.* AU - Kurz, F.T.* AU - Strom, A.* AU - Göpfert, J.* AU - Kender, Z.* AU - Le Marois, M.* AU - Brune, M.* AU - Kuner, R.* AU - Herzig, S. AU - Roden, M.* AU - Ziegler, D.* AU - Bendszus, M.* AU - Szendroedi, J.* AU - Nawroth, P.P. AU - Kopf, S.* AU - Fleming, T.* C1 - 63284 C2 - 51303 CY - One New York Plaza, Suite 4600, New York, Ny, United States TI - Correction to: Neuron-specific biomarkers predict hypo- and hyperalgesia in individuals with diabetic peripheral neuropathy. JO - Diabetologia VL - 65 PB - Springer PY - 2022 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: The aim of this study was to explore the utility of islet autoantibody (IAb) levels for the prediction of type 1 diabetes in autoantibody-positive children. METHODS: Prospective cohort studies in Finland, Germany, Sweden and the USA followed 24,662 children at increased genetic or familial risk of developing islet autoimmunity and diabetes. For the 1403 who developed IAbs (523 of whom developed diabetes), levels of autoantibodies against insulin (IAA), glutamic acid decarboxylase (GADA) and insulinoma-associated antigen-2 (IA-2A) were harmonised for analysis. Diabetes prediction models using multivariate logistic regression with inverse probability censored weighting (IPCW) were trained using 10-fold cross-validation. Discriminative power for disease was estimated using the IPCW concordance index (C index) with 95% CI estimated via bootstrap. RESULTS: A baseline model with covariates for data source, sex, diabetes family history, HLA risk group and age at seroconversion with a 10-year follow-up period yielded a C index of 0.61 (95% CI 0.58, 0.63). The performance improved after adding the IAb positivity status for IAA, GADA and IA-2A at seroconversion: C index 0.72 (95% CI 0.71, 0.74). Using the IAb levels instead of positivity indicators resulted in even better performance: C index 0.76 (95% CI 0.74, 0.77). The predictive power was maintained when using the IAb levels alone: C index 0.76 (95% CI 0.75, 0.76). The prediction was better for shorter follow-up periods, with a C index of 0.82 (95% CI 0.81, 0.83) at 2 years, and remained reasonable for longer follow-up periods, with a C index of 0.76 (95% CI 0.75, 0.76) at 11 years. Inclusion of the results of a third IAb test added to the predictive power, and a suitable interval between seroconversion and the third test was approximately 1.5 years, with a C index of 0.78 (95% CI 0.77, 0.78) at 10 years follow-up. CONCLUSIONS/INTERPRETATION: Consideration of quantitative patterns of IAb levels improved the predictive power for type 1 diabetes in IAb-positive children beyond qualitative IAb positivity status. AU - Ng, K.* AU - Anand, V.* AU - Stavropoulos, H.* AU - Veijola, R.* AU - Toppari, J.* AU - Maziarz, M.* AU - Lundgren, M.* AU - Waugh, K.C.* AU - Frohnert, B.I.* AU - Martin, F.* AU - Lou, O.* AU - Hagopian, W.* AU - Achenbach, P. C1 - 66350 C2 - 52799 SP - 93-104 TI - Quantifying the utility of islet autoantibody levels in the prediction of type 1 diabetes in children. JO - Diabetologia VL - 66 IS - 1 PY - 2022 SN - 0012-186X ER - TY - JOUR AB - Aims/hypothesis: Insulin allergy is a rare but significant clinical challenge. We aimed to develop a management workflow by (1) validating clinical criteria to guide diagnosis, based on a retrospective cohort, and (2) assessing the diagnostic performance of confirmatory tests, based on a case–control study. Methods: In the retrospective cohort, patients with suspected insulin allergy were classified into three likelihood categories according to the presence of all (likely insulin allergy; 26/52, 50%), some (possible insulin allergy; 9/52, 17%) or none (unlikely insulin allergy; 17/52, 33%) of four clinical criteria: (1) recurrent local or systemic immediate or delayed hypersensitivity reactions; (2) reactions elicited by each injection; (3) reactions centred on the injection sites; and (4) reactions observed by the investigator (i.e. in response to an insulin challenge test). All underwent intradermal reaction (IDR) tests. A subsequent case–control study assessed the diagnostic performance of IDR, skin prick and serum anti-insulin IgE tests in ten clinically diagnosed insulin allergy patients, 24 insulin-treated non-allergic patients and 21 insulin-naive patients. Results: In the retrospective cohort, an IDR test validated the clinical diagnosis in 24/26 (92%), 3/9 (33%) and 0/14 (0%) likely, possible and unlikely insulin allergy patients, respectively. In the case–control study, an IDR test was 80% sensitive and 100% specific and identified the index insulin(s). The skin prick and IgE tests had a marginal diagnostic value. Patients with IDR-confirmed insulin allergy were treated using a stepwise strategy. Conclusions/interpretation: Subject to validation, clinical likelihood criteria can effectively guide diabetologists towards an insulin allergy diagnosis before undertaking allergology tests. An IDR test shows the best diagnostic performance. A progressive management strategy can subsequently be implemented. Continuous subcutaneous insulin infusion is ultimately required in most patients. ClinicalTrials.gov: NCT01407640. Graphical abstract: [Figure not available: see fulltext.] AU - Sola-Gazagnes, A.* AU - Pecquet, C.* AU - Bèrre, S.* AU - Achenbach, P. AU - Pierson, L.A.* AU - Virmoux-Buisson, I.* AU - M’Bemba, J.* AU - Elgrably, F.* AU - Moguelet, P.* AU - Boitard, C.* AU - Caillat-Zucman, S.* AU - Laanani, M.* AU - Coste, J.* AU - Larger, E.* AU - Mallone, R.* C1 - 64950 C2 - 51994 SP - 1278-1290 TI - Insulin allergy: A diagnostic and therapeutic strategy based on a retrospective cohort and a case–control study. JO - Diabetologia VL - 65 IS - 8 PY - 2022 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: The aim of this study was to develop strategies that identify children from the general population who have late-stage presymptomatic type 1 diabetes and may, therefore, benefit from immune intervention. METHODS: We tested children from Bavaria, Germany, aged 1.75-10 years, enrolled in the Fr1da public health screening programme for islet autoantibodies (n=154,462). OGTT and HbA1c were assessed in children with multiple islet autoantibodies for diagnosis of presymptomatic stage 1 (normoglycaemia) or stage 2 (dysglycaemia) type 1 diabetes. Cox proportional hazards and penalised logistic regression of autoantibody, genetic, metabolic and demographic information were used to develop a progression likelihood score to identify children with stage 1 type 1 diabetes who progressed to stage 3 (clinical) type 1 diabetes within 2 years. RESULTS: Of 447 children with multiple islet autoantibodies, 364 (81.4%) were staged. Undiagnosed stage 3 type 1 diabetes, presymptomatic stage 2, and stage 1 type 1 diabetes were detected in 41 (0.027% of screened children), 30 (0.019%) and 293 (0.19%) children, respectively. The 2 year risk for progression to stage 3 type 1 diabetes was 48% (95% CI 34, 58) in children with stage 2 type 1 diabetes (annualised risk, 28%). HbA1c, islet antigen-2 autoantibody positivity and titre, and the 90 min OGTT value were predictors of progression in children with stage 1 type 1 diabetes. The derived progression likelihood score identified substages corresponding to ≤90th centile (stage 1a, n=258) and >90th centile (stage 1b, n=29; 0.019%) of stage 1 children with a 4.1% (95% CI 1.4, 6.7) and 46% (95% CI 21, 63) 2 year risk of progressing to stage 3 type 1 diabetes, respectively. CONCLUSIONS/INTERPRETATION: Public health screening for islet autoantibodies found 0.027% of children to have undiagnosed clinical type 1 diabetes and 0.038% to have undiagnosed presymptomatic type 1 diabetes. Of the latter group, our novel likelihood ratio score predicted approximately 50% risk of developing clinical diabetes within 2 years. AU - Weiss, A. AU - Zapardiel-Gonzalo, J. AU - Voss, F. AU - Jolink, M. AU - Stock, J. AU - Haupt, F. AU - Kick, K.* AU - Welzhofer, T.C.* AU - Heublein, A. AU - Winkler, C. AU - Achenbach, P. AU - Ziegler, A.-G. AU - Bonifacio, E. C1 - 65971 C2 - 52800 SP - 93-104 TI - Progression likelihood score identifies substages of presymptomatic type 1 diabetes in childhood public health screening. JO - Diabetologia VL - 65 IS - 12 PY - 2022 SN - 0012-186X ER - TY - JOUR AB - In the Conclusions/interpretation section of the Abstract, the following, potentially misleading, text has been changed: Original wording: ‘Public health screening for islet autoantibodies found 0.027%of children to have undiagnosed clinical type 1 diabetes and 0.038% to have undiagnosed presymptomatic type 1 diabetes. Of the latter group, our novel likelihood ratio score predicted approximately 50% to be at risk of developing clinical type 1 diabetes within 2 years.’ Modified wording: ‘Public health screening for islet autoantibodies found 0.027%of children to have undiagnosed clinical type 1 diabetes and 0.038% to have undiagnosed presymptomatic stage 2 or stage 1b type 1 diabetes, with 50% risk to develop clinical type 1 diabetes within 2 years.’ The original article has been corrected. AU - Weiss, A. AU - Zapardiel-Gonzalo, J. AU - Voss, F. AU - Jolink, M. AU - Stock, J. AU - Haupt, F. AU - Kick, K.* AU - Welzhofer, T.C.* AU - Heublein, A. AU - Winkler, C. AU - Achenbach, P. AU - Ziegler, A.-G. AU - Bonifacio, E. C1 - 66356 C2 - 52801 TI - Correction to: Progression likelihood score identifies substages of presymptomatic type 1 diabetes in childhood public health screening. JO - Diabetologia PY - 2022 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: The prevalence of type 2 diabetes is increasing worldwide, and previous studies have suggested that it is higher in individuals who are seropositive for herpesviruses. This study examines the prospective association of herpesviruses with (pre)diabetes to evaluate their potential role in diabetes aetiology. METHODS: Two follow-up examinations of the German population-based KORA cohort (F4 and FF4) were used to identify participants with normal glucose tolerance at baseline, thus being at risk for (pre)diabetes (n = 1257). All participants had repeated OGTTs and antibody measurements for herpes simplex virus (HSV) 1 and 2, varicella-zoster virus, Epstein-Barr virus, cytomegalovirus (CMV) and human herpesvirus 6 and 7. Regression models were used to evaluate the association between serostatus with (pre)diabetes incidence after a 7 year follow-up and HbA1c. RESULTS: HSV2 and CMV were associated with (pre)diabetes incidence after adjustment for sex, age, BMI, education, smoking, physical activity, parental diabetes, hypertension, lipid levels, insulin resistance and fasting glucose. Seropositivity of both viruses was also cross-sectionally associated with higher HbA1c at baseline, with the association of HSV2 being independent of confounders, including the prevalence of (pre)diabetes itself. While seropositivity for multiple herpesviruses was associated with a higher incidence of (pre)diabetes, this association was not independent of confounders. CONCLUSIONS/INTERPRETATION: The associations of HSV2 and CMV serostatus with (pre)diabetes incidence indicate that these herpesviruses may contribute to the development of impaired glucose metabolism. Our results highlight the link between viral infection and (pre)diabetes, and the need for more research evaluating viral prevention strategies. AU - Woelfle, T.* AU - Linkohr, B. AU - Waterboer, T.* AU - Thorand, B. AU - Seissler, J.* AU - Chadeau-Hyam, M.* AU - Peters, A. C1 - 65012 C2 - 52133 SP - 1328-1338 TI - Health impact of seven herpesviruses on (pre)diabetes incidence and HbA1c: Results from the KORA cohort. JO - Diabetologia VL - 65 IS - 8 PY - 2022 SN - 0012-186X ER - TY - JOUR AB - Aims/hypothesis: Oral administration of antigen can induce immunological tolerance. Insulin is a key autoantigen in childhood type 1 diabetes. Here, oral insulin was given as antigen-specific immunotherapy before the onset of autoimmunity in children from age 6 months to assess its safety and immune response actions on immunity and the gut microbiome. Methods: A phase I/II randomised controlled trial was performed in a single clinical study centre in Germany. Participants were 44 islet autoantibody-negative children aged 6 months to 2.99 years who had a first-degree relative with type 1 diabetes and a susceptible HLA DR4-DQ8-containing genotype. Children were randomised 1:1 to daily oral insulin (7.5 mg with dose escalation to 67.5 mg) or placebo for 12 months using a web-based computer system. The primary outcome was immune efficacy pre-specified as induction of antibody or T cell responses to insulin and measured in a central treatment-blinded laboratory. Results: Randomisation was performed in 44 children. One child in the placebo group was withdrawn after the first study visit and data from 22 insulin-treated and 21 placebo-treated children were analysed. Oral insulin was well tolerated with no changes in metabolic variables. Immune responses to insulin were observed in children who received both insulin (54.5%) and placebo (66.7%), and the trial did not demonstrate an effect on its primary outcome (p = 0.54). In exploratory analyses, there was preliminary evidence that the immune response and gut microbiome were modified by the INS genotype Among children with the type 1 diabetes-susceptible INS genotype (n = 22), antibody responses to insulin were more frequent in insulin-treated (72.7%) as compared with placebo-treated children (18.2%; p = 0.03). T cell responses to insulin were modified by treatment-independent inflammatory episodes. Conclusions/interpretation: The study demonstrated that oral insulin immunotherapy in young genetically at-risk children was safe, but was not associated with an immune response as predefined in the trial primary outcome. Exploratory analyses suggested that antibody responses to oral insulin may occur in children with a susceptible INS genotype, and that inflammatory episodes may promote the activation of insulin-responsive T cells. Trial registration: Clinicaltrials.gov NCT02547519 Funding: The main funding source was the German Center for Diabetes Research (DZD e.V.) Graphical abstract: [Figure not available: see fulltext.] AU - Assfalg, R. AU - Knoop, J. AU - Hoffman, K.L.* AU - Pfirrmann, M.* AU - Zapardiel-Gonzalo, J. AU - Hofelich, A.* AU - Eugster, A.* AU - Weigelt, M.* AU - Matzke, C. AU - Reinhardt, J.* AU - Fuchs, Y.* AU - Bunk, M. AU - Weiss, A. AU - Hippich, M. AU - Halfter, K.* AU - Hauck, S.M. AU - Hasford, J.* AU - Petrosino, J.F.* AU - Achenbach, P. AU - Bonifacio, E. AU - Ziegler, A.-G. C1 - 61146 C2 - 50068 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - 1079-1092 TI - Oral insulin immunotherapy in children at risk for type 1 diabetes in a randomised controlled trial. JO - Diabetologia VL - 64 IS - 5 PB - Springer PY - 2021 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: Accurate prediction of disease progression in individuals with pre-symptomatic type 1 diabetes has potential to prevent ketoacidosis and accelerate development of disease-modifying therapies. Current tools for predicting risk require multiple blood samples taken during an OGTT. Our aim was to develop and validate a simpler tool based on a single blood draw. METHODS: Models to predict disease progression using a single OGTT time point (0, 30, 60, 90 or 120 min) were developed using TrialNet data collected from relatives with type 1 diabetes and validated in independent populations at high genetic risk of type 1 diabetes (TrialNet, Diabetes Prevention Trial-Type 1, The Environmental Determinants of Diabetes in the Young [1]) and in a general population of Bavarian children who participated in Fr1da. RESULTS: Cox proportional hazards models combining plasma glucose, C-peptide, sex, age, BMI, HbA1c and insulinoma antigen-2 autoantibody status predicted disease progression in all populations. In TrialNet, the AUC for receiver operating characteristic curves for models named M60, M90 and M120, based on sampling at 60, 90 and 120 min, was 0.760, 0.761 and 0.745, respectively. These were not significantly different from the AUC of 0.760 for the gold standard Diabetes Prevention Trial Risk Score, which requires five OGTT blood samples. In TEDDY, where only 120 min blood sampling had been performed, the M120 AUC was 0.865. In Fr1da, the M120 AUC of 0.742 was significantly greater than the M60 AUC of 0.615. CONCLUSIONS/INTERPRETATION: Prediction models based on a single OGTT blood draw accurately predict disease progression from stage 1 or 2 to stage 3 type 1 diabetes. The operational simplicity of M120, its validity across different at-risk populations and the requirement for 120 min sampling to stage type 1 diabetes suggest M120 could be readily applied to decrease the cost and complexity of risk stratification. AU - Bediaga, N.G.* AU - Li-Wai-Suen, C.S.N.* AU - Haller, M.J.* AU - Gitelman, S.E.* AU - Evans-Molina, C.* AU - Gottlieb, P.A.* AU - Hippich, M. AU - Ziegler, A.-G. AU - Lernmark, A.* AU - Dimeglio, L.A.* AU - Wherrett, D.K.* AU - Colman, P.G.* AU - Harrison, L.C.* AU - Wentworth, J.M.* C1 - 62767 C2 - 51053 CY - One New York Plaza, Suite 4600, New York, Ny, United States TI - Simplifying prediction of disease progression in pre-symptomatic type 1 diabetes using a single blood sample. JO - Diabetologia PB - Springer PY - 2021 SN - 0012-186X ER - TY - JOUR AB - Aims/hypothesis: Many individuals who develop type 2 diabetes also display increased glucagon levels (hyperglucagonaemia), which we have previously found to be associated with the metabolic syndrome. The concept of a liver–alpha cell axis provides a possible link between hyperglucagonaemia and elevated liver fat content, a typical finding in the metabolic syndrome. However, this association has only been studied in individuals with non-alcoholic fatty liver disease. Hence, we searched for a link between the liver and the alpha cells in individuals with non-steatotic levels of liver fat content. We hypothesised that the glucagon–alanine index, an indicator of the functional integrity of the liver–alpha cell axis, would associate with liver fat and insulin resistance in our cohort of women with low levels of liver fat. Methods: We analysed data from 79 individuals participating in the Prediction, Prevention and Subclassification of Type 2 Diabetes (PPSDiab) study, a prospective observational study of young women at low to high risk for the development of type 2 diabetes. Liver fat content was determined by MRI. Insulin resistance was calculated as HOMA-IR. We conducted Spearman correlation analyses of liver fat content and HOMA-IR with the glucagon–alanine index (the product of fasting plasma levels of glucagon and alanine). The prediction of the glucagon–alanine index by liver fat or HOMA-IR was tested in multivariate linear regression analyses in the whole cohort as well as after stratification for liver fat content ≤0.5% (n = 39) or >0.5% (n = 40). Results: The glucagon–alanine index significantly correlated with liver fat and HOMA-IR in the entire cohort (ρ = 0.484, p < 0.001 and ρ = 0.417, p < 0.001, respectively). These associations resulted from significant correlations in participants with a liver fat content >0.5% (liver fat, ρ = 0.550, p < 0.001; HOMA-IR, ρ = 0.429, p = 0.006). In linear regression analyses, the association of the glucagon–alanine index with liver fat remained significant after adjustment for age and HOMA-IR in all participants and in those with liver fat >0.5% (β = 0.246, p = 0.0.23 and β = 0.430, p = 0.007, respectively) but not in participants with liver fat ≤0.5% (β = −0.184, p = 0.286). Conclusions/interpretation: We reproduced the previously reported association of liver fat content and HOMA-IR with the glucagon–alanine index in an independent study cohort of young women with low to high risk for type 2 diabetes. Furthermore, our data indicates an insulin-resistance-independent association of liver fat content with the glucagon–alanine index. In summary, our study supports the concept that even lower levels of liver fat (from 0.5%) are connected to relative hyperglucagonaemia, reflecting an imminent impairment of the liver–alpha cell axis.[Figure not available: see fulltext.] AU - Gar, C. AU - Haschka, S. AU - Kern-Matschilles, S. AU - Rauch, B. AU - Sacco, V. AU - Prehn, C. AU - Adamski, J. AU - Seissler, J.* AU - Wewer Albrechtsen, N.J.* AU - Holst, J.J.* AU - Lechner, A. C1 - 60723 C2 - 49559 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - 512-520 TI - The liver–alpha cell axis associates with liver fat and insulin resistance: A validation study in women with non-steatotic liver fat levels. JO - Diabetologia VL - 64 IS - 3 PB - Springer PY - 2021 SN - 0012-186X ER - TY - JOUR AB - The global epidemic of non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) and the high prevalence among individuals with type 2 diabetes has attracted the attention of clinicians specialising in liver disorders. Many drugs are in the pipeline for the treatment of NAFLD/NASH, and several glucose-lowering drugs are now being tested specifically for the treatment of liver disease. Among these are nuclear hormone receptor agonists (e.g. peroxisome proliferator-activated receptor agonists, farnesoid X receptor agonists and liver X receptor agonists), fibroblast growth factor-19 and -21, single, dual or triple incretins, sodium-glucose cotransporter inhibitors, drugs that modulate lipid or other metabolic pathways (e.g. inhibitors of fatty acid synthase, diacylglycerol acyltransferase-1, acetyl-CoA carboxylase and 11β-hydroxysteroid dehydrogenase type-1) or drugs that target the mitochondrial pyruvate carrier. We have reviewed the metabolic effects of these drugs in relation to improvement of diabetic hyperglycaemia and fatty liver disease, as well as peripheral metabolism and insulin resistance. AU - Gastaldelli, A.* AU - Stefan, N. AU - Häring, H.-U. C1 - 61827 C2 - 50466 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - 1461-1479 TI - Liver-targeting drugs and their effect on blood glucose and hepatic lipids. JO - Diabetologia VL - 64 IS - 7 PB - Springer PY - 2021 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: Neonatal beta cells carry out a programme of postnatal functional maturation to achieve full glucose responsiveness. A partial loss of the mature phenotype of adult beta cells may contribute to a reduction of functional beta cell mass and accelerate the onset of type 2 diabetes. We previously found that fetuin-A, a hepatokine increasingly secreted by the fatty liver and a determinant of type 2 diabetes, inhibits glucose-stimulated insulin secretion (GSIS) of human islets. Since fetuin-A is a ubiquitous fetal glycoprotein that declines peripartum, we examined here whether fetuin-A interferes with the functional maturity of beta cells. METHODS: The effects of fetuin-A were assessed during in vitro maturation of porcine neonatal islet cell clusters (NICCs) and in adult human islets. Expression alterations were examined via microarray, RNA sequencing and reverse transcription quantitative real-time PCR (qRT-PCR), proteins were analysed by western blotting and immunostaining, and insulin secretion was quantified in static incubations. RESULTS: NICC maturation was accompanied by the gain of glucose-responsive insulin secretion (twofold stimulation), backed up by mRNA upregulation of genes governing beta cell identity and function, such as NEUROD1, UCN3, ABCC8 and CASR (Log2 fold change [Log2FC] > 1.6). An active TGFβ receptor (TGFBR)-SMAD2/3 pathway facilitates NICC maturation, since the TGFBR inhibitor SB431542 counteracted the upregulation of aforementioned genes and de-repressed ALDOB, a gene disallowed in mature beta cells. In fetuin-A-treated NICCs, upregulation of beta cell markers and the onset of glucose responsiveness were suppressed. Concomitantly, SMAD2/3 phosphorylation was inhibited. Transcriptome analysis confirmed inhibitory effects of fetuin-A and SB431542 on TGFβ-1- and SMAD2/3-regulated transcription. However, contrary to SB431542 and regardless of cMYC upregulation, fetuin-A inhibited beta cell proliferation (0.27 ± 0.08% vs 1.0  ± 0.1% Ki67-positive cells in control NICCs). This effect was sustained by reduced expression (Log2FC ≤ -2.4) of FOXM1, CENPA, CDK1 or TOP2A. In agreement, the number of insulin-positive cells was lower in fetuin-A-treated NICCs than in control NICCs (14.4 ± 1.2% and 22.3 ± 1.1%, respectively). In adult human islets fetuin-A abolished glucose responsiveness, i.e. 1.7- and 1.1-fold change over 2.8 mmol/l glucose in control- and fetuin-A-cultured islets, respectively. In addition, fetuin-A reduced SMAD2/3 phosphorylation and suppressed expression of proliferative genes. Of note, in non-diabetic humans, plasma fetuin-A was negatively correlated (p = 0.013) with islet beta cell area. CONCLUSIONS/INTERPRETATION: Our results suggest that the perinatal decline of fetuin-A relieves TGFBR signalling in islets, a process that facilitates functional maturation of neonatal beta cells. Functional maturity remains revocable in later life, and the occurrence of a metabolically unhealthy milieu, such as liver steatosis and elevated plasma fetuin-A, can impair both function and adaptive proliferation of beta cells. DATA AVAILABILITY: The RNAseq datasets and computer code produced in this study are available in the Gene Expression Omnibus (GEO): GSE144950; https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE144950. AU - Gerst, F. AU - Kemter, E.* AU - Lorza-Gil, E. AU - Kaiser, G. AU - Fritz, A.K.* AU - Nano, R.* AU - Piemonti, L.* AU - Gauder, M.* AU - Dahl, A.* AU - Nadalin, S.* AU - Königsrainer, A.* AU - Fend, F.* AU - Birkenfeld, A.L. AU - Wagner, R. AU - Heni, M. AU - Stefan, N. AU - Wolf, E.* AU - Häring, H.-U. AU - Ullrich, S. C1 - 61684 C2 - 50392 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - 1358–1374 TI - The hepatokine fetuin-A disrupts functional maturation of pancreatic beta cells. JO - Diabetologia VL - 64 PB - Springer PY - 2021 SN - 0012-186X ER - TY - JOUR AB - Aims/hypothesis: Adipocytes are critical cornerstones of energy metabolism. While obesity-induced adipocyte dysfunction is associated with insulin resistance and systemic metabolic disturbances, adipogenesis, the formation of new adipocytes and healthy adipose tissue expansion are associated with metabolic benefits. Understanding the molecular mechanisms governing adipogenesis is of great clinical potential to efficiently restore metabolic health in obesity. Here we investigate the role of heart and neural crest derivatives-expressed 2 (HAND2) in adipogenesis. Methods: Human white adipose tissue (WAT) was collected from two cross-sectional studies of 318 and 96 individuals. In vitro, for mechanistic experiments we used primary adipocytes from humans and mice as well as human multipotent adipose-derived stem (hMADS) cells. Gene silencing was performed using siRNA or genetic inactivation in primary adipocytes from loxP and or tamoxifen-inducible Cre-ERT2 mouse models with Cre-encoding mRNA or tamoxifen, respectively. Adipogenesis and adipocyte metabolism were measured by Oil Red O staining, quantitative PCR (qPCR), microarray, glucose uptake assay, western blot and lipolysis assay. A combinatorial RNA sequencing (RNAseq) and ChIP qPCR approach was used to identify target genes regulated by HAND2. In vivo, we created a conditional adipocyte Hand2 deletion mouse model using Cre under control of the Adipoq promoter (Hand2 ) and performed a large panel of metabolic tests. Results: We found that HAND2 is an obesity-linked white adipocyte transcription factor regulated by glucocorticoids that was necessary but insufficient for adipocyte differentiation in vitro. In a large cohort of humans, WAT HAND2 expression was correlated to BMI. The HAND2 gene was enriched in white adipocytes compared with brown, induced early in differentiation and responded to dexamethasone (DEX), a typical glucocorticoid receptor (GR, encoded by NR3C1) agonist. Silencing of NR3C1 in hMADS cells or deletion of GR in a transgenic conditional mouse model results in diminished HAND2 expression, establishing that adipocyte HAND2 is regulated by glucocorticoids via GR in vitro and in vivo. Furthermore, we identified gene clusters indirectly regulated by the GR–HAND2 pathway. Interestingly, silencing of HAND2 impaired adipocyte differentiation in hMADS and primary mouse adipocytes. However, a conditional adipocyte Hand2 deletion mouse model using Cre under control of the Adipoq promoter did not mirror these effects on adipose tissue differentiation, indicating that HAND2 was required at stages prior to Adipoq expression. Conclusions/interpretation: In summary, our study identifies HAND2 as a novel obesity-linked adipocyte transcription factor, highlighting new mechanisms of GR-dependent adipogenesis in humans and mice. Data availability: Array data have been submitted to the GEO database at NCBI (GSE148699). Graphical abstract: [Figure not available: see fulltext.] AdipoqCre AU - Giroud, M. AU - Tsokanos, F.-F. AU - Caratti, G.* AU - Kotschi, S.* AU - Khani, S. AU - Jouffe, C. AU - Vogl, E.S. AU - Irmler, M. AU - Glantschnig, C. AU - Gil Lozano, M. AU - Haß, D. AU - Khan, A.A. AU - Rios Garcia, M. AU - Mattijssen, F. AU - Maida, A. AU - Tews, D.* AU - Fischer-Posovszky, P.* AU - Feuchtinger, A. AU - Virtanen, K.A.* AU - Beckers, J. AU - Wabitsch, M.* AU - Uhlenhaut, N.H. AU - Blüher, M. AU - Tuckermann, J.* AU - Scheideler, M. AU - Bartelt, A. AU - Herzig, S. C1 - 62119 C2 - 50560 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - 1850-1865 TI - HAND2 is a novel obesity-linked adipogenic transcription factor regulated by glucocorticoid signalling. JO - Diabetologia VL - 64 IS - 8 PB - Springer PY - 2021 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: We aimed to investigate the association between maternal consumption of gluten-containing foods and other selected foods during late pregnancy and offspring risk of islet autoimmunity (IA) and type 1 diabetes in The Environmental Determinants of Diabetes in the Young (TEDDY) study. METHODS: The TEDDY study recruited children at high genetic risk for type 1 diabetes at birth, and prospectively follows them for the development of IA and type 1 diabetes (n = 8556). A questionnaire on the mother's diet in late pregnancy was completed by 3-4 months postpartum. The maternal daily intake was estimated from a food frequency questionnaire for eight food groups: gluten-containing foods, non-gluten cereals, fresh milk, sour milk, cheese products, soy products, lean/medium-fat fish and fatty fish. For each food, we described the distribution of maternal intake among the four participating countries in the TEDDY study and tested the association of tertile of maternal food consumption with risk of IA and type 1 diabetes using forward selection time-to-event Cox regression. RESULTS: By 28 February 2019, 791 cases of IA and 328 cases of type 1 diabetes developed in TEDDY. There was no association between maternal late-pregnancy consumption of gluten-containing foods or any of the other selected foods and risk of IA, type 1 diabetes, insulin autoantibody-first IA or GAD autoantibody-first IA (all p ≥ 0.01). Maternal gluten-containing food consumption in late pregnancy was higher in Sweden (242 g/day), Germany (247 g/day) and Finland (221 g/day) than in the USA (199 g/day) (pairwise p < 0.05). CONCLUSIONS/INTERPRETATION: Maternal food consumption during late pregnancy was not associated with offspring risk for IA or type 1 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT00279318. AU - Johnson, R.K.* AU - Tamura, R.* AU - Frank, N.* AU - Uusitalo, U.* AU - Yang, J.* AU - Niinistö, S.* AU - Andrén Aronsson, C.* AU - Ziegler, A.-G. AU - Hagopian, W.* AU - Rewers, M.* AU - Toppari, J.* AU - Akolkar, B.* AU - Krischer, J.* AU - Virtanen, S.M.* AU - Norris, J.M.* C1 - 61671 C2 - 50379 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - 1604-1612 TI - Maternal food consumption during late pregnancy and offspring risk of islet autoimmunity and type 1 diabetes. JO - Diabetologia VL - 64 IS - 7 PB - Springer PY - 2021 SN - 0012-186X ER - TY - JOUR AB - Aims/hypothesis: Psychological stress has long been considered a possible trigger of type 1 diabetes, although prospective studies examining the link between psychological stress or life events during pregnancy and the child’s type 1 diabetes risk are rare. The objective of this study was to examine the association between life events during pregnancy and first-appearing islet autoantibodies (IA) in young children, conditioned by the child’s type 1 diabetes-related genetic risk. Methods: The IA status of 7317 genetically at-risk The Environmental Determinants of Diabetes in the Young (TEDDY) participants was assessed every 3 months from 3 months to 4 years, and bi-annually thereafter. Reports of major life events during pregnancy were collected at study inception when the child was 3 months of age and placed into one of six categories. Life events during pregnancy were examined for association with first-appearing insulin (IAA) (N = 222) or GAD (GADA) (N = 209) autoantibodies in the child until 6 years of age using proportional hazard models. Relative excess risk due to interaction (RERI) by the child’s HLA-DR and SNP profile was estimated. Results: Overall, 65% of mothers reported a life event during pregnancy; disease/injury (25%), serious interpersonal (28%) and job-related (25%) life events were most common. The association of life events during pregnancy differed between IAA and GADA as the first-appearing autoantibody. Serious interpersonal life events correlated with increased risk of GADA-first only in HLA-DR3 children with the BACH2-T allele (HR 2.28, p < 0.0001), an additive interaction (RERI 1.87, p = 0.0004). Job-related life events were also associated with increased risk of GADA-first among HLA-DR3/4 children (HR 1.53, p = 0.04) independent of serious interpersonal life events (HR 1.90, p = 0.002), an additive interaction (RERI 1.19, p = 0.004). Job-related life events correlated with reduced risk of IAA-first (HR 0.55, p = 0.004), particularly in children with the BTNL2-GG allele (HR 0.48; 95% CI 0.31, 0.76). Conclusions/interpretation: Specific life events during pregnancy are differentially related to IAA vs GADA as first-appearing IA and interact with different HLA and non-HLA genetic factors, supporting the concept of different endotypes underlying type 1 diabetes. However, the mechanisms underlying these associations remain to be discovered. Life events may be markers for other yet-to-be-identified factors important to the development of first-appearing IA. Graphical abstract: [Figure not available: see fulltext.] AU - Johnson, S.B.* AU - Lynch, K.F.* AU - Roth, R.* AU - Lundgren, M.* AU - Parikh, H.M.* AU - Akolkar, B.* AU - Hagopian, W.* AU - Krischer, J.* AU - Rewers, M.* AU - She, J.X.* AU - Toppari, J.* AU - Ziegler, A.-G. AU - Lernmark, Å.* C1 - 60926 C2 - 49988 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - 591-602 TI - First-appearing islet autoantibodies for type 1 diabetes in young children: Maternal life events during pregnancy and the child’s genetic risk. JO - Diabetologia VL - 64 IS - 3 PB - Springer PY - 2021 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: Prognostic factors and characteristics of children diagnosed with type 1 diabetes before 6 years of age were compared with those diagnosed at 6-13 years of age in the TEDDY study. METHODS: Genetically high-risk children (n = 8502) were followed from birth for a median of 9.9 years; 328 (3.9%) were diagnosed with type 1 diabetes. Cox proportional hazard model was used to assess the association of prognostic factors with the risk of type 1 diabetes in the two age groups. RESULTS: Children in the younger group tended to develop autoantibodies earlier than those in the older group did (mean age 1.5 vs 3.5 years), especially insulin autoantibodies (IAA), which developed earlier than GAD autoantibodies (GADA). Children in the younger group also progressed to diabetes more rapidly than the children in the older group did (mean duration 1.9 vs 5.4 years). Children with autoantibodies first appearing against insulinoma antigen-2 (IA-2A) were found only in the older group. The significant diabetes risk associated with the country of origin in the younger group was no longer significant in the older group. Conversely, the diabetes risk associated with HLA genotypes was statistically significant also in the older group. Initial seroconversion after and before 2 years of age was associated with decreased risk for diabetes diagnosis in children positive for multiple autoantibodies, but the diabetes risk did not decrease further with increasing age if initial seroconversion occurred after age 2. Diabetes risk associated with the minor alleles of rs1004446 (INS) was decreased in both the younger and older groups compared with other genotypes (HR 0.67). Diabetes risk was significantly increased with the minor alleles of rs2476601 (PTPN22) (HR 2.04 and 1.72), rs428595 (PPIL2) (HR 2.13 and 2.10), rs113306148 (PLEKHA1) (HR 2.34 and 2.21) and rs73043122 (RNASET2) (HR 2.31 and 2.54) (HR values represent the younger and older groups, respectively). CONCLUSIONS/INTERPRETATIONS: Diabetes at an early age is likely to be preceded by IAA autoantibodies and is a more aggressive form of the disease. Among older children, once multiple autoantibodies have been observed there does not seem to be any association between progression to diabetes and the age of the child or family history. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00279318. AU - Krischer, J.P.* AU - Liu, X.* AU - Lernmark, Å.* AU - Hagopian, W.A.* AU - Rewers, M.J.* AU - She, J.X.* AU - Toppari, J.* AU - Ziegler, A.-G. AU - Akolkar, B.* C1 - 62640 C2 - 50989 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - 2247-2257 TI - Characteristics of children diagnosed with type 1 diabetes before vs after 6 years of age in the TEDDY cohort study. JO - Diabetologia VL - 64 IS - 10 PB - Springer PY - 2021 SN - 0012-186X ER - TY - JOUR AB - Aims/hypothesis: The individual risk of progression of diabetic peripheral neuropathy is difficult to predict for each individual. Mutations in proteins that are responsible for the process of myelination are known to cause neurodegeneration and display alteration in experimental models of diabetic neuropathy. In a prospective observational human pilot study, we investigated myelin-specific circulating mRNA targets, which have been identified in vitro, for their capacity in the diagnosis and prediction of diabetic neuropathy. The most promising candidate was tested against the recently established biomarker of neural damage, neurofilament light chain protein. Methods: Schwann cells were cultured under high-glucose conditions and mRNAs of various myelin-specific genes were screened intra- and extracellularly. Ninety-two participants with type 2 diabetes and 30 control participants were enrolled and evaluated for peripheral neuropathy using neuropathy deficit scores, neuropathy symptom scores and nerve conduction studies as well as quantitative sensory testing at baseline and after 12/24 months of a follow-up period. Magnetic resonance neurography of the sciatic nerve was performed in 37 individuals. Neurofilament light chain protein and four myelin-specific mRNA transcripts derived from in vitro screenings were measured in the serum of all participants. The results were tested for associations with specific neuropathic deficits, fractional anisotropy and the progression of neuropathic deficits at baseline and after 12 and 24 months. Results: In neuronal Schwann cells and human nerve sections, myelin protein zero was identified as the strongest candidate for a biomarker study. Circulating mRNA of myelin protein zero was decreased significantly in participants with diabetic neuropathy (p < 0.001), whereas neurofilament light chain protein showed increased levels in participants with diabetic neuropathy (p < 0.05). Both variables were linked to altered electrophysiology, fractional anisotropy and quantitative sensory testing. In a receiver-operating characteristic curve analysis myelin protein zero improved the diagnostic performance significantly in combination with a standard model (diabetes duration, age, BMI, HbA1c) from an AUC of 0.681 to 0.836 for the detection of diabetic peripheral neuropathy. A follow-up study revealed that increased neurofilament light chain was associated with the development of a hyperalgesic phenotype (p < 0.05), whereas decreased myelin protein zero predicted hypoalgesia (p < 0.001) and progressive loss of nerve function 24 months in advance (HR of 6.519). Conclusions/interpretation: This study introduces a dynamic and non-invasive assessment strategy for the underlying pathogenesis of diabetic peripheral neuropathy. The diagnosis of axonal degeneration, associated with hyperalgesia, and demyelination, linked to hypoalgesia, could benefit from the usage of neurofilament light chain protein and circulating mRNA of myelin protein zero as potential biomarkers. Graphical abstract: [Figure not available: see fulltext.] AU - Morgenstern, J.* AU - Groener, J.B.* AU - Jende, J.M.E.* AU - Kurz, F.T.* AU - Strom, A.* AU - Göpfert, J.* AU - Kender, Z.* AU - Le Marois, M.* AU - Brune, M.* AU - Kuner, R.* AU - Herzig, S. AU - Roden, M.* AU - Ziegler, D.* AU - Bendszus, M.* AU - Szendroedi, J.* AU - Nawroth, P.P. AU - Kopf, S.* AU - Fleming, T.* C1 - 62936 C2 - 51177 CY - One New York Plaza, Suite 4600, New York, Ny, United States TI - Neuron-specific biomarkers predict hypo- and hyperalgesia in individuals with diabetic peripheral neuropathy. JO - Diabetologia PB - Springer PY - 2021 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: Individuals with type 2 diabetes mellitus and subclinical inflammation have stimulated coagulation, activated platelets and endothelial dysfunction. Recent studies with the direct factor Xa inhibitor rivaroxaban in combination with low-dose aspirin demonstrated a significant reduction of major cardiovascular events, especially in individuals with type 2 diabetes and proven cardiovascular disease. Therefore, we asked the question of whether treatment with rivaroxaban could influence endothelial function, arterial stiffness and platelet activation. METHODS: We conducted a multi-centre, prospective, randomised, open-label trial in 179 participants with type 2 diabetes (duration 2-20 years), subclinical inflammation (high-sensitivity C-reactive protein 2-10 mg/l) and at least two traits of the metabolic syndrome to compare the effects of the direct factor Xa inhibitor rivaroxaban (5 mg twice daily) vs aspirin (100 mg every day) on endothelial function (assessed by forearm occlusion plethysmography), skin blood flow (assessed by laser-Doppler fluxmetry), arterial stiffness (assessed by pulse wave velocity) and serum biomarkers of endothelial function and inflammation. Furthermore, we investigated phosphorylation of vasodilator-stimulated phosphoprotein (VASP) in platelets, the concentration of platelet-derived microparticles (PMPs) and the effects of isolated PMPs on HUVEC proliferation in vitro. RESULTS: Rivaroxaban treatment for 20 weeks (n = 89) resulted in a significant improvement of post-ischaemic forearm blood flow (3.6 ± 4.7 vs 1.0 ± 5.2 ml/100 ml, p = 0.004), a numerically increased skin blood flow and reduced soluble P-Selectin plasma level vs aspirin. We did not find significant differences of arterial stiffness or further biomarkers. Neither rivaroxaban nor aspirin influenced VASP phosphorylation of platelets. The number of PMPs increased significantly with both rivaroxaban (365.2 ± 372.1 vs 237.4 ± 157.1 μl-1, p = 0.005) and aspirin (266.0 ± 212.7 vs 201.7 ± 162.7 μl-1, p = 0.021). PMPs of rivaroxaban-treated participants stimulated HUVEC proliferation in vitro compared with aspirin. Rivaroxaban was associated with a higher number of bleeding events. CONCLUSIONS/INTERPRETATION: Our findings indicate that the direct factor Xa inhibitor rivaroxaban improved endothelial function in participants with type 2 diabetes and subclinical inflammation but also increased the risk of bleeding. TRIAL REGISTRATION: ClinicalTrials.gov NCT02164578. FUNDING: The study was supported by a research grant from Bayer Vital AG, Germany. AU - Pistrosch, F.* AU - Matschke, J.B.* AU - Schipp, D.* AU - Schipp, B.* AU - Henkel, E.* AU - Weigmann, I.* AU - Sradnick, J.* AU - Bornstein, S.R.* AU - Birkenfeld, A.L. AU - Hanefeld, M.* C1 - 62945 C2 - 51196 CY - One New York Plaza, Suite 4600, New York, Ny, United States TI - Rivaroxaban compared with low-dose aspirin in individuals with type 2 diabetes and high cardiovascular risk: A randomised trial to assess effects on endothelial function, platelet activation and vascular biomarkers. JO - Diabetologia PB - Springer PY - 2021 SN - 0012-186X ER - TY - JOUR AU - Achenbach, P. AU - Anand, V.* AU - Dunne, J.L.* AU - Hagopian, W.* AU - Kwon, B.* AU - Lundgren, M.* AU - Veijola, R.* AU - Frohnert, B.I.* C1 - 60109 C2 - 49859 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - S160-S160 TI - Heterogeneous islet autoantibody evolution trajectories in multi-site birth cohort studies. JO - Diabetologia VL - 63 PB - Springer PY - 2020 SN - 0012-186X ER - TY - JOUR AU - Anand, V.* AU - Achenbach, P. AU - Dunne, J.L.* AU - Hagopian, W.* AU - Kwon, B.* AU - Lundgren, M.* AU - Veijola, R.* AU - Frohnert, B.I.* C1 - 60107 C2 - 49857 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - S101-S102 TI - Visualising heterogeneous islet autoantibody trajectories of children who develope type 1 diabetes from multi-site birth cohort studies. JO - Diabetologia VL - 63 PB - Springer PY - 2020 SN - 0012-186X ER - TY - JOUR AU - Barovic, M. AU - Steinmeyer, K.* AU - Burdet, F.* AU - Forberger, A.* AU - Schöniger, E. AU - Richter, D. AU - Kipke, N. AU - Ibberson, M.* AU - Aust, D.* AU - Schulte, A.* AU - Solimena, M. C1 - 60119 C2 - 49867 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - S163-S164 TI - Exploring islet amyloidosis in type 2 diabetes in metabolically profiled pancreatectomised surgical donors. JO - Diabetologia VL - 63 PB - Springer PY - 2020 SN - 0012-186X ER - TY - JOUR AU - Bauer, I. AU - Schleger, F. AU - Fritsche, L. AU - Schneider, N. AU - Breuer, M. AU - Weiss, M.* AU - Pauluschke-Froehlich, J.* AU - Birkenfeld, A.L.* AU - Heni, M.* AU - Preissl, H. AU - Fritsche, A.* C1 - 60100 C2 - 49852 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - S211-S212 TI - Maternal mental state correlates with maternal insulin sensitivity and interleukin-6 levels in late pregnancy. JO - Diabetologia VL - 63 PB - Springer PY - 2020 SN - 0012-186X ER - TY - JOUR AU - Bovy, N.* AU - Boitard, C.* AU - Achenbach, P. AU - Leslie, R.D.* AU - Dayan, C.* AU - Keymeulen, B.* AU - Owen, K.R.* AU - Carlier, V.* AU - Van Mechelen, M.* AU - Van Rampelbergh, J.* C1 - 60104 C2 - 49855 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - S26-S27 TI - Long-term follow-up study of type 1 diabetes patients previously treated with IMCY-0098 or placebo in young adults with recent-onset type 1 diabetes. JO - Diabetologia VL - 63 PB - Springer PY - 2020 SN - 0012-186X ER - TY - JOUR AU - Brings, S.* AU - Fleming, T.* AU - Herzig, S. AU - Nawroth, P.P.* AU - Kopf, S.* C1 - 60111 C2 - 49861 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - S384-S385 TI - Urinary cathepsin levels are predictive of the improvement of albuminuria and are associated with elevated excretion of free glucosepane. JO - Diabetologia VL - 63 PB - Springer PY - 2020 SN - 0012-186X ER - TY - JOUR AU - Cobo-Vuilleumier, N.* AU - Martin-Vazquez, E.* AU - Lorenzo, P.I.* AU - Diaz-Contreras, I.* AU - Martin, F.* AU - Gerdes, J.M. AU - Ferrer, J.* AU - Romero-Zerbo, Y.S.* AU - Garcia, M.* AU - Bermudez-Silva, F.J.* AU - Gannon, M.* AU - Collombat, P.* AU - Gauthier, B.R.* C1 - 60113 C2 - 49863 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - S182-S183 TI - Lrh1/nr5a2 conveys the anti-diabetic effects of the agonist bl001 and promotes alpha-to-beta-cell conversion in streptozotocin-treated mice. JO - Diabetologia VL - 63 PB - Springer PY - 2020 SN - 0012-186X ER - TY - JOUR AU - De Luca, C.* AU - Suleiman, M.* AU - Schulte, A.M.* AU - Eizirik, D.L.* AU - Tesi, M.* AU - Baronti, W.* AU - Bosi, E.* AU - Solimena, M. AU - Cnop, M.* AU - Marchetti, P.* AU - Marselli, L.* C1 - 60114 C2 - 49864 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - S179-S179 TI - Factors affecting function of human pancreatic islets after isolation. JO - Diabetologia VL - 63 PB - Springer PY - 2020 SN - 0012-186X ER - TY - JOUR AU - Gallegos, P.A. AU - Balcacean, D. AU - Zapardiel-Gonzalo, J. AU - Richardson, S.* AU - Akhbari, P.* AU - Morgan, N.* AU - Nelson, G.* AU - Gerling, I.* AU - Kusmartseva, I.* AU - Pugliese, A.* AU - Rodriguez-Calvo, T. C1 - 60103 C2 - 49854 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - S157-S157 TI - Presence of markers associated with viral infections in the pancreas before and after onset of type 1 diabetes. JO - Diabetologia VL - 63 PB - Springer PY - 2020 SN - 0012-186X ER - TY - JOUR AU - Ghalwash, M.* AU - Anand, V.* AU - Hagopian, W.* AU - Lundgren, M.* AU - Rewers, M.* AU - Veijola, R.* AU - Ziegler, A.-G. AU - Dunne, J.* C1 - 60117 C2 - 49866 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - S181-S181 TI - Optimal ages for screening for type 1 diabetes risk in children. JO - Diabetologia VL - 63 PB - Springer PY - 2020 SN - 0012-186X ER - TY - JOUR AU - Hummel, J. AU - Benkendorff, C. AU - Vosseler, A. AU - Fritsche, L. AU - Kullmann, S. AU - Birkenfeld, A.L. AU - Preissl, H. AU - Häring, H.-U. AU - Fritsche, A. AU - Peter, A. AU - Wagner, R. AU - Heni, M. C1 - 60123 C2 - 49871 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - S14-S14 TI - Brain insulin sensitivity is modulated by menstrual cycle. JO - Diabetologia VL - 63 PB - Springer PY - 2020 SN - 0012-186X ER - TY - JOUR AB - Aims/hypothesis Treatment with the alpha 3 beta 4 nicotinic acetylcholine receptor (nAChR) agonist, 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP), improves glucose tolerance in diet-induced obese (DIO) mice, but the physiological and molecular mechanisms are unknown. Methods DMPP (10 mg/kg body weight, s.c.) was administered either in a single injection (acute) or daily for up to 14 days (chronic) in DIO wild-type (WT) and Chrnb4 knockout (KO) mice and glucose tolerance, tissue-specific tracer-based glucose metabolism, and insulin signalling were assessed. Results In WT mice, but not in Chrnb4 KO mice, single acute treatment with DMPP induced transient hyperglycaemia, which was accompanied by high plasma adrenaline (epinephrine) levels, upregulated hepatic gluconeogenic genes, and decreased hepatic glycogen content. In contrast to these acute effects, chronic DMPP treatment in WT mice elicited improvements in glucose tolerance already evident after three consecutive days of DMPP treatment. After seven days of DMPP treatment, glucose tolerance was markedly improved, also in comparison with mice that were pair-fed to DMPP-treated mice. The glycaemic benefit of chronic DMPP was absent in Chrnb4 KO mice. Chronic DMPP increased insulin-stimulated glucose clearance into brown adipose tissue (+69%), heart (+93%), gastrocnemius muscle (+74%) and quadriceps muscle (+59%), with no effect in white adipose tissues. After chronic DMPP treatment, plasma adrenaline levels did not increase following an injection with DMPP. In glucose-stimulated skeletal muscle, we detected a decreased phosphorylation of the inhibitory Ser640 phosphorylation site on glycogen synthase and a congruent increase in glycogen accumulation following chronic DMPP treatment. Conclusions/interpretation Our data suggest that DMPP acutely induces adrenaline release and hepatic glycogenolysis, while chronic DMPP-mediated activation of beta 4-containing nAChRs improves peripheral insulin sensitivity independently of changes in body weight via mechanisms that could involve increased non-oxidative glucose disposal into skeletal muscle. AU - Jall, S. AU - de Angelis, M. AU - Lundsgaard, A.M.* AU - Fritzen, A.M.* AU - Nicolaisen, T.S.* AU - Klein, A.B.* AU - Novikoff, A. AU - Sachs, S. AU - Richter, E.A.* AU - Kiens, B.* AU - Schramm, K.-W. AU - Tschöp, M.H. AU - Stemmer, K. AU - Clemmensen, C. AU - Müller, T.D. AU - Kleinert, M. C1 - 58538 C2 - 48228 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - 1236-1247 TI - Pharmacological targeting of α3β4 nicotinic receptors improves peripheral insulin sensitivity in mice with diet-induced obesity. JO - Diabetologia VL - 63 IS - 6 PB - Springer PY - 2020 SN - 0012-186X ER - TY - JOUR AU - Khamis, A.* AU - Canouil, M.* AU - Marselli, L.* AU - Boutry, R.* AU - Suleiman, M. AU - Jonckheere, N.* AU - Schulte, A.M.* AU - Solimena, M.* AU - Bonnefond, A.* AU - Van Seuningen, I.* AU - Ibberson, M.* AU - Joerns, A.* AU - Lenzen, S.* AU - Marchetti, P.* AU - Froguel, P.* C1 - 60126 C2 - 49872 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - S109-S109 TI - Pnliprp1 hypermethylation in human exocrine pancreas reveals a link between diabetes and pancreatic cancer. JO - Diabetologia VL - 63 PB - Springer PY - 2020 SN - 0012-186X ER - TY - JOUR AB - Aims/hypothesis: It is well established that physical activity, abdominal ectopic fat and glycaemic regulation are related but the underlying structure of these relationships is unclear. The previously proposed twin-cycle hypothesis (TC) provides a mechanistic basis for impairment in glycaemic control through the interactions of substrate availability, substrate metabolism and abdominal ectopic fat accumulation. Here, we hypothesise that the effect of physical activity in glucose regulation is mediated by the twin-cycle. We aimed to examine this notion in the Innovative Medicines Initiative Diabetes Research on Patient Stratification (IMI DIRECT) Consortium cohorts comprised of participants with normal or impaired glucose regulation (cohort 1: N ≤ 920) or with recently diagnosed type 2 diabetes (cohort 2: N ≤ 435). Methods: We defined a structural equation model that describes the TC and fitted this within the IMI DIRECT dataset. A second model, twin-cycle plus physical activity (TC-PA), to assess the extent to which the effects of physical activity in glycaemic regulation are mediated by components in the twin-cycle, was also fitted. Beta cell function, insulin sensitivity and glycaemic control were modelled from frequently sampled 75 g OGTTs (fsOGTTs) and mixed-meal tolerance tests (MMTTs) in participants without and with diabetes, respectively. Abdominal fat distribution was assessed using MRI, and physical activity through wrist-worn triaxial accelerometry. Results are presented as standardised beta coefficients, SE and p values, respectively. Results: The TC and TC-PA models showed better fit than null models (TC: χ2 = 242, p = 0.004 and χ2 = 63, p = 0.001 in cohort 1 and 2, respectively; TC-PA: χ2 = 180, p = 0.041 and χ2 = 60, p = 0.008 in cohort 1 and 2, respectively). The association of physical activity with glycaemic control was primarily mediated by variables in the liver fat cycle. Conclusions/interpretation: These analyses partially support the mechanisms proposed in the twin-cycle model and highlight mechanistic pathways through which insulin sensitivity and liver fat mediate the association between physical activity and glycaemic control. AU - Koivula, R.W.* AU - Atabaki-Pasdar, N.* AU - Giordano, G.N.* AU - White, T.* AU - Adamski, J. AU - Bell, J.D.* AU - Beulens, J.* AU - Brage, S.* AU - Brunak, S.* AU - De Masi, F.* AU - Dermitzakis, E.T.* AU - Forgie, I.M.* AU - Frost, G.* AU - Hansen, T.* AU - Hansen, T.H.* AU - Hattersley, A.* AU - Kokkola, T.* AU - Kurbasic, A.* AU - Laakso, M.* AU - Mari, A.* AU - McDonald, T.J.* AU - Pedersen, O.* AU - Rutters, F.* AU - Schwenk, J.M.* AU - Teare, H.J.A.* AU - Thomas, E.L.* AU - Viñuela, A.* AU - Mahajan, A.* AU - McCarthy, M.I.* AU - Ruetten, H.* AU - Walker, M.* AU - Pearson, E.* AU - Pavo, I.* AU - Franks, P.W.* C1 - 58787 C2 - 48322 SP - 744-756 TI - The role of physical activity in metabolic homeostasis before and after the onset of type 2 diabetes: An IMI DIRECT study. JO - Diabetologia VL - 63 IS - 4 PY - 2020 SN - 0012-186X ER - TY - JOUR AB - © 2020, Springer-Verlag GmbH Germany, part of Springer Nature. Unfortunately, ‘Present address’ was omitted from one of the addresses provided for Mark I. McCarthy (#26). The corrected address details are given on the following page. AU - Koivula, R.W.* AU - Atabaki-Pasdar, N.* AU - Giordano, G.N.* AU - White, T.* AU - Adamski, J. AU - Bell, J.D.* AU - Beulens, J.* AU - Brage, S.* AU - Brunak, S.* AU - De Masi, F.* AU - Dermitzakis, E.T.* AU - Forgie, I.M.* AU - Frost, G.* AU - Hansen, T.* AU - Hansen, T.H.* AU - Hattersley, A.* AU - Kokkola, T.* AU - Kurbasic, A.* AU - Laakso, M.* AU - Mari, A.* AU - McDonald, T.J.* AU - Pedersen, O.* AU - Rutters, F.* AU - Schwenk, J.M.* AU - Teare, H.J.A.* AU - Thomas, E.L.* AU - Viñuela, A.* AU - Mahajan, A.* AU - McCarthy, M.I.* AU - Ruetten, H.* AU - Walker, M.* AU - Pearson, E.* AU - Pavo, I.* AU - Franks, P.W.* C1 - 60540 C2 - 50219 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - 260-261 TI - Correction to: The role of physical activity in metabolic homeostasis before and after the onset of type 2 diabetes: an IMI DIRECT study (Diabetologia, (2020), 63, 4, (744-756), 10.1007/s00125-019-05083-6). JO - Diabetologia VL - 64 IS - 1 PB - Springer PY - 2020 SN - 0012-186X ER - TY - JOUR AU - Kullmann, S. AU - Wagner, R. AU - Hummel, J. AU - Dannecker, C. AU - Vosseler, A. AU - Fritsche, L. AU - Kantartzis, K. AU - Machann, J. AU - Häring, H.-U. AU - Fritsche, A. AU - Preissl, H. AU - Heni, M. C1 - 60101 C2 - 49851 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - S13-S14 TI - Empagliflozin improves insulin sensitivity of the hypothalamus in humans with prediabetes. JO - Diabetologia VL - 63 PB - Springer PY - 2020 SN - 0012-186X ER - TY - JOUR AU - Kwon, B.* AU - Achenbach, P. AU - Anand, V.* AU - Dunne, J.L.* AU - Hagopian, W.* AU - Lundgren, M.* AU - Veijola, R.* AU - Frohnert, B.I.* C1 - 60108 C2 - 49858 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - S159-S159 TI - A visual analytics method to explore the evolution of autoantibodies during progression to type 1 diabetes in multi-site birth cohort studies. JO - Diabetologia VL - 63 PB - Springer PY - 2020 SN - 0012-186X ER - TY - JOUR AU - Lamprinou, A.* AU - Machann, J.* AU - Schick, F.* AU - Eckstein, S.S. AU - Man, C.D.* AU - Visentin, R.* AU - Stefan, N.* AU - Birkenfeld, A.L.* AU - Peter, A.* AU - Häring, H.-U. AU - Fritsche, A.* AU - Heni, M.* AU - Wagner, R.* C1 - 60110 C2 - 49860 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - S36-S37 TI - Evaluation of determinants of hepatic insulin clearance: a Mendelian randomisation study. JO - Diabetologia VL - 63 PB - Springer PY - 2020 SN - 0012-186X ER - TY - JOUR AU - Marinicova, Z. AU - Ghosh, M.* AU - Knoch, K.-P. AU - Petzold, A. AU - Wegbrod, C. AU - Soenmez, A. AU - Scharfmann, R.* AU - Stevanovic, S.* AU - Solimena, M. C1 - 60102 C2 - 49853 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - S111-S111 TI - Presentation of insulin granule derived peptides on MHC I in Enterovirus-infected beta cells and type 1 diabetes. JO - Diabetologia VL - 63 PB - Springer PY - 2020 SN - 0012-186X ER - TY - JOUR AB - Aims/hypothesis We studied the association of plasma ascorbic acid with the risk of developing islet autoimmunity and type 1 diabetes and examined whether SNPs in vitamin C transport genes modify these associations. Furthermore, we aimed to determine whether the SNPs themselves are associated with the risk of islet autoimmunity or type 1 diabetes. Methods We used a risk set sampled nested case-control design within an ongoing international multicentre observational study: The Environmental Determinants of Diabetes in the Young (TEDDY). The TEDDY study followed children with increased genetic risk from birth to endpoints of islet autoantibodies (350 cases, 974 controls) and type 1 diabetes (102 cases, 282 controls) in six clinical centres. Control participants were matched for family history of type 1 diabetes, clinical centre and sex. Plasma ascorbic acid concentration was measured at ages 6 and 12 months and then annually up to age 6 years. SNPs in vitamin C transport genes were genotyped using the ImmunoChip custom microarray. Comparisons were adjusted for HLA genotypes and for background population stratification. Results Childhood plasma ascorbic acid (mean +/- SD 10.76 +/- 3.54 mg/l in controls) was inversely associated with islet autoimmunity risk (adjusted OR 0.96 [95% CI 0.92, 0.99] per +1 mg/l), particularly islet autoimmunity, starting with insulin autoantibodies (OR 0.94 [95% CI 0.88, 0.99]), but not with type 1 diabetes risk (OR 0.93 [95% Cl 0.86, 1.02]). The SLC2A2 rs5400 SNP was associated with increased risk of type 1 diabetes (OR 1.77 [95% CI 1.12, 2.80]), independent of plasma ascorbic acid (OR 0.92 [95% CI 0.84, 1.00]). Conclusions/interpretation Higher plasma ascorbic acid levels may protect against islet autoimmunity in children genetically at risk for type 1 diabetes. Further studies are warranted to confirm these findings. Data availability The datasets generated and analysed during the current study will be made available in the NIDDK Central Repository at . AU - Mattila, M.* AU - Erlund, I.* AU - Lee, H.S.* AU - Niinistö, S.* AU - Uusitalo, U.* AU - Andrén Aronsson, C.* AU - Hummel, S. AU - Parikh, H.* AU - Rich, S.S.* AU - Hagopian, W.* AU - Toppari, J.* AU - Lernmark, Å.* AU - Ziegler, A.-G. AU - Rewers, M.* AU - Krischer, J.P.* AU - Norris, J.M.* AU - Virtanen, S.M.* C1 - 57352 C2 - 47736 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - 278-286 TI - Plasma ascorbic acid and the risk of islet autoimmunity and type 1 diabetes: The TEDDY study. JO - Diabetologia VL - 63 IS - 2 PB - Springer PY - 2020 SN - 0012-186X ER - TY - JOUR AU - Oquendo, M.B. AU - Lorza-Gil, E. AU - Gerst, F. AU - Fend, F.* AU - Koenigsrainer, A.* AU - Wagner, R. AU - Heni, M. AU - Häring, H.-U. AU - Birkenfeld, A.L. AU - Ullrich, S. AU - Siegel-Axel, D. C1 - 60120 C2 - 49869 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - S254-S255 TI - Comparison between in vitro differentiation of pancreatic and subcutaneous adipocytes of subjects with normal glucose tolerance. JO - Diabetologia VL - 63 PB - Springer PY - 2020 SN - 0012-186X ER - TY - JOUR AU - Scarale, M.* AU - De Cosmo, S.* AU - Prehn, C. AU - Schena, F.* AU - Adamski, J. AU - Trischitta, V.* AU - Menzaghi, C.* C1 - 60095 C2 - 49848 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - S3-S3 TI - Circulating metabolites significantly improve the prediction of renal dysfunction in type 2 diabetes. JO - Diabetologia VL - 63 PB - Springer PY - 2020 SN - 0012-186X ER - TY - JOUR AU - Scarale, M.* AU - De Cosmo, S.* AU - Prehn, C. AU - Schena, F.* AU - Adamski, J. AU - Trischitta, V.* AU - Menzaghi, C.* C1 - 60096 C2 - 49849 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - S3-S4 TI - Building clinical risk score systems for predicting all-cause and cardiovascular-specific mortality among type 2 diabetes patients. JO - Diabetologia VL - 63 IS - 1 PB - Springer PY - 2020 SN - 0012-186X ER - TY - JOUR AU - Suleiman, M.* AU - De Luca, C.* AU - Schulte, A.M.* AU - Eizirik, D.L.* AU - Tesi, M.* AU - Gianetti, E.* AU - Solimena, M. AU - Bosi, E.* AU - Cnop, M.* AU - Marchetti, P.* AU - Marselli, L.* C1 - 60112 C2 - 49862 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - S196-S196 TI - Glucose-lowering therapy and ex-vivo beta cell function in type 2 diabetes. JO - Diabetologia VL - 63 PB - Springer PY - 2020 SN - 0012-186X ER - TY - JOUR AU - van Krieken, P.P.* AU - Odermatt, T.S.* AU - Blüher, M. AU - Wueest, S.* AU - Konrad, D.* C1 - 60106 C2 - 49856 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - S21-S22 TI - Oncostatin M inhibits browning of white adipose tissue via gp130 signalling. JO - Diabetologia VL - 63 PB - Springer PY - 2020 SN - 0012-186X ER - TY - JOUR AB - The discovery of insulin in 1921 has been one of greatest scientific achievements of the 20th century. Since then, the availability of insulin has shifted the focus of diabetes treatment from trying to keep patients alive to saving and improving the life of millions. Throughout this time, basic and clinical research has advanced our understanding of insulin synthesis and action, both in healthy and pathological conditions. Yet, multiple aspects of insulin production remain unknown. In this review, we focus on the most recent findings on insulin synthesis, highlighting their relevance in diabetes.Graphical abstract AU - Vasiljevic, J. AU - Torkko, J.M. AU - Knoch, K.-P. AU - Solimena, M. C1 - 60037 C2 - 49181 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - 1981-1989 TI - The making of insulin in health and disease. JO - Diabetologia VL - 63 IS - 10 PB - Springer PY - 2020 SN - 0012-186X ER - TY - JOUR AU - Vasiljevic, J. AU - Vasiljevic, D.* AU - Niehage, C.* AU - Wegbrod, C. AU - Ganss, K. AU - Soenmez, A. AU - Friedrich, A. AU - Hoflack, B.* AU - Selbach, M.* AU - Solimena, M. C1 - 60121 C2 - 49868 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - S7-S8 TI - Post-transcriptional co-regulation of insulin secretory granule proteins. JO - Diabetologia VL - 63 PB - Springer PY - 2020 SN - 0012-186X ER - TY - JOUR AU - Vosseler, A. AU - Fritsche, L. AU - Hummel, J. AU - Dannecker, C. AU - Stefan, N. AU - Birkenfeld, A.L. AU - Häring, H.-U. AU - Fritsche, A. AU - Wagner, R. AU - Heni, M. C1 - 60099 C2 - 49850 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - S258-S258 TI - Postprandial thermogenesis is reduced in obesity. JO - Diabetologia VL - 63 PB - Springer PY - 2020 SN - 0012-186X ER - TY - JOUR AU - Wagner, L. AU - Kullmann, S. AU - Veit, R. AU - Schneeweiss, P.* AU - Niess, A.* AU - Preissl, H. AU - Birkenfeld, A.L. AU - Peter, A. AU - Häring, H.-U. AU - Böhm, A. AU - Weigert, C. AU - Heni, M. C1 - 60115 C2 - 49865 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - S98-S98 TI - Exercise changes neuronal processing of food cues in sedentary overweight and obese adults. JO - Diabetologia VL - 63 PB - Springer PY - 2020 SN - 0012-186X ER - TY - JOUR AU - Wigger, L.* AU - Barovic, M. AU - Brunner, A.D.* AU - Marzetta, F.* AU - Schöniger, E. AU - Mehl, F.* AU - Kipke, N. AU - Simons, K.* AU - Distler, M.* AU - Schulte, A.M.* AU - Mann, M.* AU - Ibberson, M.* AU - Solimena, M. C1 - 60122 C2 - 49870 CY - One New York Plaza, Suite 4600, New York, Ny, United States SP - S106-S106 TI - Cross-sectional multi-omics insight from islet and plasma samples into the progression to type 2 diabetes in metabolically profiled pancreatectomised surgical donors. JO - Diabetologia VL - 63 PB - Springer PY - 2020 SN - 0012-186X ER - TY - JOUR AU - Ziegler, A.-G. AU - Bonifacio, E. C1 - 59207 C2 - 48669 CY - One New York Plaza, Suite 4600, New York, Ny, United States TI - Why is the presence of autoantibodies against GAD associated with a relatively slow progression to clinical diabetes? JO - Diabetologia PB - Springer PY - 2020 SN - 0012-186X ER - TY - JOUR AB - Aims/hypothesis The beta cell protein tetraspanin 7 is a target of autoantibodies in individuals with type 1 diabetes. The aim of this study was to identify autoantibody epitope-containing regions and key residues for autoantibody binding.Methods Autoantibody epitope regions were identified by immunoprecipitation of luciferase-tagged single or multiple tetraspanin 7 domains using tetraspanin 7 antibody-positive sera. Subsequently, amino acids (AAs) relevant for autoantibody binding were identified by single AA mutations.Results In tetraspanin 7 antibody-positive sera, antibody binding was most frequent to tetraspanin 7 proteins that contained the NH2-terminal cytoplasmic domain 1 (C1; up to 39%) or COOH-terminal C3 (up to 22%). Binding to C3 was more frequent when the domain was expressed along with the flanking transmembrane domain, suggesting that conformation is likely to be important. Binding to external domains was not observed. Single AA mutations of C3 identified residues Y246, E247 and R239 as critical for COOH-terminal binding of 9/10, 10/10 and 8/10 sera tested, respectively. Mutation of cysteines adjacent to the transmembrane domain at either residues C235 or C236 resulted in both decreased (8/178 and 15/178 individuals, respectively; >twofold decrease) and increased (30/178 and 13/178 individuals, respectively; >twofold increase) binding in participant sera vs wild-type protein.Conclusions/interpretation We hypothesise that conformation and, potentially, modification of protein terminal ends of tetraspanin 7 may be important for autoantibody binding in type 1 diabetes. AU - Eugster, A.* AU - Kraus, G.* AU - Lidzba, V.* AU - Müller, D.* AU - Jolink, M. AU - Ziegler, A.-G. AU - Bonifacio, E. C1 - 55873 C2 - 46645 CY - 233 Spring St, New York, Ny 10013 Usa SP - 805-810 TI - Cytoplasmic ends of tetraspanin 7 harbour epitopes recognised by autoantibodies in type 1 diabetes. JO - Diabetologia VL - 62 IS - 5 PB - Springer PY - 2019 SN - 0012-186X ER - TY - JOUR AU - Fritsche, L. AU - Hartkopf, J. AU - Hummel, J. AU - Dannecker, C. AU - Wagner, R. AU - Heni, M. AU - Häring, H.-U. AU - Preissl, H. AU - Fritsche, A. C1 - 57073 C2 - 47522 CY - 233 Spring St, New York, Ny 10013 Usa SP - S447-S448 TI - Gestational weight gain but not gestational diabetes associate with altered heart rate variability in 2 year old children. JO - Diabetologia VL - 62 PB - Springer PY - 2019 SN - 0012-186X ER - TY - JOUR AU - Gallegos, P.A. AU - Balcacean, D. AU - Zapardiel-Gonzalo, J. AU - Richardson, S.* AU - Morgan, N.* AU - Akhbari, P.* AU - von Herrath, M.* AU - Kusmartseva, I.* AU - Pugliese, A.* AU - Rodriguez-Calvo, T. C1 - 57070 C2 - 47498 CY - 233 Spring St, New York, Ny 10013 Usa SP - S203-S203 TI - Enterovirus as triggers of disease? New insights from autoantibody positive and type 1 diabetic nPOD donors. JO - Diabetologia VL - 62 PB - Springer PY - 2019 SN - 0012-186X ER - TY - JOUR AU - Gerst, F. AU - Kemter, E.* AU - Kaiser, G. AU - Lorza-Gil, E. AU - Fritz, A.K.* AU - Wolf, E.* AU - Häring, H.-U. AU - Ullrich, S. C1 - 57062 C2 - 47516 CY - 233 Spring St, New York, Ny 10013 Usa SP - S228-S228 TI - Fetuin-A inhibits functional maturation of insulin secreting beta cells. JO - Diabetologia VL - 62 PB - Springer PY - 2019 SN - 0012-186X ER - TY - JOUR AU - Gil, E.L. AU - Kaiser, G. AU - Ulven, E.R.* AU - Gerst, F. AU - Häring, H.-U.* AU - Ulven, T.* AU - Ullrich, S. C1 - 57071 C2 - 47499 CY - 233 Spring St, New York, Ny 10013 Usa SP - S213-S213 TI - Expression of FFA2 and FFA3 and their role in human, mouse and rat insulin secreting cells. JO - Diabetologia VL - 62 PB - Springer PY - 2019 SN - 0012-186X ER - TY - JOUR AU - Henke, C. AU - Chen, C. AU - Bornstein, S.R.* AU - de Cabo, R.* AU - Speier, S. AU - Birkenfeld, A.L.* C1 - 57075 C2 - 47502 CY - 233 Spring St, New York, Ny 10013 Usa SP - S219-S220 TI - Mechanisms of age-dependent amplification of insulin secretion. JO - Diabetologia VL - 62 PB - Springer PY - 2019 SN - 0012-186X ER - TY - JOUR AU - Kahl, S.* AU - Gancheva, S.* AU - Strassburger, K.* AU - Herder, C.* AU - Machann, J. AU - Kupriyanova, Y.* AU - Kabisch, S.* AU - Henkel, E.* AU - Kantartzis, K. AU - Kopf, S.* AU - Kasperk, C.* AU - Stefan, N. AU - Pfeiffer, A.* AU - Birkenfeld, A.L.* AU - Roden, M.* C1 - 57079 C2 - 47471 CY - 233 Spring St, New York, Ny 10013 Usa SP - S124-S124 TI - Empagliflozin as metabolically active compound for treatment of non-alcoholic fatty liver disease in type 2 diabetes. JO - Diabetologia VL - 62 PB - Springer PY - 2019 SN - 0012-186X ER - TY - JOUR AU - Kaiser, G. AU - Ulven, T.* AU - Krippeit-Drews, P.* AU - Häring, H.-U. AU - Drews, G.* AU - Ullrich, S. C1 - 57076 C2 - 47503 CY - 233 Spring St, New York, Ny 10013 Usa SP - S208-S208 TI - Stimulation of FFA1/GPR40 raises the intracellular Ca2+ concentration via activation of TrpM3 channels in beta cells. JO - Diabetologia VL - 62 PB - Springer PY - 2019 SN - 0012-186X ER - TY - JOUR AU - Klymenko, O.* AU - Brecklinghaus, T.* AU - Dille, M.* AU - Springer, C.* AU - de Wendt, C.* AU - Altenhofen, D.* AU - Knebel, B.* AU - Chadt, A.* AU - Pfluger, P.T. AU - Al-Hasani, H.* AU - Kabra, D.* C1 - 57058 C2 - 47512 CY - 233 Spring St, New York, Ny 10013 Usa SP - S136-S136 TI - HDAC5 regulates IL-6 transcription and enhances insulin signalling in skeletal muscle. JO - Diabetologia VL - 62 PB - Springer PY - 2019 SN - 0012-186X ER - TY - JOUR AB - Aims/hypothesis Here, we describe the characteristics of the Innovative Medicines Initiative (IMI) Diabetes Research on Patient Stratification (DIRECT) epidemiological cohorts at baseline and follow-up examinations (18, 36 and 48 months of follow-up). Methods From a sampling frame of 24,682 adults of European ancestry enrolled in population-based cohorts across Europe, participants at varying risk of glycaemic deterioration were identified using a risk prediction algorithm (based on age, BMI, waist circumference, use of antihypertensive medication, smoking status and parental history of type 2 diabetes) and enrolled into a prospective cohort study (n = 2127) (cohort 1, prediabetes risk). We also recruited people from clinical registries with type 2 diabetes diagnosed 6-24 months previously (n = 789) into a second cohort study (cohort 2, diabetes). Follow-up examinations took place at similar to 18 months (both cohorts) and at similar to 48 months (cohort 1) or similar to 36 months (cohort 2) after baseline examinations. The cohorts were studied in parallel using matched protocols across seven clinical centres in northern Europe. Results Using ADA 2011 glycaemic categories, 33% (n = 693) of cohort 1 (prediabetes risk) had normal glucose regulation and 67% (n = 1419) had impaired glucose regulation. Seventy-six per cent of participants in cohort 1 was male. Cohort 1 participants had the following characteristics (mean +/- SD) at baseline: age 62 (6.2) years; BMI 27.9 (4.0) kg/m(2); fasting glucose 5.7 (0.6) mmol/l; 2 h glucose 5.9 (1.6) mmol/l. At the final follow-up examination the participants' clinical characteristics were as follows: fasting glucose 6.0 (0.6) mmol/l; 2 h OGTT glucose 6.5 (2.0) mmol/l. In cohort 2 (diabetes), 66% (n = 517) were treated by lifestyle modification and 34% (n = 272) were treated with metformin plus lifestyle modification at enrolment. Fifty-eight per cent of participants in cohort 2 was male. Cohort 2 participants had the following characteristics at baseline: age 62 (8.1) years; BMI 30.5 (5.0) kg/m(2); fasting glucose 7.2 (1.4) mmol/l; 2 h glucose 8.6 (2.8) mmol/l. At the final follow-up examination, the participants' clinical characteristics were as follows: fasting glucose 7.9 (2.0) mmol/l; 2 h mixed-meal tolerance test glucose 9.9 (3.4) mmol/l. Conclusions/interpretation The IMI DIRECT cohorts are intensely characterised, with a wide-variety of metabolically relevant measures assessed prospectively. We anticipate that the cohorts, made available through managed access, will provide a powerful resource for biomarker discovery, multivariate aetiological analyses and reclassification of patients for the prevention and treatment of type 2 diabetes. AU - Koivula, R.W.* AU - Forgie, I.M.* AU - Kurbasic, A.* AU - Viñuela, A.* AU - Heggie, A.* AU - Giordano, G.N.* AU - Hansen, T.H.* AU - Hudson, M.* AU - Koopman, A.D.M.* AU - Rutters, F.* AU - Siloaho, M.* AU - Allin, K.H.* AU - Brage, S.* AU - Brorsson, C.A.* AU - Dawed, A.Y.* AU - De Masi, F.* AU - Groves, C.J.* AU - Kokkola, T.* AU - Mahajan, A.* AU - Perry, M.H.* AU - Rauh, S.P.* AU - Ridderstråle, M.* AU - Teare, H.J.A.* AU - Thomas, E.L.* AU - Tura, A.* AU - Vestergaard, H.* AU - White, T.* AU - Adamski, J. AU - Bell, J.D.* AU - Beulens, J.W.* AU - Brunak, S.* AU - Dermitzakis, E.T.* AU - Froguel, P.* AU - Frost, G.* AU - Gupta, R.* AU - Hansen, T.* AU - Hattersley, A.* AU - Jablonka, B.* AU - Kaye, J.* AU - Laakso, M.* AU - McDonald, T.J.* AU - Pedersen, O.* AU - Schwenk, J.M.* AU - Pavo, I.* AU - Mari, A.* AU - McCarthy, M.I.* AU - Ruetten, H.* AU - Walker, M.* AU - Pearson, E.* AU - Franks, P.W.* C1 - 56337 C2 - 47009 CY - 233 Spring St, New York, Ny 10013 Usa SP - 1601-1615 TI - Discovery of biomarkers for glycaemic deterioration before and after the onset of type 2 diabetes: Descriptive characteristics of the epidemiological studies within the IMI DIRECT Consortium. JO - Diabetologia VL - 62 IS - 9 PB - Springer PY - 2019 SN - 0012-186X ER - TY - JOUR AU - Marchetti, P.* AU - Schulte, A.M.* AU - Marselli, L.* AU - Schöniger, E. AU - Bugliani, M.* AU - Kramer, W.* AU - Overbergh, L.* AU - Ullrich, S. AU - Gloyn, A.L.* AU - Ibberson, M.* AU - Rutter, G.* AU - Froguel, P.* AU - Groop, L.* AU - McCarthy, M.I.* AU - Dotta, F.* AU - Scharfmann, R.* AU - Magnan, C.* AU - Eizirik, D.L.* AU - Mathieu, C.* AU - Cnop, M.* AU - Thorens, B.* AU - Solimena, M. C1 - 56330 C2 - 47002 CY - 233 Spring St, New York, Ny 10013 Usa SP - 1514-1516 TI - Fostering improved human islet research: A European perspective. JO - Diabetologia VL - 62 IS - 8 PB - Springer PY - 2019 SN - 0012-186X ER - TY - JOUR AU - Oquendo, M.B. AU - Lorza-Gil, E. AU - Gerst, F. AU - Jaghutriz, B.A. AU - Fend, F.* AU - Koenigsrainer, A.* AU - Wagner, R. AU - Heni, M. AU - Häring, H.-U. AU - Ullrich, S. AU - Siegel-Axel, D. C1 - 57080 C2 - 47472 CY - 233 Spring St, New York, Ny 10013 Usa SP - S295-S295 TI - Characterisation of the gene expression of pancreatic preadipocytes and adipocytes from patients with different metabolic status. JO - Diabetologia VL - 62 PB - Springer PY - 2019 SN - 0012-186X ER - TY - JOUR AU - Schreiner, B.* AU - Kosmidis, P.* AU - Scharpf, M.* AU - Nono, J.L. AU - Koenigsrainer, A.* AU - Fend, F.* AU - Peter, A. AU - Häring, H.-U. AU - Siegel-Axel, D. C1 - 57078 C2 - 47505 CY - 233 Spring St, New York, Ny 10013 Usa SP - S309-S310 TI - Perinodal fat cells differ from other fat cell locations regarding fat accumulation, expression of cytokines, chemoattractants, adhesion molecules and ECM components. JO - Diabetologia VL - 62 PB - Springer PY - 2019 SN - 0012-186X ER - TY - JOUR AU - Siegel-Axel, D. AU - Schreiner, B.* AU - Wagner, R. AU - Jaghutriz, B.A. AU - Ullrich, S. AU - Fend, F.* AU - Koenigsrainer, A.* AU - Heni, M. AU - Peter, A. AU - Häring, H.-U. C1 - 57077 C2 - 47504 CY - 233 Spring St, New York, Ny 10013 Usa SP - S318-S318 TI - Pancreatic fat cells and fetuin-A/palmitate stimulate monocyte migration and remodelling of extracellular matrix. JO - Diabetologia VL - 62 PB - Springer PY - 2019 SN - 0012-186X ER - TY - JOUR AB - Aims/hypothesis In the context of diabetes, the health benefit of antioxidant treatment has been widely debated. In this study, we investigated the effect of antioxidant treatment during the development of insulin resistance and hyperphagia in obesity and partial lipodystrophy. Methods We studied the role of antioxidants in the regulation of insulin resistance using the tamoxifen-inducible fat-specific insulin receptor knockout (iFIRKO) mouse model, which allowed us to analyse the antioxidant's effect in a time-resolved manner. In addition, leptin-deficient ob/ob mice were used as a hyperphagic, chronically obese and diabetic mouse model to validate the beneficial effect of antioxidants on metabolism. Results Acute induction of insulin receptor knockout in adipocytes changed the substrate preference to fat before induction of a diabetic phenotype including hyperinsulinaemia and hyperglycaemia. In healthy chow-fed animals as well as in morbidly obese mice, this diabetic phase could be reversed within a few weeks. Furthermore, after the induction of insulin receptor knockout in mature adipocytes, iFIRKO mice were protected from subsequent obesity development through high-fat diet feeding. By genetic tracing we show that the persistent fat mass loss in mice after insulin receptor knockout in adipocytes is not caused by the depletion of adipocytes. Treatment of iFIRKO mice with antioxidants postponed and reduced hyperglycaemia by increasing insulin sensitivity. In ob/ob mice, antioxidants rescued both hyperglycaemia and hyperphagia. Conclusions/interpretation We conclude that fat mass reduction through insulin resistance in adipocytes is not reversible. Furthermore, it seems unlikely that adipocytes undergo apoptosis during the process of extreme lipolysis, as a consequence of insulin resistance. Antioxidants have a beneficial health effect not only during the acute phase of diabetes development, but also in a temporary fashion once chronic obesity and diabetes have been established. AU - Straub, L.G.* AU - Efthymiou, V.* AU - Grandl, G. AU - Balaz, M.* AU - Challa, T.D.* AU - Truscello, L.* AU - Horvath, C.* AU - Moser, C.* AU - Rachamin, Y.* AU - Arnold, M.* AU - Sun, W.* AU - Modica, S.* AU - Wolfrum, C.* C1 - 56576 C2 - 47156 CY - 233 Spring St, New York, Ny 10013 Usa SP - 2094-2105 TI - Antioxidants protect against diabetes by improving glucose homeostasis in mouse models of inducible insulin resistance and obesity. JO - Diabetologia VL - 62 IS - 11 PB - Springer PY - 2019 SN - 0012-186X ER - TY - JOUR AB - Health systems and governments are increasingly required to implement measures that target at-risk populations to prevent noncommunicable diseases. In this review we lay out what governments should be doing to prevent diabetes throughout the life course. The following four target groups were used to structure the specific recommendations: (1) pregnant women and young families, (2) children and adolescents, (3) working age population, and (4) the elderly. The evidence to date supports the effectiveness of some known government policy measures, such as sugar taxes and regulatory measures in the (pre-)school setting for children and adolescents. Many of these appear to be more effective if they are part of a bundle of strategies and if they are supplemented by communication strategies. Although there is a current focus on strategies that target the individual, governments can make use of evidence-based population-level prevention strategies. More research and continuous evaluation of the overall and subgroup-specific effectiveness of policy strategies using high-quality longitudinal studies are needed. AU - Timpel, P.* AU - Harst, L.* AU - Reifegerste, D.* AU - Weihrauch-Blüher, S.* AU - Schwarz, P.E. C1 - 56805 C2 - 47346 SP - 1842-1853 TI - What should governments be doing to prevent diabetes throughout the life course? JO - Diabetologia VL - 62 IS - 10 PY - 2019 SN - 0012-186X ER - TY - JOUR AU - Ullrich, S. AU - Gerst, F. AU - Kemter, E.* AU - Kaiser, G. AU - Lorza-Gil, E. AU - Fritz, A.K.* AU - Wolf, E.* AU - Häring, H.-U. C1 - 57061 C2 - 47515 CY - 233 Spring St, New York, Ny 10013 Usa SP - S230-S230 TI - Aldolase B is a marker of functional immaturity of type 2 diabetic beta cells. JO - Diabetologia VL - 62 PB - Springer PY - 2019 SN - 0012-186X ER - TY - JOUR AU - Van Rampelbergh, J.* AU - Boitard, C.* AU - Achenbach, P. AU - Leslie, R.D.* AU - Dayan, C.* AU - Keymeulen, B.* AU - Owen, K.R.* AU - Lapauw, B.* AU - Carlier, V.* AU - Ahangarani, R.R.* AU - Gebruers, E.* AU - Vanderelst, L.* AU - Van Mechelen, M.* AU - Vandepapeliere, P.* C1 - 57072 C2 - 47500 CY - 233 Spring St, New York, Ny 10013 Usa SP - S352-S353 TI - Phase Ib clinical trial of IMCY-0098 in young adults with recent-onsent type 1 diabetes. JO - Diabetologia VL - 62 PB - Springer PY - 2019 SN - 0012-186X ER - TY - JOUR AB - Aims/hypothesis This study aimed to evaluate associations of height as well as components of height (sitting height and leg length) with risk of type 2 diabetes and to explore to what extent associations are explainable by liver fat and cardiometabolic risk markers.Methods A case-cohort study within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study comprising 26,437 participants who provided blood samples was designed. We randomly selected a subcohort of 2500 individuals (2029 diabetes-free at baseline and with anamnestic, anthropometrical and metabolic data for analysis). Of the 820 incident diabetes cases identified in the full cohort during 7 years of follow-up, 698 remained for analyses after similar exclusions.Results After adjustment for age, potential lifestyle confounders, education and waist circumference, greater height was related to lower diabetes risk (HR per 10 cm, men 0.59 [95% CI 0.47, 0.75] and women 0.67 [0.51, 0.88], respectively). Leg length was related to lower risk among men and women, but only among men if adjusted for total height. Adjustment for liver fat and triacylglycerols, adiponectin and C-reactive protein substantially attenuated associations between height and diabetes risk, particularly among women.Conclusions/interpretation We observed inverse associations between height and risk of type 2 diabetes, which was largely related to leg length among men. The inverse associations may be partly driven by lower liver fat content and a more favourable cardiometabolic profile. AU - Wittenbecher, C.* AU - Kuxhaus, O.* AU - Boeing, H.* AU - Stefan, N. AU - Schulze, M.B.* C1 - 56861 C2 - 47349 CY - 233 Spring St, New York, Ny 10013 Usa SP - 2211-2221 TI - Associations of short stature and components of height with incidence of type 2 diabetes: Mediating effects of cardiometabolic risk factors. JO - Diabetologia VL - 62 IS - 12 PB - Springer PY - 2019 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: Adult-onset type 1 diabetes, in which the 65 kDa isoform of GAD (GAD65) is a major autoantigen, has a broad clinical phenotype encompassing variable need for insulin therapy. This study aimed to evaluate whether autoantibodies against N-terminally truncated GAD65 more closely defined a type 1 diabetes phenotype associated with insulin therapy. METHODS: Of 1114 participants with adult-onset diabetes from the Action LADA (latent autoimmune diabetes in adults) study with sufficient sera, we selected those designated type 1 (n = 511) or type 2 diabetes (n = 603) and retested the samples in radiobinding assays for human full-length GAD65 autoantibodies (f-GADA) and N-terminally truncated (amino acids 96-585) GAD65 autoantibodies (t-GADA). Individuals' clinical phenotypes were analysed according to antibody binding patterns. RESULTS: Overall, 478 individuals were f-GADA-positive, 431 were t-GADA-positive and 628 were negative in both assays. Risk of insulin treatment was augmented in t-GADA-positive individuals (OR 4.69 [95% CI 3.57, 6.17]) compared with f-GADA-positive individuals (OR 3.86 [95% CI 2.95, 5.06]), irrespective of diabetes duration. Of 55 individuals who were f-GADA-positive but t-GADA-negative, i.e. with antibody binding restricted to the N-terminus of GAD65, the phenotype was similar to type 2 diabetes with low risk of progression to insulin treatment. Compared with these individuals with N-terminal GAD65-restricted GADA, t-GADA-positive individuals were younger at diagnosis (p = 0.005), leaner (p < 0.0001) and more often had multiple diabetes-associated autoantibodies (28.3% vs 7.3%; p = 0.0005). CONCLUSIONS/INTERPRETATION: In individuals with adult-onset diabetes, presence of N-terminally truncated GAD65 autoantibodies is associated with the clinical phenotype of autoimmune type 1 diabetes and predicts insulin therapy.   AU - Achenbach, P. AU - Hawa, M.I.* AU - Krause, S. AU - Lampasona, V.* AU - Jerram, S.T.* AU - Williams, A.J.K.* AU - Bonifacio, E.* AU - Ziegler, A.-G. AU - Leslie, R.D.* C1 - 53699 C2 - 44913 SP - 1644-1649 TI - Autoantibodies to N-terminally truncated GAD improve clinical phenotyping of individuals with adult-onset diabetes: Action LADA 12. JO - Diabetologia VL - 61 IS - 7 PY - 2018 SN - 0012-186X ER - TY - JOUR AU - Gerst, F. AU - Fritz, A.* AU - Gil, E.L. AU - Kaiser, G. AU - Wolf, E.* AU - Häring, H.-U. AU - Ullrich, S. AU - Kemter, E.* C1 - 54349 C2 - 45493 CY - 233 Spring St, New York, Ny 10013 Usa SP - S205-S206 TI - Fetuin-A impairs islet differentiation and function via inhibition of TGFbeta-1 signalling. JO - Diabetologia VL - 61 PB - Springer PY - 2018 SN - 0012-186X ER - TY - JOUR AU - Gil, E.L. AU - Gerst, F. AU - Deschl, U.* AU - Häring, H.-U. AU - Ullrich, S. AU - Beilmann, M.* C1 - 54340 C2 - 45473 CY - 233 Spring St, New York, Ny 10013 Usa SP - S122-S122 TI - Acetate stimulates insulin secretion of human pancreatic microislets. JO - Diabetologia VL - 61 PB - Springer PY - 2018 SN - 0012-186X ER - TY - JOUR AU - Heni, M. AU - Wagner, R. AU - Willmann, C. AU - Jaghutriz, B.A. AU - Vosseler, A. AU - Kuebler, C.* AU - Peter, A. AU - Häring, H.-U. AU - Preissl, H. AU - Kullmann, S. AU - Fritsche, A. C1 - 54344 C2 - 45471 CY - 233 Spring St, New York, Ny 10013 Usa SP - S72-S72 TI - Brain insulin action stimulates pancreatic insulin secretion: Results from hyperglycaemic clamps. JO - Diabetologia VL - 61 PB - Springer PY - 2018 SN - 0012-186X ER - TY - JOUR AU - Herder, C.* AU - Kannenberg, J.M.* AU - Carstensen-Kirberg, M.* AU - Strom, A.* AU - Boenhof, G.J.* AU - Rathmann, W.* AU - Huth, C. AU - Koenig, W.* AU - Heier, M. AU - Krumsiek, J. AU - Peters, A. AU - Meisinger, C. AU - Roden, M.* AU - Thorand, B. AU - Ziegler, D.* C1 - 54338 C2 - 45475 CY - 233 Spring St, New York, Ny 10013 Usa SP - S467-S467 TI - A systemic inflammatory signature reflecting crosstalk between innate and adaptive immunity is associated with polyneuropathy: KORA F4/FF4 Study. JO - Diabetologia VL - 61 PB - Springer PY - 2018 SN - 0012-186X ER - TY - JOUR AB - Insoluble cereal fibres have been shown in large prospective cohort studies to be highly effective in preventing type 2 diabetes, but there is a lack of interventional data. Our 2 year randomised double-blind prospective intervention study compared the effect of an insoluble oat fibre extract with that of placebo on glucose metabolism and incidence of diabetes. METHODS: A total of 180 participants with impaired glucose tolerance underwent a modified version of the 1 year lifestyle training programme PREvention of DIAbetes Self-management (PREDIAS) and were randomised to receive a fibre supplement (n = 89; 7.5 g of insoluble fibre per serving) or placebo (n = 91; 0.8 g of insoluble fibre per serving) twice daily for 2 years. Eligible participants were men and women, were at least 18 years old and did not report corticosteroid or other intensive anti-inflammatory treatment, fibre intolerance or any of the following disorders: overt diabetes, chronic or malignant disease, or severe cardiopulmonary, endocrine, psychiatric, gastrointestinal, autoimmune or eating disorder. Participants were recruited at two clinical wards in Berlin and Nuthetal. The allocation was blinded to participants and study caregivers (physicians, dietitians, study nurses). Randomisation was conducted by non-clinical staff, providing neutrally numbered supplement tins. Both supplements were similar in their visual, olfactory and gustatory appearance. Intention-to-treat analysis was applied to all individuals. RESULTS: After 1 year, 2 h OGTT levels decreased significantly in both groups but without a significant difference between the groups (fibre -0.78 ± 1.88 mmol/l [p ≤ 0.001] vs placebo -0.46 ± 1.80 mmol/l [p = 0.020]; total difference 0.32 ± 0.29 mmol/l; not significant). The 2 year incidence of diabetes was 9/89 (fibre group) compared with 16/91 (placebo group; difference not significant). As secondary outcomes, the change in HbA1c level was significantly different between the two groups (-0.2 ± 4.6 mmol/mol [-0.0 ± 0.0%; not significant] vs +1.2 ± 5.2 mmol/mol [+0.1 ± 0.0%; not significant]; total difference 1.4 ± 0.7 mmol/mol [0.1 + 0.0%]); p = 0.018); insulin sensitivity and hepatic insulin clearance increased in both groups. After 2 years, improved insulin sensitivity was still present in both groups, although the effect size had diminished. Separate analysis of the sexes revealed a significantly greater reduction in 2 h glucose levels for women in the fibre group (-0.88 ± 1.59 mmol/l [p ≤ 0.001] vs -0.22 ± 1.52 mmol/l [p = 0.311]; total difference 0.67 ± 0.31 mmol/l; p = 0.015). Levels of fasting glucose, adipokines and inflammatory markers remained unchanged in the two groups. Significantly increased fibre intake was restricted to the fibre group, despite dietary counselling for both groups. No severe side effects occurred. CONCLUSIONS/INTERPRETATION: We cannot currently provide strong evidence for a beneficial effect of insoluble cereal fibre on glycaemic metabolism, although further studies may support minor effects of fibre supplementation in reducing glucose levels, insulin resistance and the incidence of type 2 diabetes. TRIAL REGISTRATION: clinicaltrials.gov NCT01681173 Funding: German Diabetes Foundation (grant no. 232/11/08). AU - Honsek, C.* AU - Kabisch, S.* AU - Kemper, M.* AU - Gerbracht, C.* AU - Arafat, A.M.* AU - Birkenfeld, A.L. AU - Dambeck, U.* AU - Osterhoff, M.A.* AU - Weickert, M.O.* AU - Pfeiffer, A.F.H.* C1 - 53529 C2 - 44743 SP - 1295-1305 TI - Fibre supplementation for the prevention of type 2 diabetes and improvement of glucose metabolism: The randomised controlled Optimal Fibre Trial (OptiFiT). JO - Diabetologia VL - 61 IS - 6 PY - 2018 SN - 0012-186X ER - TY - JOUR AU - Kappler, L.* AU - Hoene, M.* AU - Li, J.* AU - Hu, C.* AU - von Toerne, C. AU - Kollipara, L.* AU - Hoffmann, C.* AU - Böhm, A. AU - Hauck, S.M. AU - Xu, G.* AU - Häring, H.-U. AU - Peter, A. AU - Sickmann, A.* AU - Weigert, C. AU - Lehmann, R. C1 - 54345 C2 - 45470 CY - 233 Spring St, New York, Ny 10013 Usa SP - S271-S271 TI - Linking of bioenergetic function of mitochondria to tissue-specific molecular fingerprints in mice and humans. JO - Diabetologia VL - 61 PB - Springer PY - 2018 SN - 0012-186X ER - TY - JOUR AU - Knoch, K.-P. AU - Petzold, A. AU - Wegbrod, C. AU - Soenmez, A. AU - Münster, C. AU - Friedrich, A. AU - Marinicova, Z.Z. AU - Merl-Pham, J. AU - Hauck, S.M. AU - Solimena, M. C1 - 54343 C2 - 45472 CY - 233 Spring St, New York, Ny 10013 Usa SP - S150-S150 TI - CVB5 proteases 2A reduces insulin granule maturation only indirect. JO - Diabetologia VL - 61 PB - Springer PY - 2018 SN - 0012-186X ER - TY - JOUR AU - Kullmann, S. AU - Veit, R. AU - Heni, M. AU - Horstman, L. AU - Hege, M.A. AU - Rogers, P.J.* AU - Brunstrom, J.M.* AU - Häring, H.-U. AU - Fritsche, A. AU - Preissl, H. C1 - 54346 C2 - 45469 CY - 233 Spring St, New York, Ny 10013 Usa SP - S336-S336 TI - Insulin influences mindset-induced brain response and behaviour on portion size selection for lunch. JO - Diabetologia VL - 61 PB - Springer PY - 2018 SN - 0012-186X ER - TY - JOUR AB - Aims/hypothesis: Multiple islet autoimmunity increases risk of diabetes, but not all individuals positive for two or more islet autoantibodies progress to disease within a decade. Major islet autoantibodies recognise insulin (IAA), GAD (GADA), islet antigen-2 (IA-2A) and zinc transporter 8 (ZnT8A). Here we describe the baseline characteristics of a unique cohort of ‘slow progressors’ (n = 132) who were positive for multiple islet autoantibodies (IAA, GADA, IA-2A or ZnT8A) but did not progress to diabetes within 10 years. Methods: Individuals were identified from five studies (BABYDIAB, Germany; Diabetes Autoimmunity Study in the Young [DAISY], USA; All Babies in Southeast Sweden [ABIS] , Sweden; Bart’s Oxford Family Study [BOX], UK and the Pittsburgh Family Study, USA). Multiple islet autoantibody characteristics were determined using harmonised assays where possible. HLA class II risk was compared between slow progressors and rapid progressors (n = 348 diagnosed < 5 years old from BOX) using the χ 2 test. Results: In the first available samples with detectable multiple antibodies, the most frequent autoantibodies were GADA (92%), followed by ZnT8A (62%), IAA (59%) and IA-2A (41%). High risk HLA class II genotypes were less frequent in slow (28%) than rapid progressors (42%, p = 0.011), but only two slow progressors carried the protective HLA DQ6 allele. Conclusion: No distinguishing characteristics of slow progressors at first detection of multiple antibodies have yet been identified. Continued investigation of these individuals may provide insights into slow progression that will inform future efforts to slow or prevent progression to clinical diabetes. AU - Long, A.E.* AU - Wilson, I.V.* AU - Becker, D.J.* AU - Libman, I.M.* AU - Arena, V.C.* AU - Wong, F.S.* AU - Steck, A.K.* AU - Rewers, M.J.* AU - Yu, L.* AU - Achenbach, P. AU - Casas, R.* AU - Ludvigsson, J.* AU - Williams, A.J.K.* AU - Gillespie, K.M.* C1 - 53250 C2 - 44645 SP - 1484–1490 TI - Characteristics of slow progression to diabetes in multiple islet autoantibody-positive individuals from five longitudinal cohorts: The SNAIL study. JO - Diabetologia VL - 61 IS - 6 PY - 2018 SN - 0012-186X ER - TY - JOUR AB - Immune biomarkers of type 1 diabetes are many and diverse. Some of these, such as the autoantibodies, are well established but not discriminative enough to deal with the heterogeneity inherent to type 1 diabetes progression. As an alternative, high hopes are placed on T cell assays, which give insight into the cells that actually target the beta cell or play a crucial role in maintaining tolerance. These assays are approaching a level of robustness that may allow for solid conclusions on both disease progression and therapeutic efficacy of immune interventions. In addition, 'omics' approaches to biomarker discovery are rapidly progressing. The potential emergence of novel biomarkers creates a need for the introduction of bioinformatics and 'big data' analysis systems for the integration of the multitude of biomarker data that will be available, to translate these data into clinical tools. It is worth noting that it is unlikely that the same markers will apply to all individuals. Instead, individualised signatures of biomarkers, combining autoantibodies, T cell profiles and other biomarkers, will need to be used to classify at-risk patients into various categories, thus enabling personalised prediction, prevention and treatment approaches. To achieve this goal, the standardisation of assays for biomarker discovery, the integration of analyses and data from biomarker studies and, most importantly, the careful clinical characterisation of individuals providing samples for these studies are critical. Longitudinal sample-collection initiatives, like INNODIA, should lead to novel biomarker discovery, not only providing a better understanding of type 1 diabetes onset and progression, but also yielding biomarkers of therapeutic efficacy of interventions to prevent or arrest type 1 diabetes. AU - Mathieu, C.* AU - Lahesmaa, R.* AU - Bonifacio, E. AU - Achenbach, P. AU - Tree, T.* C1 - 54400 C2 - 45549 CY - 233 Spring St, New York, Ny 10013 Usa SP - 2252-2258 TI - Immunological biomarkers for the development and progression of type 1 diabetes. JO - Diabetologia VL - 61 IS - 11 PB - Springer PY - 2018 SN - 0012-186X ER - TY - JOUR AU - Niersmann, C.* AU - Hauck, S.M. AU - Kannenberg, J.M.* AU - Roehrig, K.* AU - von Toerne, C. AU - Roden, M.* AU - Herder, C.* AU - Carstensen-Kirberg, M.* C1 - 54347 C2 - 45468 CY - 233 Spring St, New York, Ny 10013 Usa SP - S254-S255 TI - Omentin-induced secretion of proteins by primary human adipocytes and stimulation of the innate immune system. JO - Diabetologia VL - 61 PB - Springer PY - 2018 SN - 0012-186X ER - TY - JOUR AB - Exposure to an intrauterine hyperglycaemic environment has been suggested to increase the offspring's later risk for being overweight or having metabolic abnormalities, but conclusive evidence for pregnancies affected by maternal type 1 diabetes is still lacking. This study aims to analyse the relationship between maternal type 1 diabetes and the offspring's metabolic health and investigate whether birthweight and/or changes in the offspring's metabolome are in the potential pathway.We analysed data from 610 and 2169 offspring having a first-degree relative with type 1 diabetes from the TEENDIAB and BABYDIAB/BABYDIET cohorts, respectively. Anthropometric and metabolic outcomes, assessed longitudinally at 0.3-18 years of age, were compared between offspring of mothers with type 1 diabetes and offspring of non-diabetic mothers but with fathers or siblings with type 1 diabetes using mixed regression models. Non-targeted metabolomic measurements were carried out in 500 individuals from TEENDIAB and analysed with maternal type 1 diabetes and offspring overweight status.The offspring of mothers with type 1 diabetes had a higher BMI SD score (SDS) and an increased risk for being overweight than the offspring of non-diabetic mothers (e.g. OR for overweight status in TEENDIAB 2.40 [95% CI 1.41, 4.06]). Further, waist circumference SDS, fasting levels of glucose, insulin and C-peptide, and insulin resistance and abdominal obesity were significantly increased in the offspring of mothers with type 1 diabetes, even when adjusted for potential confounders and birthweight. Metabolite patterns related to androgenic steroids and branched-chain amino acids were found to be associated with offspring's overweight status, but no significant associations were observed between maternal type 1 diabetes and metabolite concentrations in the offspring.Maternal type 1 diabetes is associated with offspring's overweight status and metabolic health in later life, but this is unlikely to be caused by alterations in the offspring's metabolome. AU - Pitchika, A. AU - Jolink, M. AU - Winkler, C. AU - Hummel, S. AU - Hummel, N. AU - Krumsiek, J. AU - Kastenmüller, G. AU - Raab, J. AU - Kordonouri, O.* AU - Ziegler, A.-G. AU - Beyerlein, A. C1 - 53955 C2 - 45131 CY - 233 Spring St, New York, Ny 10013 Usa SP - 2319–2332 TI - Associations of maternal type 1 diabetes with childhood adiposity and metabolic health in the offspring: A prospective cohort study. JO - Diabetologia VL - 61 IS - 11 PB - Springer PY - 2018 SN - 0012-186X ER - TY - JOUR AU - Saussenthaler, S.* AU - Ouni, M.* AU - Jaehnert, M.* AU - Huypens, P. AU - Beckers, J. AU - Schuermann, A.* C1 - 54335 C2 - 45492 CY - 233 Spring St, New York, Ny 10013 Usa SP - S259-S259 TI - Interindividual susceptibility to type 2 diabetes in mice: Hepatic transcriptome and DNA methylome profiling. JO - Diabetologia VL - 61 PB - Springer PY - 2018 SN - 0012-186X ER - TY - JOUR AU - Siegel-Axel, D. AU - Gerst, F. AU - Ullrich, S. AU - Stefan, N. AU - Sipos, B.* AU - Haen, S.P.* AU - Fend, F.* AU - Koenigsrainer, A.* AU - Schleicher, E. AU - Häring, H.-U. C1 - 54339 C2 - 45474 CY - 233 Spring St, New York, Ny 10013 Usa SP - S289-S290 TI - Differences in extracellular matrix expression in pancreatic fat cells of non-diabetic, pre-diabetic and diabetic individuals. JO - Diabetologia VL - 61 PB - Springer PY - 2018 SN - 0012-186X ER - TY - JOUR AB - Aims/hypothesis Pancreatic islet beta cell failure causes type 2 diabetes in humans. To identify transcriptomic changes in type 2 diabetic islets, the Innovative Medicines Initiative for Diabetes: Improving beta-cell function and identification of diagnostic biomarkers for treatment monitoring in Diabetes (IMIDIA) consortium (www.imidia.org) established a comprehensive, unique multicentre biobank of human islets and pancreas tissues from organ donors and metabolically phenotyped pancreatectomised patients (PPP). Methods Affymetrix microarrays were used to assess the islet transcriptome of islets isolated either by enzymatic digestion from 103 organ donors (OD), including 84 non-diabetic and 19 type 2 diabetic individuals, or by laser capture microdissection (LCM) from surgical specimens of 103 PPP, including 32 non-diabetic, 36 with type 2 diabetes, 15 with impaired glucose tolerance (IGT) and 20 with recent-onset diabetes (< 1 year), conceivably secondary to the pancreatic disorder leading to surgery (type 3c diabetes). Bioinformatics tools were used to (1) compare the islet transcriptome of type 2 diabetic vs non-diabetic OD and PPP as well as vs IGT and type 3c diabetes within the PPP group; and (2) identify transcription factors driving gene co-expression modules correlated with insulin secretion ex vivo and glucose tolerance in vivo. Selected genes of interest were validated for their expression and function in beta cells. Results Comparative transcriptomic analysis identified 19 genes differentially expressed (false discovery rate <= 0.05, fold change >= 1.5) in type 2 diabetic vs non-diabetic islets from OD and PPP. Nine out of these 19 dysregulated genes were not previously reported to be dysregulated in type 2 diabetic islets. Signature genes included TMEM37, which inhibited Ca2+-influx and insulin secretion in beta cells, and ARG2 and PPP1R1A, which promoted insulin secretion. Systems biology approaches identified HNF1A, PDX1 and REST as drivers of gene co-expression modules correlated with impaired insulin secretion or glucose tolerance, and 14 out of 19 differentially expressed type 2 diabetic islet signature genes were enriched in these modules. None of these signature genes was significantly dysregulated in islets of PPP with impaired glucose tolerance or type 3c diabetes. Conclusions/interpretation These studies enabled the stringent definition of a novel transcriptomic signature of type 2 diabetic islets, regardless of islet source and isolation procedure. Lack of this signature in islets from PPP with IGT or type 3c diabetes indicates differences possibly due to peculiarities of these hyperglycaemic conditions and/or a role for duration and severity of hyperglycaemia. Alternatively, these transcriptomic changes capture, but may not precede, beta cell failure. AU - Solimena, M. AU - Schulte, A.M.* AU - Marselli, L.* AU - Ehehalt, F. AU - Richter, D.* AU - Kleeberg, M. AU - Mziaut, H. AU - Knoch, K.-P. AU - Parnis, J.* AU - Bugliani, M.* AU - Siddiq, A.* AU - Jörns, A.* AU - Burdet, F.* AU - Liechti, R.* AU - Suleiman, M.* AU - Margerie, D.* AU - Syed, F.* AU - Distler, M.* AU - Grützmann, R.* AU - Petretto, E.* AU - Moreno-Moral, A.* AU - Wegbrod, C. AU - Sönmez, A. AU - Pfriem, K. AU - Friedrich, A. AU - Meinel, J.* AU - Wollheim, C.B.* AU - Baretton, G.B.* AU - Scharfmann, R.* AU - Nogoceke, E.* AU - Bonifacio, E. AU - Sturm, D. AU - Meyer-Puttlitz, B.* AU - Boggi, U.* AU - Saeger, H.-D. AU - Filipponi, F.* AU - Lesche, M.* AU - Meda, P.* AU - Dahl, A.* AU - Wigger, L.* AU - Xenarios, I.* AU - Falchi, M.* AU - Thorens, B.* AU - Weitz, J. AU - Bokvist, K.* AU - Lenzen, S.* AU - Rutter, G.A.* AU - Froguel, P.* AU - von Bülow, M.* AU - Ibberson, M.* AU - Marchetti, P.* C1 - 52600 C2 - 44075 CY - New York SP - 641–657 TI - Systems biology of the IMIDIA biobank from organ donors and pancreatectomised patients defines a novel transcriptomic signature of islets from individuals with type 2 diabetes. JO - Diabetologia VL - 61 IS - 3 PB - Springer PY - 2018 SN - 0012-186X ER - TY - JOUR AU - Stadion, M.* AU - Kluth, O.* AU - Gottmann, P.* AU - Aga, H.* AU - Krus, U.* AU - Gerdes, J.M. AU - Ling, C.* AU - Schuermann, A.* C1 - 54337 C2 - 45476 CY - 233 Spring St, New York, Ny 10013 Usa SP - S194-S194 TI - The impact of cilia-genes on pancreatic beta cell replication and the risk of type 2 diabetes. JO - Diabetologia VL - 61 PB - Springer PY - 2018 SN - 0012-186X ER - TY - JOUR AB - Aims/hypothesis: Tissue-resident macrophages sense the microenvironment and respond by producing signals that act locally to maintain a stable tissue state. It is now known that pancreatic islets contain their own unique resident macrophages, which have been shown to promote proliferation of the insulin-secreting beta cell. However, it is unclear how beta cells communicate with islet-resident macrophages. Here we hypothesised that islet macrophages sense changes in islet activity by detecting signals derived from beta cells. Methods: To investigate how islet-resident macrophages respond to cues from the microenvironment, we generated mice expressing a genetically encoded Ca 2+ indicator in myeloid cells. We produced living pancreatic slices from these mice and used them to monitor macrophage responses to stimulation of acinar, neural and endocrine cells. Results: Islet-resident macrophages expressed functional purinergic receptors, making them exquisite sensors of interstitial ATP levels. Indeed, islet-resident macrophages responded selectively to ATP released locally from beta cells that were physiologically activated with high levels of glucose. Because ATP is co-released with insulin and is exclusively secreted by beta cells, the activation of purinergic receptors on resident macrophages facilitates their awareness of beta cell secretory activity. Conclusions/interpretation: Our results indicate that islet macrophages detect ATP as a proxy signal for the activation state of beta cells. Sensing beta cell activity may allow macrophages to adjust the secretion of factors to promote a stable islet composition and size. AU - Weitz, J.R.* AU - Makhmutova, M.* AU - Almaça, J.* AU - Stertmann, J. AU - Aamodt, K.* AU - Brissova, M.* AU - Speier, S. AU - Rodriguez-Diaz, R.* AU - Caicedo, A.* C1 - 51955 C2 - 43616 CY - New York SP - 182–192 TI - Mouse pancreatic islet macrophages use locally released ATP to monitor beta cell activity. JO - Diabetologia VL - 61 IS - 1 PB - Springer PY - 2018 SN - 0012-186X ER - TY - JOUR AU - Willmann, C. AU - Heni, M. AU - Linder, K. AU - Wagner, R. AU - Stefan, N. AU - Machann, J. AU - Häring, H.-U. AU - Fritsche, A. C1 - 54336 C2 - 45477 CY - 233 Spring St, New York, Ny 10013 Usa SP - S78-S78 TI - Effects of increased fiber and reduced red meat intake, combined with caloric restriction, on cardiometabolic risk: A randomised and controlled dietary intervention study. JO - Diabetologia VL - 61 PB - Springer PY - 2018 SN - 0012-186X ER - TY - JOUR AB - The asymptomatic phase of type 1 diabetes is recognised by the presence of beta cell autoantibodies in the absence of hyperglycaemia. We propose that an accurate description of this stage is provided by the name 'Autoimmune Beta Cell Disorder' (ABCD). Specifically, we suggest that this nomenclature and diagnosis will, in a proactive manner, shift the paradigm towards type 1 diabetes being first and foremost an immune-mediated disease and only later a metabolic disease, presaging more active therapeutic intervention in the asymptomatic stage of disease, before end-stage beta cell failure. Furthermore, we argue that accepting ABCD as a diagnosis will be critical in order to accelerate pharmaceutical, academic and public activities leading to clinical trials that could reverse beta cell autoimmunity and halt progression to symptomatic insulin-requiring type 1 diabetes. We recognize that there are both opportunities and challenges in the implementation of the ABCD concept but hope that the notion of 'asymptomatic autoimmune disease' as a disorder will be widely discussed and eventually accepted. AU - Bonifacio, E.* AU - Mathieu, C.* AU - Nepom, G.T.* AU - Ziegler, A.-G. AU - Anhalt, H.* AU - Haller, M.J.* AU - Harrison, L.C.* AU - Hebrok, M.* AU - Kushner, J.A.* AU - Norris, J.M.* AU - Peakman, M.* AU - Powers, A.C.* AU - Todd, J.A.* AU - Atkinson, M.A.* C1 - 50227 C2 - 42330 CY - New York SP - 35-38 TI - Rebranding asymptomatic type 1 diabetes: The case for autoimmune beta cell disorder as a pathological and diagnostic entity. JO - Diabetologia VL - 60 IS - 1 PB - Springer PY - 2017 SN - 0012-186X ER - TY - JOUR AU - Dawed, A.Y.* AU - Mari, A.* AU - McDonald, T.J.* AU - Hong, M.G.* AU - Sharma, S. AU - Robertson, N.R.* AU - Mahajan, A.* AU - Walker, M.* AU - Gough, S.C.* AU - Zhou, K.* AU - Forgie, I.* AU - Ruetten, H.* AU - Jones, A.G.* AU - Pearson, E.R.* C1 - 52142 C2 - 43768 CY - New York SP - S393-S393 TI - GLP-1 receptor variants markedly differentiate glycaemic response to GLP-1 receptor agonists: A DIRECT study. JO - Diabetologia VL - 60 PB - Springer PY - 2017 SN - 0012-186X ER - TY - JOUR AB - Aims/hypothesis: During the A/H1N1 2009 (A/California/04/2009) pandemic, mass vaccination with a squalene-containing vaccine, Pandemrix®, was performed in Sweden and Finland. The vaccination was found to cause narcolepsy in children and young adults with the HLA-DQ 6.2 haplotype. The aim of this study was to investigate if exposure to Pandemrix® similarly increased the risk of islet autoimmunity or type 1 diabetes. Methods: In The Environmental Determinants of Diabetes in the Young (TEDDY) study, children are followed prospectively for the development of islet autoimmunity and type 1 diabetes. In October 2009, when the mass vaccination began, 3401 children at risk for islet autoimmunity and type 1 diabetes were followed in Sweden and Finland. Vaccinations were recorded and autoantibodies against insulin, GAD65 and insulinoma-associated protein 2 were ascertained quarterly before the age of 4 years and semi-annually thereafter. Results: By 5 August 2010, 2413 of the 3401 (71%) children observed as at risk for an islet autoantibody or type 1 diabetes on 1 October 2009 had been vaccinated with Pandemrix®. By 31 July 2016, 232 children had at least one islet autoantibody before 10 years of age, 148 had multiple islet autoantibodies and 96 had developed type 1 diabetes. The risk of islet autoimmunity was not increased among vaccinated children. The HR (95% CI) for the appearance of at least one islet autoantibody was 0.75 (0.55, 1.03), at least two autoantibodies was 0.85 (0.57, 1.26) and type 1 diabetes was 0.67 (0.42, 1.07). In Finland, but not in Sweden, vaccinated children had a lower risk of islet autoimmunity (0.47 [0.29, 0.75]), multiple autoantibodies (0.50 [0.28, 0.90] ) and type 1 diabetes (0.38 [0.20, 0.72]) compared with those who did not receive Pandemrix®. The analyses were adjusted for confounding factors. Conclusions/interpretation: Children with an increased genetic risk for type 1 diabetes who received the Pandemrix® vaccine during the A/H1N1 2009 pandemic had no increased risk of islet autoimmunity, multiple islet autoantibodies or type 1 diabetes. In Finland, the vaccine was associated with a reduced risk of islet autoimmunity and type 1 diabetes. AU - Elding Larsson, H.* AU - Lynch, K.F.* AU - Lönnrot, M.* AU - Haller, M.J.* AU - Lernmark, Å.* AU - Hagopian, W.A.* AU - She, J.X.* AU - Simell, O.* AU - Toppari, J.* AU - Ziegler, A.-G. AU - Akolkar, B.* AU - Krischer, J.P.* AU - Rewers, M.J.* AU - Hyöty, H.* C1 - 52099 C2 - 43740 CY - New York SP - 193–202 TI - Pandemrix® vaccination is not associated with increased risk of islet autoimmunity or type 1 diabetes in the TEDDY study children. JO - Diabetologia VL - 61 IS - 1 PB - Springer PY - 2017 SN - 0012-186X ER - TY - JOUR AU - Eriksson, O.* AU - Bossart, M.* AU - Haack, T.B.* AU - Laitinen, I.* AU - Larsen, P.* AU - Plettenburg, O. AU - Johansson, L.* AU - Pierrou, S.* AU - Wagner, M.* AU - Velikyan, I.* C1 - 52141 C2 - 43769 CY - New York SP - S400-S400 TI - First-in-class PET tracer for the glucagon receptor. JO - Diabetologia VL - 60 PB - Springer PY - 2017 SN - 0012-186X ER - TY - JOUR AB - Aims/hypothesis Obesity-linked ectopic fat accumulation is associated with the development of type 2 diabetes. Whether pancreatic and liver steatosis impairs insulin secretion is controversial. We examined the crosstalk of human pancreatic fat cells with islets and the role of diabetogenic factors, i.e. palmitate and fetuin-A, a hepatokine released from fatty liver. Methods Human pancreatic resections were immunohistochemically stained for insulin, glucagon, somatostatin and the macrophage/monocyte marker CD68. Pancreatic adipocytes were identified by Oil Red O and adiponectin staining. Primary pancreatic pre-adipocytes and differentiated adipocytes were co-cultured with human islets isolated from organ donors and the metabolic crosstalk between fatty liver and fatty pancreas was mimicked by the addition of palmitate and fetuin-A. Insulin secretion was evaluated by ELISA and RIA. Cytokine expression and secretion were assessed by RTPCR and multiplex assay, respectively. Subcellular distribution of proteins was examined by confocal microscopy and protein phosphorylation by western blotting. Results In human pancreatic parenchyma, highly differentiated adipocytes were detected in the proximity of islets with normal architecture and hormone distribution. Infiltration of adipocytes was associated with an increased number of CD68-positive cells within islets. In isolated primary pancreatic preadipocytes and differentiated adipocytes, palmitate and fetuin-A induced IL6, CXCL8 and CCL2 mRNA expression. Cytokine production was toll-like receptor 4 (TLR4)-dependent and further accentuated in pre-adipocytes when co-cultured with islets. In islets, IL6 and CXCL8 mRNA levels were also increased by fetuin-A and palmitate. Only in macrophages within the isolated islets, palmitate and fetuin-A stimulated the production of the cytotoxic cytokine IL-1 beta. Palmitate, but not fetuin-A, exerted pro-apoptotic effects in islet cells. Instead, fetuin-A impaired glucose-induced insulin secretion in a TLR4-independent, but c-Jun N-terminal kinase- and Ca2+-dependent, manner. Conclusions/interpretation These results provide the first evidence that fetuin-A-mediated metabolic crosstalk of fatty liver with islets may contribute to obesity-linked glucose blindness of beta cells, while fatty pancreas may exacerbate local inflammation. AU - Gerst, F. AU - Wagner, R. AU - Kaiser, G. AU - Panse, M.* AU - Heni, M. AU - Machann, J. AU - Bongers, M.N.* AU - Sartorius, T.* AU - Sipos, B.* AU - Fend, F.* AU - Thiel, C.* AU - Nadalin, S.* AU - Koenigsrainer, A.* AU - Stefan, N. AU - Fritsche, A. AU - Häring, H.-U. AU - Ullrich, S. AU - Siegel-Axel, D. C1 - 52203 C2 - 43837 CY - New York SP - 2240-2251 TI - Metabolic crosstalk between fatty pancreas and fatty liver: Effects on local inflammation and insulin secretion. JO - Diabetologia VL - 60 IS - 11 PB - Springer PY - 2017 SN - 0012-186X ER - TY - JOUR AU - Herder, C.* AU - Kannenberg, J.M.* AU - Niersmann, C.* AU - Huth, C. AU - Carstensen-Kirberg, M.* AU - Wittenbecher, C.* AU - Schulze, M.* AU - Blueher, M.* AU - Rathmann, W.* AU - Peters, A. AU - Roden, M.* AU - Meisinger, C. AU - Thorand, B. C1 - 52143 C2 - 43767 CY - New York SP - S270-S270 TI - Higher serum levels of omentin-1 are associated with increases in glycaemia and incident type 2 diabetes: KORA F4/FF4 study. JO - Diabetologia VL - 60 PB - Springer PY - 2017 SN - 0012-186X ER - TY - JOUR AU - Kemter, E.* AU - Cohrs, C.M. AU - Schäfer, M.* AU - Schuster, M.* AU - Steinmeyer, K.* AU - Wolf-van Buerck, L.* AU - Wolf, A.* AU - Wuensch, A.* AU - Kurome, M.* AU - Kessler, B.* AU - Zakhartchenko, V.* AU - Loehn, M.* AU - Ivashchenko, Y.* AU - Seissler, J.* AU - Schulte, A.M.* AU - Speier, S. AU - Wolf, E.* C1 - 50846 C2 - 43485 CY - New York SP - 1152-1156 TI - INS-eGFP transgenic pigs: A novel reporter system for studying maturation, growth and vascularisation of neonatal islet-like cell clusters. JO - Diabetologia VL - 60 IS - 6 PB - Springer PY - 2017 SN - 0012-186X ER - TY - JOUR AB - Aims/hypothesis: Diabetic retinopathy is a severe complication of diabetes mellitus that often leads to blindness. Because the pathophysiology of diabetic retinopathy is not fully understood and novel therapeutic interventions require testing, there is a need for reliable animal models that mimic all the complications of diabetic retinopathy. Pig eyes share important anatomical and physiological similarities with human eyes. Previous studies have demonstrated that INSC94Y transgenic pigs develop a stable diabetic phenotype and ocular alterations such as cataracts. The aim of this study was to conduct an in-depth analysis of pathological changes in retinas from INSC94Y pigs exposed to hyperglycaemia for more than 2 years, representing a chronic diabetic condition. Methods: Eyes from six INSC94Ypigs and six age-matched control littermates were analysed via histology and immunohistochemistry. For histological analyses of retinal (layer) thickness, sections were stained with H&E or Mallory’s trichrome. For comparison of protein expression patterns and vessel courses, sections were stained with different antibodies in immunohistochemistry. Observed lesions were compared with reported pathologies in human diabetic retinopathy. Results: INSC94Ypigs developed several signs of diabetic retinopathy similar to those seen in humans, such as intraretinal microvascular abnormalities, symptoms of proliferative diabetic retinopathy and central retinal oedema in a region that is cone rich, like the human macula. Conclusions/interpretation: The INSC94Ypig is an interesting model for studying the pathophysiology of diabetic retinopathy and for testing novel therapeutic strategies. AU - Kleinwort, K.J.H.* AU - Amann, B.* AU - Hauck, S.M. AU - Hirmer, S.* AU - Blutke, A.* AU - Renner, S.* AU - Uhl, P.B.* AU - Lutterberg, K.* AU - Sekundo, W.* AU - Wolf, E.* AU - Deeg, C.A.* C1 - 51113 C2 - 42761 CY - New York SP - 1541–1549 TI - Retinopathy with central oedema in an INSC94Y transgenic pig model of long-term diabetes. JO - Diabetologia VL - 60 IS - 8 PB - Springer PY - 2017 SN - 0012-186X ER - TY - JOUR AB - Aims/hypothesis: Regulation of energy balance involves the participation of many factors, including nutrients, among which are circulating lipids, acting as peripheral signals informing the central nervous system of the energy status of the organism. It has been shown that neuronal lipoprotein lipase (LPL) participates in the control of energy balance by hydrolysing lipid particles enriched in triacylglycerols. Here, we tested the hypothesis that LPL in the mediobasal hypothalamus (MBH), a well-known nucleus implicated in the regulation of metabolic homeostasis, could also contribute to the regulation of body weight and glucose homeostasis. Methods: We injected an adeno-associated virus (AAV) expressing Cre–green fluorescent protein into the MBH of Lpl-floxed mice (and wild-type mice) to specifically decrease LPL activity in the MBH. In parallel, we injected an AAV overexpressing Lpl into the MBH of wild-type mice. We then studied energy homeostasis and hypothalamic ceramide content. Results: The partial deletion of Lpl in the MBH in mice led to an increase in body weight compared with controls (37.72 ± 0.7 g vs 28.46 ± 0.12, p < 0.001) associated with a decrease in locomotor activity. These mice developed hyperinsulinaemia and glucose intolerance. This phenotype also displayed reduced expression of Cers1 in the hypothalamus as well as decreased concentration of several C18 species of ceramides and a 3-fold decrease in total ceramide intensity. Conversely, overexpression of Lpl specifically in the MBH induced a decrease in body weight. Conclusions/interpretation: Our study shows that LPL in the MBH is an important regulator of body weight and glucose homeostasis. AU - Laperrousaz, E.* AU - Moullé, V.S.* AU - Denis, R.G.* AU - Kassis, N.* AU - Berland, C. AU - Colsch, B.* AU - Fioramonti, X.* AU - Philippe, E.* AU - Lacombe, A.* AU - Vanacker, C.* AU - Butin, N.* AU - Bruce, K.D.* AU - Wang, H.* AU - Wang, Y.* AU - Gao, Y. AU - García-Cáceres, C. AU - Prévot, V.* AU - Tschöp, M.H. AU - Eckel, R.H.* AU - Le Stunff, H.* AU - Luquet, S.* AU - Magnan, C.* AU - Cruciani-Guglielmacci, C.* C1 - 51118 C2 - 42841 SP - 1314-1324 TI - Lipoprotein lipase in hypothalamus is a key regulator of body weight gain and glucose homeostasis in mice. JO - Diabetologia VL - 60 IS - 7 PY - 2017 SN - 0012-186X ER - TY - JOUR AB - Aims/hypothesis: Respiratory infections and onset of islet autoimmunity are reported to correlate positively in two small prospective studies. The Environmental Determinants of Diabetes in the Young (TEDDY) study is the largest prospective international cohort study on the environmental determinants of type 1 diabetes that regularly monitors both clinical infections and islet autoantibodies. The aim was to confirm the influence of reported respiratory infections and to further characterise the temporal relationship with autoantibody seroconversion. Methods: During the years 2004–2009, 8676 newborn babies with HLA genotypes conferring an increased risk of type 1 diabetes were enrolled at 3 months of age to participate in a 15 year follow-up. In the present study, the association between parent-reported respiratory infections and islet autoantibodies at 3 month intervals up to 4 years of age was evaluated in 7869 children. Time-dependent proportional hazard models were used to assess how the timing of respiratory infections related to persistent confirmed islet autoimmunity, defined as autoantibody positivity against insulin, GAD and/or insulinoma antigen-2, concordant at two reference laboratories on two or more consecutive visits. Results: In total, 87,327 parent-reported respiratory infectious episodes were recorded while the children were under study surveillance for islet autoimmunity, and 454 children seroconverted. The number of respiratory infections occurring in a 9 month period was associated with the subsequent risk of autoimmunity (p < 0.001). For each 1/year rate increase in infections, the hazard of islet autoimmunity increased by 5.6% (95% CI 2.5%, 8.8%). The risk association was linked primarily to infections occurring in the winter (HR 1.42 [95% CI 1.16, 1.74]; p < 0.001). The types of respiratory infection independently associated with autoimmunity were common cold, influenza-like illness, sinusitis, and laryngitis/tracheitis, with HRs (95% CI) of 1.38 (1.11, 1.71), 2.37 (1.35, 4.15), 2.63 (1.22, 5.67) and 1.76 (1.04, 2.98), respectively. Conclusions/interpretation: Recent respiratory infections in young children correlate with an increased risk of islet autoimmunity in the TEDDY study. Further studies to identify the potential causative viruses with pathogen-specific assays should focus especially on the 9 month time window leading to autoantibody seroconversion. AU - Lönnrot, M.* AU - Lynch, K.F.* AU - Elding Larsson, H.* AU - Lernmark, Å.* AU - Rewers, M.J.* AU - Törn, C.* AU - Burkhardt, B.R.* AU - Briese, T.* AU - Hagopian, W.A.* AU - She, J.X.* AU - Simell, O.G.* AU - Toppari, J.* AU - TEDDY Study Group (Ziegler, A.-G. AU - Beyerlein, A. AU - Hummel, M. AU - Hummel, S. AU - Janz, N. AU - Knopff, A. AU - Peplow, C. AU - Roth, R. AU - Scholz, M. AU - Stock, J. AU - Strauss, E. AU - Warncke, K. AU - Wendel, L. AU - Winkler, C.) AU - Akolkar, B.* AU - Krischer, J.P.* AU - Hyöty, H.* C1 - 51711 C2 - 43429 SP - 1931-1940 TI - Respiratory infections are temporally associated with initiation of type 1 diabetes autoimmunity: The TEDDY study. JO - Diabetologia VL - 60 IS - 10 PY - 2017 SN - 0012-186X ER - TY - JOUR AB - The authors regret that the SNP in SH2B3 was incorrectly referred to as rs3184505 instead of rs3184504 on both mentions in this paper (Methods section and Table 1). AU - Lönnrot, M.* AU - Lynch, K.F.* AU - Elding Larsson, H.* AU - Lernmark, Å.* AU - Rewers, M.J.* AU - Törn, C.* AU - Burkhardt, B.R.* AU - Briese, T.* AU - Hagopian, W.A.* AU - She, J.X.* AU - Simell, O.G.* AU - Toppari, J.* AU - Ziegler, A.-G. AU - Akolkar, B.* AU - Krischer, J.P.* AU - Hyöty, H.* C1 - 52270 C2 - 43860 CY - New York SP - 254-254 TI - Correction to: Respiratory infections are temporally associated with initiation of type 1 diabetes autoimmunity: The TEDDY study. JO - Diabetologia VL - 61 IS - 1 PB - Springer PY - 2017 SN - 0012-186X ER - TY - JOUR AU - Lutz, S.Z. AU - Hennenlotter, J.* AU - Scharpf, M.* AU - Guirguis, A.* AU - Peter, A. AU - Staiger, H. AU - Fritsche, A. AU - Todenhoefer, T.* AU - Heni, M. AU - Stenzl, A.* AU - Häring, H.-U. C1 - 52138 C2 - 43772 CY - New York SP - S565-S565 TI - Complex interplay between androgen, estrogen and insulin receptor gene expression in prostate cancer depending on diabetes status. JO - Diabetologia VL - 60 PB - Springer PY - 2017 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: Circulating metabolites have been shown to reflect metabolic changes during the development of type 2 diabetes. In this study we examined the association of metabolite levels and pairwise metabolite ratios with insulin responses after glucose, glucagon-like peptide-1 (GLP-1) and arginine stimulation. We then investigated if the identified metabolite ratios were associated with measures of OGTT-derived beta cell function and with prevalent and incident type 2 diabetes. METHODS: We measured the levels of 188 metabolites in plasma samples from 130 healthy members of twin families (from the Netherlands Twin Register) at five time points during a modified 3 h hyperglycaemic clamp with glucose, GLP-1 and arginine stimulation. We validated our results in cohorts with OGTT data (n = 340) and epidemiological case-control studies of prevalent (n = 4925) and incident (n = 4277) diabetes. The data were analysed using regression models with adjustment for potential confounders. RESULTS: There were dynamic changes in metabolite levels in response to the different secretagogues. Furthermore, several fasting pairwise metabolite ratios were associated with one or multiple clamp-derived measures of insulin secretion (all p < 9.2 × 10(-7)). These associations were significantly stronger compared with the individual metabolite components. One of the ratios, valine to phosphatidylcholine acyl-alkyl C32:2 (PC ae C32:2), in addition showed a directionally consistent positive association with OGTT-derived measures of insulin secretion and resistance (p ≤ 5.4 × 10(-3)) and prevalent type 2 diabetes (ORVal_PC ae C32:2 2.64 [β 0.97 ± 0.09], p = 1.0 × 10(-27)). Furthermore, Val_PC ae C32:2 predicted incident diabetes independent of established risk factors in two epidemiological cohort studies (HRVal_PC ae C32:2 1.57 [β 0.45 ± 0.06]; p = 1.3 × 10(-15)), leading to modest improvements in the receiver operating characteristics when added to a model containing a set of established risk factors in both cohorts (increases from 0.780 to 0.801 and from 0.862 to 0.865 respectively, when added to the model containing traditional risk factors + glucose). CONCLUSIONS/INTERPRETATION: In this study we have shown that the Val_PC ae C32:2 metabolite ratio is associated with an increased risk of type 2 diabetes and measures of insulin secretion and resistance. The observed effects were stronger than that of the individual metabolites and independent of known risk factors. AU - Molnos, S. AU - Wahl, S. AU - Haid, M. AU - Eekhoff, E.M.W.* AU - Pool, R.* AU - Floegel, A.* AU - Deelen, J.* AU - Much, D. AU - Prehn, C. AU - Breier, M. AU - Draisma, H.H.* AU - van Leeuwen, N.* AU - Simonis-Bik, A.M.C.* AU - Jonsson, A.* AU - Willemsen, G.* AU - Bernigau, W.* AU - Wang-Sattler, R. AU - Suhre, K. AU - Peters, A. AU - Thorand, B. AU - Herder, C.* AU - Rathmann, W.* AU - Roden, M.* AU - Gieger, C. AU - Kramer, M.H.H.* AU - van Heemst, D.* AU - Pedersen, H.K.* AU - Gudmundsdottir, V.* AU - Schulze, M.B.* AU - Pischon, T.* AU - de Geus, E.J.C.* AU - Boeing, H.* AU - Boomsma, D.I.* AU - Ziegler, A.-G. AU - Slagboom, P.E.* AU - Hummel, S. AU - Beekman, M.* AU - Grallert, H. AU - Brunak, S.* AU - McCarthy, M.I.* AU - Gupta, R.* AU - Pearson, E.R.* AU - Adamski, J. AU - 't Hart, L.M.* C1 - 51957 C2 - 43612 CY - New York SP - 117-129 TI - Metabolite ratios as potential biomarkers for type 2 diabetes: A DIRECT study. JO - Diabetologia VL - 61 IS - 1 PB - Springer PY - 2017 SN - 0012-186X ER - TY - JOUR AU - Morgenstern, J.* AU - Fuchs, B.* AU - Schumacher, D.* AU - Herzig, S. AU - Freichel, M.* AU - Nawroth, P.P.* AU - Fleming, T.* C1 - 52139 C2 - 43771 CY - New York SP - S507-S508 TI - Loss of glyoxalase 1 in various mammalian cells is associated with an increased resistance against environmental stressors. JO - Diabetologia VL - 60 PB - Springer PY - 2017 SN - 0012-186X ER - TY - JOUR AU - Neukam, M. AU - Ganss, K. AU - Vasiljevic, J. AU - Soenmez, A. AU - Kurth, T.* AU - Hauck, S.M. AU - Solimena, M. C1 - 52148 C2 - 43765 CY - New York SP - S23-S23 TI - A novel method for the background-free purification of age-distinct insulin secretory granules for proteomic and lipidomic analyses. JO - Diabetologia VL - 60 PB - Springer PY - 2017 SN - 0012-186X ER - TY - JOUR AB - Over a relatively short period, obesity and type 2 diabetes have come to represent a large medical and economic burden to global societies. The epidemic rise in the prevalence of obesity has metabolic consequences and is paralleled by an increased occurrence of other diseases, such as diabetes, cancer and cardiovascular complications. Together, obesity and type 2 diabetes constitute one of the more preventable causes of premature death and the identification of novel, safe and effective anti-obesity drugs is of utmost importance. Pharmacological attempts to treat obesity have had limited success, with notable adverse effects, rendering bariatric surgery as the only current therapy for substantially improving body weight. Novel unimolecular, multifunctional peptides have emerged as one of the most promising medicinal approaches to enhance metabolic efficacy and restore normal body weight. In this review, we will mainly focus on the discovery and translational relevance of dual agonists that pharmacologically function at the receptors for glucagon and glucagon-like peptide-1. Such peptides have advanced to clinical evaluation and inspired the pursuit of multiple related approaches to achieving polypharmacy within single molecules. AU - Sánchez-Garrido, M.A. AU - Brandt, S. AU - Clemmensen, C. AU - Müller, T.D. AU - DiMarchi, R.D.* AU - Tschöp, M.H. C1 - 51622 C2 - 43327 CY - New York SP - 1851–1861 TI - GLP-1/glucagon receptor co-agonism for treatment of obesity. JO - Diabetologia VL - 60 IS - 10 PB - Springer PY - 2017 SN - 0012-186X ER - TY - JOUR AB - Aims/hypothesis Lifestyle intervention is effective to prevent type 2 diabetes. However, a considerable long-term non-response occurs to a standard lifestyle intervention. We investigated which risk phenotypes at baseline and their changes during the lifestyle intervention predict long-term glycaemic non-response to the intervention. Methods Of 300 participants at high risk for type 2 diabetes who participated in a 24 month lifestyle intervention with diet modification and increased physical activity, 190 participants could be re-examined after 8.7 +/- 1.6 years. All individuals underwent a five-point 75 g OGTT and measurements of body fat compartments and liver fat content with MRI and spectroscopy at baseline, 9 and 24 months during the lifestyle intervention, and at long-term follow-up. Fasting proinsulin to insulin conversion (PI/I ratio) and insulin sensitivity and secretion were calculated from the OGTT. Non-response to lifestyle intervention was defined as no decrease in glycaemia, i.e. no decrease in AUC for glucose at 0-120 min during OGTT (AUCglucose(0-120) (min)). Results Before the lifestyle intervention, 56% of participants had normal glucose regulation and 44% individuals had impaired fasting glucose and/or impaired glucose tolerance. At long-term follow-up, 11% had developed diabetes. Multivariable regression analysis with adjustment for age, sex, BMI and change in BMI during the lifestyle intervention revealed that baseline insulin secretion and insulin sensitivity, as well as change in insulin sensitivity during the lifestyle intervention, predicted long-term glycaemic control after 9 years. In addition, increased hepatic lipid content as well as impaired fasting proinsulin conversion at baseline were newly detected phenotypes that independently predicted long-term glycaemic control. Conclusions/interpretation Increased hepatic lipid content and impaired proinsulin conversion are new predictors, independent of change in body weight, for non-response to lifestyle intervention in addition to the confirmed factors, impaired insulin secretion and insulin sensitivity. AU - Schmid, V.* AU - Wagner, R. AU - Sailer, C. AU - Fritsche, L. AU - Kantartzis, K. AU - Peter, A. AU - Heni, M. AU - Häring, H.-U. AU - Stefan, N. AU - Fritsche, A. C1 - 52387 C2 - 43941 CY - New York SP - 2341-2351 TI - Non-alcoholic fatty liver disease and impaired proinsulin conversion as newly identified predictors of the long-term non-response to a lifestyle intervention for diabetes prevention: Results from the TULIP study. JO - Diabetologia VL - 60 IS - 12 PB - Springer PY - 2017 SN - 0012-186X ER - TY - JOUR AU - Siegel-Axel, D. AU - Wagner, R. AU - Guthoff, M.* AU - Machann, J.* AU - Nadalin, S.* AU - Stefan, N. AU - Fritsche, A. AU - Saleem, M.A.* AU - Schick, F.* AU - Fend, F.* AU - Koenigsrainer, A.* AU - Heyne, N.* AU - Häring, H.-U. AU - Schleicher, E. C1 - 52140 C2 - 43770 CY - New York SP - S483-S483 TI - The 'fatty kidney': Crosstalk of renal sinus fat with glomerular cells under the influence of the hepatokine fetuin-A. JO - Diabetologia VL - 60 PB - Springer PY - 2017 SN - 0012-186X ER - TY - JOUR AU - Stirm, L. AU - Fritsche, L. AU - Fritsche, A. AU - Häring, H.-U. AU - Staiger, H. C1 - 52147 C2 - 43766 CY - New York SP - S44-S44 TI - Apelinergic system in placenta of women with gestational diabetes. JO - Diabetologia VL - 60 PB - Springer PY - 2017 SN - 0012-186X ER - TY - JOUR AB - Aims/hypothesis We sought to identify minimal sets of serum peptide signatures as markers for islet autoimmunity and predictors of progression rates to clinical type 1 diabetes in a case–control study. Methods A double cross-validation approach was applied to first prioritise peptides from a shotgun proteomic approach in 45 islet autoantibody-positive and -negative children from the BABYDIAB/BABYDIET birth cohorts. Targeted proteomics for 82 discriminating peptides were then applied to samples from another 140 children from these cohorts. Results A total of 41 peptides (26 proteins) enriched for the functional category lipid metabolism were significantly different between islet autoantibody-positive and autoantibody-negative children. Two peptides (from apolipoprotein M and apolipoprotein C-IV) were sufficient to discriminate autoantibody-positive from autoantibody-negative children. Hepatocyte growth factor activator, complement factor H, ceruloplasmin and age predicted progression time to type 1 diabetes with a significant improvement compared with age alone. Conclusion/interpretation Distinct peptide signatures indicate islet autoimmunity prior to the clinical manifestation of type 1 diabetes and enable refined staging of the presymptomatic disease period.   AU - von Toerne, C. AU - Laimighofer, M. AU - Achenbach, P. AU - Beyerlein, A. AU - de Las Heras Gala, T. AU - Krumsiek, J. AU - Theis, F.J. AU - Ziegler, A.-G. AU - Hauck, S.M. C1 - 48610 C2 - 41848 SP - 287-295 TI - Peptide serum markers in islet autoantibody-positive children. JO - Diabetologia VL - 60 IS - 2 PY - 2017 SN - 0012-186X ER - TY - JOUR AU - 't Hart, L.M.* AU - Molnos, S. AU - Eekhoff, E.* AU - Flogel, A.* AU - Grallert, H. AU - Wahl, S. AU - McCarthy, M.I.* AU - Gupta, R.* AU - Pearson, E.R.* AU - Much, D. AU - Hummel, S. AU - Beckman, M.* AU - Adamski, J. C1 - 51052 C2 - 42709 CY - New York SP - S142-S143 TI - A metabolite ratio associates with measures of insulin secretion and altered risk of type 2 diabetes; a DIRECT study. JO - Diabetologia VL - 59 PB - Springer PY - 2016 SN - 0012-186X ER - TY - JOUR AB - Metabolomics is instrumental in the analysis of disease mechanisms and biomarkers of disease. The human metabolome is influenced by genetics and environmental interactions and reveals characteristic signatures of disease. Population studies with metabolomics require special study designs and care needs to be taken with pre-analytics. Gas chromatography coupled to mass spectrometry, liquid chromatography coupled to mass spectrometry or NMR are popular techniques used for metabolomic analyses in human cohorts. Metabolomics has been successfully used in the biomarker search for disease prediction and progression, for analyses of drug action and for the development of companion diagnostics. Several metabolites or metabolite classes identified by metabolomics have gained much attention in the field of diabetes research in the search for early disease detection, differentiation of progressor types and compliance with medication. This review summarises a presentation given at the ‘New approaches beyond genetics’ symposium at the 2015 annual meeting of the EASD. AU - Adamski, J. C1 - 49696 C2 - 40804 CY - New York SP - 2497-2502 TI - Key elements of metabolomics in the study of biomarkers of diabetes. JO - Diabetologia VL - 59 IS - 12 PB - Springer PY - 2016 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: Pancreatic beta cells maintain glucose homeostasis and beta cell dysfunction is a major risk factor in developing diabetes. Therefore, understanding the developmental regulatory networks that define a fully functional beta cell is important for elucidating the genetic origins of the disease. Aldehyde dehydrogenase activity has been associated with stem/progenitor cells and we have previously shown that Aldh1b1 is specifically expressed in pancreas progenitor pools. Here we address the hypothesis that Aldh1b1 may regulate the timing of the appearance and eventual functionality of beta cells. METHODS: We generated an Aldh1b1-knockout mouse line (Aldh1b1 (tm1lacZ)) and used this to study pancreatic development, beta cell functionality and glucose homeostasis in the absence of Aldh1b1 function. RESULTS: Differentiation in the developing pancreas of Aldh1b1 (tm1lacZ) null mice was accelerated. Transcriptome analyses of newborn and adult islets showed misregulation of key beta cell transcription factors and genes crucial for beta cell function. Functional analyses showed that glucose-stimulated insulin secretion was severely compromised in islets isolated from null mice. Several key features of beta cell functionality were affected, including control of oxidative stress, glucose sensing, stimulus-coupling secretion and secretory granule biogenesis. As a result of beta cell dysfunction, homozygous mice developed glucose intolerance and age-dependent hyperglycaemia. CONCLUSIONS/INTERPRETATION: These findings show that Aldh1b1 influences the timing of the transition from the pancreas endocrine progenitor to the committed beta cell and demonstrate that changes in the timing of this transition lead to beta cell dysfunction and thus constitute a diabetes risk factor later in life. Gene Expression Omnibus (GEO) accession: GSE58025. AU - Anastasiou, V. AU - Ninou, E.* AU - Alexopoulou, D.* AU - Stertmann, J. AU - Müller, A. AU - Dahl, A.* AU - Solimena, M. AU - Speier, S. AU - Serafimidis, I.* AU - Gavalas, A. C1 - 47410 C2 - 39302 SP - 139-150 TI - Aldehyde dehydrogenase activity is necessary for beta cell development and functionality in mice. JO - Diabetologia VL - 59 IS - 1 PY - 2016 SN - 0012-186X ER - TY - JOUR AU - Berti, L. AU - Raedle, B. AU - Häring, H.-U. AU - Hrabě de Angelis, M. AU - Staiger, H. C1 - 51040 C2 - 42724 CY - New York SP - S274-S274 TI - Mitogenic activity of the metabolically relevant hepatokine FGF21 in human carcinoma cells. JO - Diabetologia VL - 59 PB - Springer PY - 2016 SN - 0012-186X ER - TY - JOUR AU - Bohn, B.* AU - Prinz, N.* AU - Schoefl, C.* AU - Zimmer, V.* AU - Hummel, M. AU - Heise, N.* AU - Siegel, E.* AU - Karges, W.* AU - Riedl, M.* AU - Holl, R.W.* C1 - 51034 C2 - 42736 CY - New York SP - S550-S550 TI - Are recommended goals for secondary prevention of myocardial infarction or stroke achieved in real life? A German/Austrian DPV analysis of 29,325 patients with type 2 diabetes. JO - Diabetologia VL - 59 PB - Springer PY - 2016 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: Autoantibodies against pancreatic islets and infections by enteroviruses are associated with type 1 diabetes, but the specificity of immune responses within the type 1 diabetic pancreas is poorly characterised. We investigated whether pancreatic lymph nodes could provide a source of antigen-specific B cells for analysis of immune responses within the (pre)diabetic pancreas. METHODS: Human IgG antibodies were cloned from single B lymphocytes sorted from pancreatic lymph node cells of three organ donors positive for islet autoantibodies, and from the peripheral blood of a patient with type 1 diabetes. Antibodies to insulinoma-associated antigen 2 (IA-2), GAD65, zinc transporter 8 (ZnT8) and Coxsackie B virus proteins were assayed by immunoprecipitation and by immunofluorescence on pancreatic sections. RESULTS: Human IgG antibodies (863) were successfully cloned and produced from 4,092 single B cells from lymph nodes and peripheral blood. Reactivity to the protein tyrosine phosphatase domain of the IA-2 autoantigen was detected in two cloned antibodies: one derived from a pancreatic lymph node and one from peripheral blood. Epitopes for these two antibodies were similar to each other and to those for circulating antibodies in type 1 diabetes. The remaining 861 antibodies were negative for reactivity to IA-2, GAD65 or ZnT8 by both assays tested. Reactivity to a Coxsackie viral protein 2 was detected in one antibody derived from a peripheral blood B cell, but not from lymph nodes. CONCLUSIONS/INTERPRETATION: We show evidence for the infrequent presence of autoantigen-specific IgG(+) B lymphocytes in the pancreatic-draining lymph nodes of islet autoantibody-positive individuals. AU - Catani, M.* AU - Walther, D.* AU - Christie, M.R.* AU - McLaughlin, K.A.* AU - Bonifacio, E. AU - Eugster, A.* C1 - 47411 C2 - 39304 CY - New York SP - 294-298 TI - Isolation of human monoclonal autoantibodies derived from pancreatic lymph node and peripheral blood B cells of islet autoantibody-positive patients. JO - Diabetologia VL - 59 IS - 2 PB - Springer PY - 2016 SN - 0012-186X ER - TY - JOUR AU - Chhabra, N.F. AU - Wu, M. AU - Fütterer, M. AU - Irmler, M. AU - Beckers, J. AU - Götz, M. AU - Rozman, J. AU - Przemeck, G.K.H. AU - Hrabě de Angelis, M. C1 - 51039 C2 - 42723 CY - New York SP - S259-S259 TI - Systemic metabolic effects exerted by a point mutation in the RED subdomain of PAX6. JO - Diabetologia VL - 59 PB - Springer PY - 2016 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: Progression to type 1 diabetes in children and adolescents is not uniform. Based on individual genetic background and environment, islet autoimmunity may develop at variable age, exhibit different autoantibody profiles and progress to clinical diabetes at variable rates. Here, we aimed to quantify the qualitative dynamics of sequential islet autoantibody profiles in order to identify longitudinal patterns that stratify progression rates to type 1 diabetes in multiple-autoantibody-positive children. METHODS: Qualitative changes in antibody status on follow-up and progression rate to diabetes were analysed in 88 children followed from birth in the prospective BABYDIAB study who developed multiple autoantibodies against insulin (IAA), GAD (GADA), insulinoma-associated antigen-2 (IA-2A) and/or zinc transporter 8 (ZnT8A). An algorithm was developed to define similarities in sequential autoantibody profiles and hierarchical clustering was performed to group children with similar profiles. RESULTS: We defined nine clusters that distinguished children with respect to their sequential profiles of IAA, GADA, IA-2A and ZnT8A. Progression from first autoantibody appearance to clinical diabetes between clusters ranged from 6% (95% CI [0, 16.4]) to 73% (28.4, 89.6) within 5 years. Delayed progression was observed in children who were positive for only two autoantibodies, and for a cluster of 12 children who developed three or four autoantibodies but were IAA-negative in their last samples, nine of whom lost IAA positivity during follow-up. Among all children who first seroconverted to IAA positivity and developed at least two other autoantibodies (n = 57), the 10 year risk of diabetes was 23% (0, 42.9) in those who became IAA-negative during follow-up compared with 76% (58.7, 85.6) in those who remained IAA-positive (p = 0.004). CONCLUSIONS/INTERPRETATION: The novel clustering approach provides a tool for stratification of islet autoantibody-positive individuals that has prognostic relevance, and new opportunities in elucidating disease mechanisms. Our data suggest that losing IAA reactivity is associated with delayed progression to type 1 diabetes in multiple-islet-autoantibody-positive children. AU - Endesfelder, D. AU - Hagen, M. AU - Winkler, C. AU - Haupt, F. AU - Zillmer, S. AU - Knopff, A. AU - Bonifacio, E. AU - Ziegler, A.-G. AU - zu Castell, W. AU - Achenbach, P. C1 - 49063 C2 - 41598 CY - New York SP - 2172-2180 TI - A novel approach for the analysis of longitudinal profiles reveals delayed progression to type 1 diabetes in a subgroup of multiple-islet-autoantibody-positive children. JO - Diabetologia VL - 59 IS - 10 PB - Springer PY - 2016 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: Identification of novel biomarkers for type 2 diabetes and their genetic determinants could lead to improved understanding of causal pathways and improve risk prediction. METHODS: In this study, we used data from non-targeted metabolomics performed using liquid chromatography coupled with tandem mass spectrometry in three Swedish cohorts (Uppsala Longitudinal Study of Adult Men [ULSAM], n = 1138; Prospective Investigation of the Vasculature in Uppsala Seniors [PIVUS], n = 970; TwinGene, n = 1630). Metabolites associated with impaired fasting glucose (IFG) and/or prevalent type 2 diabetes were assessed for associations with incident type 2 diabetes in the three cohorts followed by replication attempts in the Cooperative Health Research in the Region of Augsburg (KORA) S4 cohort (n = 855). Assessment of the association of metabolite-regulating genetic variants with type 2 diabetes was done using data from a meta-analysis of genome-wide association studies. RESULTS: Out of 5961 investigated metabolic features, 1120 were associated with prevalent type 2 diabetes and IFG and 70 were annotated to metabolites and replicated in the three cohorts. Fifteen metabolites were associated with incident type 2 diabetes in the four cohorts combined (358 events) following adjustment for age, sex, BMI, waist circumference and fasting glucose. Novel findings included associations of higher values of the bile acid deoxycholic acid and monoacylglyceride 18:2 and lower concentrations of cortisol with type 2 diabetes risk. However, adding metabolites to an existing risk score improved model fit only marginally. A genetic variant within the CYP7A1 locus, encoding the rate-limiting enzyme in bile acid synthesis, was found to be associated with lower concentrations of deoxycholic acid, higher concentrations of LDL-cholesterol and lower type 2 diabetes risk. Variants in or near SGPP1, GCKR and FADS1/2 were associated with diabetes-associated phospholipids and type 2 diabetes. CONCLUSIONS/INTERPRETATION: We found evidence that the metabolism of bile acids and phospholipids shares some common genetic origin with type 2 diabetes. ACCESS TO RESEARCH MATERIALS: Metabolomics data have been deposited in the Metabolights database, with accession numbers MTBLS93 (TwinGene), MTBLS124 (ULSAM) and MTBLS90 (PIVUS). AU - Fall, T.* AU - Salihovic, S.* AU - Brandmaier, S. AU - Nowak, C.* AU - Ganna, A.* AU - Gustafsson, S.* AU - Broeckling, C.D.* AU - Prenni, J.E.* AU - Kastenmüller, G. AU - Peters, A. AU - Magnusson, P.K.* AU - Wang-Sattler, R. AU - Giedraitis, V.* AU - Berne, C.* AU - Gieger, C. AU - Pedersen, N.L.* AU - Ingelsson, E.* AU - Lind, L.* C1 - 49079 C2 - 41595 CY - New York SP - 2114-2124 TI - Non-targeted metabolomics combined with genetic analyses identifies bile acid synthesis and phospholipid metabolism as being associated with incident type 2 diabetes. JO - Diabetologia VL - 59 IS - 10 PB - Springer PY - 2016 SN - 0012-186X ER - TY - JOUR AU - Fütterer, M. AU - Chhabra, N.F. AU - Irmler, M. AU - Beckers, J. AU - Przemeck, G.K.H. AU - Hrabě de Angelis, M. C1 - 51045 C2 - 42729 CY - New York SP - S188-S188 TI - Dll1-and Dll4-mediated Notch signalling in adult pancreatic beta cells is essential for the structural integrity of islets and maintenance of glucose homeostasis. JO - Diabetologia VL - 59 PB - Springer PY - 2016 SN - 0012-186X ER - TY - JOUR AU - Gerst, F. AU - Wagner, R. AU - Siegel-Axel, D. AU - Gabriele, K. AU - Panse, M.* AU - Sartorius, T.* AU - Rammensee, H.-G.* AU - Stefan, N. AU - Sipos, B.* AU - Fend, F.* AU - Nadalin, S.* AU - Koenigsrainer, A.* AU - Häring, H.-U. AU - Ullrich, S. C1 - 51043 C2 - 42727 CY - New York SP - S217-S217 TI - Crosstalk of fatty liver with fatty pancreas impairs islet function in humans. JO - Diabetologia VL - 59 PB - Springer PY - 2016 SN - 0012-186X ER - TY - JOUR AU - Hawlitschek, C.* AU - Ferrari, U.* AU - Banning, F.* AU - Freibothe, I.* AU - Sacco, V.* AU - Wichmann, C.* AU - Reif, S.* AU - Potzel, A.* AU - Prehn, C. AU - Sommer, N.N.* AU - Hetterich, H.* AU - Adamski, J. AU - Seissler, J.* AU - Lechner, A.* C1 - 51051 C2 - 42707 CY - New York SP - S162-S162 TI - Elevated glutamate and branched chain amino acid levels in overweight/obese individuals: Links to insulin resistance and visceral adiposity. JO - Diabetologia VL - 59 PB - Springer PY - 2016 SN - 0012-186X ER - TY - JOUR AB - Aims/hypothesis: Variations in FTO are the strongest common genetic determinants of adiposity, and may partly act by influencing dopaminergic signalling in the brain leading to altered reward processing that promotes increased food intake. Therefore, we investigated the impact of such an interaction on body composition, and peripheral and brain insulin sensitivity. Methods: Participants from the Tübingen Family study (n = 2245) and the Malmö Diet and Cancer study (n = 2921) were genotyped for FTO SNP rs8050136 and ANKK1 SNP rs1800497. Insulin sensitivity in the caudate nucleus, an important reward area in the brain, was assessed by fMRI in 45 participants combined with intranasal insulin administration. Results: We found evidence of an interaction between variations in FTO and an ANKK1 polymorphism that associates with dopamine (D2) receptor density. In cases of reduced D2 receptor availability, as indicated by the ANKK1 polymorphism, FTO variation was associated with increased body fat and waist circumference and reduced peripheral insulin sensitivity. Similarly, altered central insulin sensitivity was observed in the caudate nucleus in individuals with the FTO obesity-risk allele and diminished D2 receptors. Conclusions/interpretation: The effects of variations in FTO are dependent on dopamine D2 receptor density (determined by the ANKK1 polymorphism). Carriers of both risk alleles might, therefore, be at increased risk of obesity and diabetes. AU - Heni, M. AU - Kullmann, S. AU - Ahlqvist, E.* AU - Wagner, R. AU - Machicao, F. AU - Staiger, H. AU - Häring, H.U. AU - Almgren, P.* AU - Groop, L.C.* AU - Small, D.M.* AU - Fritsche, A. AU - Preissl, H. C1 - 49515 C2 - 30620 CY - New York SP - 1-10 TI - Interaction between the obesity-risk gene FTO and the dopamine D2 receptor gene ANKK1/TaqIA on insulin sensitivity. JO - Diabetologia VL - 59 IS - 12 PB - Springer PY - 2016 SN - 0012-186X ER - TY - JOUR AU - Herder, C.* AU - de Las Heras Gala, T. AU - Carstensen-Kirberg, M.* AU - Huth, C. AU - Zierer, A. AU - Sudduth-Klinger, J.* AU - Peretz, D.* AU - Wahl, S. AU - Meisinger, C. AU - Peters, A. AU - Roden, M.* AU - Koenig, W.* AU - Thorand, B. C1 - 51036 C2 - 42734 CY - New York SP - S527-S527 TI - Increased serum levels of interleukin-1 receptor antagonist (IL-1ra) precede coronary heart disease: Meta-analysis of 4 prospective cohort studies. JO - Diabetologia VL - 59 PB - Springer PY - 2016 SN - 0012-186X ER - TY - JOUR AU - Kluth, O.* AU - Muehlbauer, E.* AU - Matzke, D.* AU - Kamitz, A.* AU - Jaehnert, M.* AU - Staiger, H. AU - Haering, H.U.* AU - Joost, H.G.* AU - Schuermann, A.* C1 - 51049 C2 - 42708 CY - New York SP - S168-S168 TI - Identification and functional characterisation of diabetes genes in mice. JO - Diabetologia VL - 59 PB - Springer PY - 2016 SN - 0012-186X ER - TY - JOUR AU - Kopf, S.* AU - Groener, J.B.* AU - Ziagaki, A.* AU - Oikonomou, D.* AU - Fleming, T.* AU - Herzig, S. AU - Nawroth, P.P.* C1 - 51037 C2 - 42733 CY - New York SP - S521-S521 TI - Impaired lung function as a diabetes related complication. JO - Diabetologia VL - 59 PB - Springer PY - 2016 SN - 0012-186X ER - TY - JOUR AU - Krueger, J.* AU - Scholz, M.* AU - Marzi, C. AU - Grallert, H. AU - Ladenvall, C.* AU - Thorand, B. AU - Groop, L.* AU - Thiery, J.* AU - Fischer-Rosinsky, A.* AU - Pfeiffer, A.* AU - Spranger, J.* AU - Gieger, C. AU - Stumvoll, M.* AU - Kovacs, P.* AU - Toenjes, A.* C1 - 51048 C2 - 42706 CY - New York SP - S176-S177 TI - Genome wide meta-analysis identifies novel regulators of circulating serum progranulin. JO - Diabetologia VL - 59 PB - Springer PY - 2016 SN - 0012-186X ER - TY - JOUR AB - Pancreatic beta cells differ in terms of glucose responsiveness, insulin secretion and proliferative capacity; however, the molecular pathways that regulate this cellular heterogeneity are unknown. We have identified the Wnt–planar cell polarity (PCP) effector Flattop (FLTP) as a biomarker that identifies mature beta cells in the islets of Langerhans. Interestingly, three-dimensional architecture and Wnt–PCP ligands are sufficient to trigger mouse and human beta cell maturation. These results highlight the fact that novel biomarkers shed light on the long-standing mystery of beta cell heterogeneity and identify the Wnt–PCP pathway as triggering beta cell maturation. Understanding heterogeneity in the islets of Langerhans might allow targeting of beta cell subpopulations for regenerative therapy and provide building principles for stem cell-derived islets. This review summarises a presentation given at the ‘Can we make a better beta cell?’ symposium at the 2015 annual meeting of the EASD. It is accompanied by two other reviews on topics from this symposium (by Amin Ardestani and Kathrin Maedler, DOI: 10.1007/s00125-016-3892-9, and by Harry Heimberg and colleagues, DOI: 10.1007/s00125-016-3879-6) and a commentary by the Session Chair, Shanta Persaud (DOI: 10.1007/s00125-016-3870-2). AU - Migliorini, A. AU - Roscioni, S. AU - Lickert, H. C1 - 49123 C2 - 41657 CY - New York SP - 1838-1842 TI - Targeting insulin-producing beta cells for regenerative therapy. JO - Diabetologia VL - 59 IS - 9 PB - Springer PY - 2016 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: Lactation for >3 months in women with gestational diabetes is associated with a reduced risk of type 2 diabetes that persists for up to 15 years postpartum. However, the underlying mechanisms are unknown. We examined whether in women with gestational diabetes lactation for >3 months is associated with altered metabolomic signatures postpartum. METHODS: We enrolled 197 women with gestational diabetes at a median of 3.6 years (interquartile range 0.7-6.5 years) after delivery. Targeted metabolomics profiles (including 156 metabolites) were obtained during a glucose challenge test. Comparisons of metabolite concentrations and ratios between women who lactated for >3 months and women who lactated for ≤3 months or not at all were performed using linear regression with adjustment for age and BMI at the postpartum visit, time since delivery, and maternal education level, and correction for multiple testing. Gaussian graphical modelling was used to generate metabolite networks. RESULTS: Lactation for >3 months was associated with a higher total lysophosphatidylcholine/total phosphatidylcholine ratio; in women with short-term follow-up, it was also associated with lower leucine concentrations and a lower total branched-chain amino acid concentration. Gaussian graphical modelling identified subgroups of closely linked metabolites within phosphatidylcholines and branched-chain amino acids that were affected by lactation for >3 months and have been linked to the pathophysiology of type 2 diabetes in previous studies. CONCLUSIONS/INTERPRETATION: Lactation for >3 months in women with gestational diabetes is associated with changes in the metabolomics profile that have been linked to the early pathogenesis of type 2 diabetes. AU - Much, D. AU - Beyerlein, A. AU - Kindt, A. AU - Krumsiek, J. AU - Stückler, F. AU - Rossbauer, M. AU - Hofelich, A. AU - Wiesenäcker, D. AU - Hivner, S. AU - Herbst, M. AU - Römisch-Margl, W. AU - Prehn, C. AU - Adamski, J. AU - Kastenmüller, G. AU - Theis, F.J. AU - Ziegler, A.-G. AU - Hummel, S. C1 - 49105 C2 - 41590 CY - New York SP - 2193-2202 TI - Lactation is associated with altered metabolomic signatures in women with gestational diabetes. JO - Diabetologia VL - 59 IS - 10 PB - Springer PY - 2016 SN - 0012-186X ER - TY - JOUR AU - Much, D. AU - Beyerlein, A. AU - Kindt, A. AU - Krumsiek, J. AU - Rossbauerl, M. AU - Hofelich, A. AU - Hivner, S. AU - Herbst, M. AU - Römisch-Margl, W. AU - Prehn, C. AU - Adamski, J. AU - Kastenmüller, G. AU - Theis, F.J. AU - Ziegler, A.-G. AU - Hummel, S. C1 - 51044 C2 - 42728 CY - New York SP - S187-S187 TI - Lactation is associated with altered metabolomic signatures in women with gestational diabetes. JO - Diabetologia VL - 59 PB - Springer PY - 2016 SN - 0012-186X ER - TY - JOUR AU - Müller, A. AU - Ivanova-Cederstroem, A. AU - Münster, C. AU - Kurth, T.* AU - Verbavatz, J.-M.* AU - Solimena, M. C1 - 51047 C2 - 42731 CY - New York SP - S194-S195 TI - Ultrastructural analysis of insulin secretory granule ageing by super resolution and transmission electron microscopy. JO - Diabetologia VL - 59 PB - Springer PY - 2016 SN - 0012-186X ER - TY - JOUR AU - Neukam, M. AU - Müller, A. AU - Sönmez, A. AU - Solimena, M. C1 - 51046 C2 - 42730 CY - New York SP - S193-S194 TI - FLIM-based pH measurements reveal incretin-induced rejuvenation of aged insulin secretory granules. JO - Diabetologia VL - 59 PB - Springer PY - 2016 SN - 0012-186X ER - TY - JOUR AU - Osterhoff, M.A.* AU - Schueler, R.* AU - Frahnow, T.* AU - Machann, J. AU - Klose, C.* AU - Surma, M.A.* AU - Simons, K.* AU - Hornemann, S.* AU - Kruse, M.* AU - Pfeiffer, A.F.H.* C1 - 51055 C2 - 42712 CY - New York SP - S67-S67 TI - Specific phospholipids are differently associated to human visceral and non-visceral adipose tissue depending on the inflammatory state in the NUGAT Twin study. JO - Diabetologia VL - 59 PB - Springer PY - 2016 SN - 0012-186X ER - TY - JOUR AB - Diet-induced obesity and its metabolic comorbidities constitute an overwhelming health crisis and there is an urgent need for safe and effective pharmacological interventions. Being largely shelved for decades, scientists are now revisiting the anti-obesity virtues of leptin. Whereas it remains evident that leptin as a stand-alone therapy is not an effective approach, the potential for employing sensitising pharmacology to unleash the weight-lowering properties of leptin has injected new hope into the field. Fascinatingly, these leptin-sensitising agents seem to act via distinct metabolic pathways and may thus, in parallel with their clinical development, serve as important research tools to progress our understanding of the molecular, physiological and behavioural pathways underlying energy homeostasis and obesity pathophysiology. This review summarises a presentation given at the 'Is leptin coming back?' symposium at the 2015 annual meeting of the EASD. It is accompanied by two other reviews on topics from this symposium (by Thomas Meek and Gregory Morton, DOI: 10.1007/s00125-016-3898-3 , and by Gerald Shulman and colleagues, DOI: 10.1007/s00125-016-3909-4 ) and an overview by the Session Chair, Ulf Smith (DOI: 10.1007/s00125-016-3894-7 ). AU - Quarta, C. AU - Sánchez-Garrido, M.A. AU - Tschöp, M.H. AU - Clemmensen, C. C1 - 48148 C2 - 39952 CY - New York SP - 920-927 TI - Renaissance of leptin for obesity therapy. JO - Diabetologia VL - 59 IS - 5 PB - Springer PY - 2016 SN - 0012-186X ER - TY - JOUR AB - Aims/hypothesis: Lysosomal acid lipase (LAL) hydrolyses cholesteryl esters and triacylglycerols (TG) within lysosomes to mobilise NEFA and cholesterol. Since LAL-deficient (Lal-/-) mice suffer from progressive loss of adipose tissue and severe accumulation of lipids in hepatic lysosomes, we hypothesised that LAL deficiency triggers alternative energy pathway(s). Methods: We studied metabolic adaptations in Lal-/- mice. Results: Despite loss of adipose tissue, Lal-/- mice show enhanced glucose clearance during insulin and glucose tolerance tests and have increased uptake of [3H]2-deoxy-D-glucose into skeletal muscle compared with wild-type mice. In agreement, fasted Lal-/- mice exhibit reduced glucose and glycogen levels in skeletal muscle. We observed 84% decreased plasma leptin levels and significantly reduced hepatic ATP, glucose, glycogen and glutamine concentrations in fed Lal-/- mice. Markedly reduced hepatic acyl-CoA concentrations decrease the expression of peroxisome proliferator-activated receptor α (PPARα) target genes. However, treatment of Lal-/- mice with the PPARα agonist fenofibrate further decreased plasma TG (and hepatic glucose and glycogen) concentrations in Lal-/- mice. Depletion of hepatic nuclear factor 4α and forkhead box protein a2 in fasted Lal-/- mice might be responsible for reduced expression of microsomal TG transfer protein, defective VLDL synthesis and drastically reduced plasma TG levels. Conclusions/interpretation: Our findings indicate that neither activation nor inactivation of PPARα per se but rather the availability of hepatic acyl-CoA concentrations regulates VLDL synthesis and subsequent metabolic adaptations in Lal-/- mice. We conclude that decreased plasma VLDL production enhances glucose uptake into skeletal muscle to compensate for the lack of energy supply. AU - Radovic, B.* AU - Vujić, N.* AU - Leopold, C.* AU - Schlager, S.* AU - Goeritzer, M.* AU - Patankar, J.V.* AU - Korbelius, M.* AU - Kolb, D.* AU - Reindl, J.* AU - Wegscheider, M.* AU - Tomin, T.* AU - Birner-Gruenberger, R.* AU - Schittmayer, M.* AU - Groschner, L.* AU - Magnes, C.* AU - Diwoky, C.* AU - Frank, S.* AU - Steyrer, E.* AU - Du, H.* AU - Graier, W.F.* AU - Madl, T. AU - Kratky, D.* C1 - 48628 C2 - 41240 SP - 1743-1752 TI - Lysosomal acid lipase regulates VLDL synthesis and insulin sensitivity in mice. JO - Diabetologia VL - 59 IS - 8 PY - 2016 SN - 0012-186X ER - TY - JOUR AU - Rottenkolber, M.* AU - Muschet, C. AU - Breier, M. AU - Fugmann, M. AU - Sacco, V. AU - Weise, M. AU - Prehn, C. AU - Grallert, H. AU - Bidlingmaier, M.* AU - Hrabě de Angelis, M. AU - Seissler, J. AU - Reincke, M.* AU - Adamski, J. AU - Ferrari, U. AU - Lechner, A. C1 - 51053 C2 - 42710 CY - New York SP - S127-S127 TI - Targeted metabolomics to predict the primary success of metformin monotherapy in type 2 diabetes. JO - Diabetologia VL - 59 PB - Springer PY - 2016 SN - 0012-186X ER - TY - JOUR AU - Schmid, V. AU - Sailer, C. AU - Fritsche, L. AU - Heni, M. AU - Wagner, R. AU - Stefan, N. AU - Häring, H.-U. AU - Fritsche, A. C1 - 51041 C2 - 42725 CY - New York SP - S171-S171 TI - Liver fat content and insulin secretion failure are associated with the long-term success of a lifestyle intervention to prevent type 2 diabetes: Results of the TULIP study. JO - Diabetologia VL - 59 PB - Springer PY - 2016 SN - 0012-186X ER - TY - JOUR AU - Siegel-Axel, D. AU - Gerst, F. AU - Panse, M. AU - Wagner, R. AU - Machann, J. AU - Stefan, N. AU - Sipos, B.* AU - Fend, F.* AU - Nadalin, S.* AU - Koenigsrainer, A.* AU - Häring, H.-U. AU - Ullrich, S. C1 - 51054 C2 - 42711 CY - New York SP - S79-S79 TI - The interplay of fatty liver with fatty pancreas accenuates local islet inflammation in humans. JO - Diabetologia VL - 59 PB - Springer PY - 2016 SN - 0012-186X ER - TY - JOUR AU - Solimena, M. AU - Schulte, A.M.* C1 - 51050 C2 - 42705 CY - New York SP - S169-S169 TI - System biology of the IMIDIA biobank from organ donors and pancreatectomised patients defines the transcriptomic signature of type 2 diabetes islets. JO - Diabetologia VL - 59 PB - Springer PY - 2016 SN - 0012-186X ER - TY - JOUR AU - Stirm, L. AU - Huypens, P. AU - Sass, S. AU - Fritsche, L. AU - Fritsche, A. AU - Beckers, J. AU - Hrabě de Angelis, M. AU - Staiger, H. AU - Häring, H.-U. C1 - 51056 C2 - 42713 CY - New York SP - S47-S47 TI - miRNA signatures in maternal whole blood cells of women with gestational diabetes. JO - Diabetologia VL - 59 PB - Springer PY - 2016 SN - 0012-186X ER - TY - JOUR AU - Teperino, R. AU - Lu, T.T.* AU - Matz-Soja, M.* AU - Kovarova, M.* AU - Dalgaard, K.* AU - Selvaraj, M.* AU - Basilicata, M.* AU - Lempradl, A.* AU - Ruf, M.* AU - Gebhardt, R.* AU - Schleicher, E.* AU - Pospisilik, J.A.* C1 - 51038 C2 - 42732 CY - New York SP - S307-S307 TI - Polycomb controls metabolic homeostasis through a novel liver-to-adipose axis. JO - Diabetologia VL - 59 PB - Springer PY - 2016 SN - 0012-186X ER - TY - JOUR AU - Ustunel, B.E.* AU - Friedrich, K.* AU - Berriel Diaz, M. AU - Stremmel, W.* AU - Blueher, M.* AU - Herzig, S. C1 - 51042 C2 - 42726 CY - New York SP - S234-S234 TI - Transforming growth factor beta-like stimulated clone 22 D4 promotes diabetic hyperglycaemia and insulin resistance. JO - Diabetologia VL - 59 PB - Springer PY - 2016 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: Individuals at a high risk of type 2 diabetes demonstrate moderate impairments in glucose metabolism years before the clinical manifestation of type 2 diabetes, a state called 'prediabetes'. In order to elucidate the pathophysiological processes leading to type 2 diabetes, we aimed to identify protein biomarkers associated with prediabetes. METHODS: In a proteomics study, we used targeted selected reaction monitoring (SRM)-MS to quantify 23 candidate proteins in the plasma of 439 randomly selected men and women aged 47-76 years from the population-based German KORA F4 study. Cross-sectional associations of protein levels with prediabetes (impaired fasting glucose and/or impaired glucose tolerance), type 2 diabetes, glucose levels in both the fasting state and 2 h after an OGTT, fasting insulin and insulin resistance were investigated using regression models adjusted for technical covariables, age, sex, BMI, smoking, alcohol intake, physical inactivity, actual hypertension, triacylglycerol levels, total cholesterol/HDL-cholesterol ratio, and high-sensitivity C-reactive protein levels. RESULTS: Mannan-binding lectin serine peptidase 1 (MASP1; OR per SD 1.77 [95% CI 1.26, 2.47]), thrombospondin 1 (THBS1; OR per SD 1.55 [95% CI 1.16, 2.07]) and glycosylphosphatidylinositol-specific phospholipase D1 (GPLD1; OR per SD 1.40 [95% CI 1.01, 1.94]) were positively associated with prediabetes, and apolipoprotein A-IV (ApoA-IV; OR per SD 0.75 [95% CI 0.56, 1.00]) was inversely associated with prediabetes. MASP1 was positively associated with fasting and 2 h glucose levels. ApoA-IV was inversely and THBS1 was positively associated with 2 h glucose levels. MASP1 associations with prediabetes and fasting glucose resisted Bonferroni correction. Type 2 diabetes associations were partly influenced by glucose-lowering medication. CONCLUSIONS/INTERPRETATION: We discovered novel and independent associations of prediabetes and related traits with MASP1, and some evidence for associations with THBS1, GPLD1 and ApoA-IV, suggesting a role for these proteins in the pathophysiology of type 2 diabetes. AU - von Toerne, C. AU - Huth, C. AU - de Las Heras Gala, T. AU - Kronenberg, F.* AU - Herder, C.* AU - Koenig, W.* AU - Meisinger, C. AU - Rathmann, W.* AU - Waldenberger, M. AU - Roden, M.* AU - Peters, A. AU - Thorand, B. AU - Hauck, S.M. C1 - 48905 C2 - 41472 CY - New York SP - 1882-1892 TI - MASP1, THBS1, GPLD1 and ApoA-IV are novel biomarkers associated with prediabetes: The KORA F4 study. JO - Diabetologia VL - 59 IS - 9 PB - Springer PY - 2016 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: Autoantibodies to pancreatic beta cell proteins are markers of asymptomatic type 1 diabetes. The aim was to determine whether autoantibodies to the beta cell protein tetraspanin 7 would improve the ability to identify autoimmunity against pancreatic beta cells. METHODS: Full length and external domain fragments of tetraspanin 7 were expressed as luciferase-tagged fusion proteins and used in immunoprecipitation assays to measure autoantibodies in samples from 363 patients with type 1 diabetes at onset of disease, 503 beta cell autoantibody negative first-degree relatives of patients, and 212 relatives with autoantibodies to insulin, glutamic acid decarboxylase, insulinoma antigen 2 or zinc transporter 8. RESULTS: Antibody binding was observed against the full length and external domains of tetraspanin 7, and was strongest against the full length protein. Autoantibodies that could be inhibited by untagged tetraspanin 7 were detected in 5 (1%) of 503 autoantibody negative relatives, 3 (3.2%) of 94 autoantibody negative patients, 95 (35.3%) of 269 autoantibody positive patients, 1 (1%) of 98 single autoantibody positive relatives and 25 (21.9%) of 114 multiple autoantibody positive relatives. Progression to diabetes did not differ between multiple autoantibody positive relatives with and without tetraspanin 7 autoantibodies. CONCLUSIONS/INTERPRETATION: Tetraspanin 7 is an autoantigen in type 1 diabetes. Tetraspanin 7 autoantibodies are a marker of type 1 diabetes, but provide minor additional value to existing autoantibodies in identifying beta cell autoimmunity. AU - Walther, D.* AU - Eugster, A.* AU - Jergens, S. AU - Gavrisan, A.* AU - Weinzierl, C. AU - Telieps, T. AU - Winkler, C. AU - Ziegler, A.-G. AU - Bonifacio, E.* C1 - 48668 C2 - 41260 CY - New York SP - 1973-1976 TI - Tetraspanin 7 autoantibodies in type 1 diabetes. JO - Diabetologia VL - 59 IS - 9 PB - Springer PY - 2016 SN - 0012-186X ER - TY - JOUR AB - Aims/hypothesis Genome-wide association (GWA) studies have identified hundreds of common genetic variants associated with obesity and type 2 diabetes. These studies have usually focused on additive association tests. Identifying deviations from additivity may provide new biological insights and explain some of the missing heritability for these diseases. Methods We performed a GWA study using a dominance deviation model for BMI, obesity (29,925 cases) and type 2 diabetes (4,040 cases) in 120,286 individuals of British ancestry from the UK Biobank study. We also investigated whether single nucleotide polymorphisms previously shown to be associated with these traits showed any enrichment for departures from additivity. Results Known obesity-associated variants in FTO showed strong evidence of deviation from additivity (p(DOMDEV) = 3 x 10(-5)) through a recessive effect of the allele associated with higher BMI. The average BMI of individuals carrying zero, one or two BMI-raising alleles was 27.27 (95% CI 27.22, 27.31) kg/m(2), 27.54 (95% CI 27.50, 27.58) kg/m(2) and 28.07 (95% CI 28.00, 28.14) kg/m(2), respectively. A similar effect was observed in 105,643 individuals from the GIANT Consortium (p(DOMDEV) = 0.003; meta-analysis p(DOMDEV) = 1 x 10(-7)). For type 2 diabetes, we detected a recessive effect (p(DOMDEV) = 5 x 10(-4)) at CDKAL1. Relative to homozygous non-risk allele carriers, homozygous risk allele carriers had an OR of 1.48 (95% CI 1.32, 1.65), while the heterozygous group had an OR of 1.06 (95% CI 0.99, 1.14), a result consistent with that of a previous study. We did not identify any novel associations at genome-wide significance. Conclusions/interpretation Although we found no evidence of widespread non-additive genetic effects contributing to obesity and type 2 diabetes risk, we did find robust examples of recessive effects at the FTO and CDKAL1 loci. AU - Wood, A.R.* AU - Tyrrell, J.* AU - Beaumont, R.* AU - Jones, S.E.* AU - Tuke, M.A.* AU - Ruth, K.S.* AU - Yaghootkar, H.* AU - Freathy, R.M.* AU - Murray, A.* AU - Frayling, T.M.* AU - Weedon, M.N.* AU - GIANT Consortium (Chen, C.M. AU - Gieger, C. AU - Grallert, H. AU - Heid, I.M. AU - Heinrich, J. AU - Illig, T. AU - Lamina, C. AU - Meitinger, T. AU - Peters, A. AU - Rzehak, P. AU - Thiering, E. AU - Wichmann, H.-E.) C1 - 49070 C2 - 31323 CY - New York SP - 1214-1221 TI - Variants in the FTO and CDKAL1 loci have recessive effects on risk of obesity and type 2 diabetes, respectively. JO - Diabetologia VL - 59 IS - 6 PB - Springer PY - 2016 SN - 0012-186X ER - TY - JOUR AU - Affourtit, C.* AU - Barlow, J.* AU - Jensen, V.H.* AU - Jastroch, M. C1 - 46850 C2 - 37882 CY - New York SP - S228-S229 TI - Palmitate-induced impairment of glucose-stimulated insulin secretion by pancreatic beta cells is disconnected from concomitant mitochondrial respiratory defects. JO - Diabetologia VL - 58 PB - Springer PY - 2015 SN - 0012-186X ER - TY - JOUR AU - Böhm, A. AU - Schnauder, G.* AU - Schneeweiss, P.* AU - Hudemann, J.* AU - Niess, A.* AU - Hoffmann, C. AU - Weigert, C. AU - Machann, J. AU - Staiger, H. AU - Fritsche, A. AU - Stefan, N. AU - Häring, H.-U. C1 - 46847 C2 - 37883 CY - New York SP - S258 TI - Reduced and adverse metabolic response to supervised 8-week endurance exercise in a group at high risk for type 2 diabetes. JO - Diabetologia VL - 58 PB - Springer PY - 2015 SN - 0012-186X ER - TY - JOUR AU - Chmiel, R. AU - Giannopoulou, E.Z. AU - Winkler, C. AU - Achenbach, P. AU - Ziegler, A.-G. AU - Bonifacio, E. C1 - 42805 C2 - 35351 CY - New York SP - 411-413 TI - Progression from single to multiple islet autoantibodies often occurs soon after seroconversion: Implications for early screening. JO - Diabetologia VL - 58 IS - 2 PB - Springer PY - 2015 SN - 0012-186X ER - TY - JOUR AU - Gerst, F. AU - Kaiser, G. AU - Sartorius, T. AU - Stefan, N. AU - Häring, H.-U. AU - Ullrich, S. C1 - 46840 C2 - 37888 CY - New York SP - S45 TI - The hepatokine fetuin-A has TLR4 dependent and independent effects in islets. JO - Diabetologia VL - 58 PB - Springer PY - 2015 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: Forkhead box protein O1 (FOXO1) is a transcription factor essential for beta cell fate. Protein kinase B-dependent phosphorylation of FOXO1 at S256 (P-FOXO1) enables its binding to 14-3-3 dimers and nuclear export. Dephosphorylated FOXO1 enters nuclei and activates pro-apoptotic genes. Since our previous observations suggest that protein kinase C delta (PKCδ) induces nuclear accumulation of FOXO1, the underlying mechanism was examined. METHODS: In human islets, genetically modified mice and INS-1E cells apoptosis was assessed by TUNEL staining. Subcellular translocation of proteins was examined by confocal microscopy and signalling pathways were analysed by western blotting and overlay assay. RESULTS: In PKCδ-overexpressing (PKCδ-tg) mouse islet cells and INS-1E cells FOXO1 accumulated in nuclei, surprisingly, as P-FOXO1. PKCδ-tg decelerated IGF-1-dependent stimulation of nuclear export, indicating that changes in export caused nuclear retention of P-FOXO1. Nuclear accumulation of P-FOXO1 was accompanied by increased phosphorylation of 14-3-3ζ at S58 and reduced dimerisation of 14-3-3ζ. Palmitic acid further augmented phosphorylation of 14-3-3ζ and triggered nuclear accumulation of FOXO1 in both INS-1E and human islet cells. Furthermore, the overexpression of a phosphomimicking mutant of 14-3-3ζ (S58D) enhanced nuclear FOXO1. In accordance with the nuclear accumulation of P-FOXO1, PKCδ overexpression alone did not increase apoptotic cell death. Additionally, insulin secretion and glucose homeostasis in PKCδ-overexpressing mice remained unaffected. CONCLUSIONS/INTERPRETATION: These results suggest that PKCδ-mediated phosphorylation of 14-3-3ζ contributes to the nuclear retention of FOXO1, even when FOXO1 is phosphorylated as under non-stress conditions. P-FOXO1 does not induce pro-apoptotic genes, but may rather exert beneficial effects on beta cells.   AU - Gerst, F. AU - Kaiser, G. AU - Panse, M.* AU - Sartorius, T. AU - Pujol, A.* AU - Hennige, A.M.* AU - Machicao, F. AU - Lammers, R.* AU - Bosch, F.* AU - Häring, H.-U. AU - Ullrich, S. C1 - 46932 C2 - 39064 SP - 2819-2831 TI - Protein kinase Cδ regulates nuclear export of FOXO1 through phosphorylation of the chaperone 14-3-3ζ. JO - Diabetologia VL - 58 IS - 12 PY - 2015 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: Autoantibodies that precede type 1 diabetes frequently develop in early childhood and target distinct beta cell proteins. The aim of this study was to determine the heterogeneity of islet autoantibody development and fate. METHODS: The ages of development of insulin autoantibodies (IAA) and GAD autoantibodies (GADA), followed by multiple islet autoantibodies and progression to diabetes were examined in 2,441 children participating in two German birth cohorts. RESULTS: In 218 children who developed islet autoantibodies, the first islet autoantibody-positive sample was characterised by single IAA in 80 (37%), multiple islet autoantibodies in 68 (31%) and single GADA in 63 (29%) children. Of the children who were single antibody positive at seroconversion, 35 (44%) IAA-positive and 15 (24%) GADA-positive children developed multiple islet autoantibodies. Single persistent antibodies had heterogeneous affinities; GADA were also heterogeneous in their binding to N-terminally truncated GAD65 and in an ELISA. Progression to diabetes occurred in >50% of children within 10 years in all groups that developed multiple islet autoantibodies and in 44% of children with persistent single high-affinity IAA or persistent single GADA that were positive in both a radiobinding assay and ELISA. The earliest autoantibody development was seen in children with single IAA that progressed to multiple islet autoantibodies or in those with persistent high-affinity single IAA, with a sharp peak in incidence observed at age 9 months. The peak incidence occurred at age 2 years for children who underwent seroconversion directly to multiple islet autoantibodies and at 5 years for children who first seroconverted to GADA and subsequently developed other autoantibodies. Seroconversion to low-affinity IAA or persistent single GADA occurred at a low incidence after the age of 9 months. CONCLUSIONS/INTERPRETATION: Children of different ages have differing susceptibilities to autoimmunisation against specific beta cell autoantigens. AU - Giannopoulou, E.Z. AU - Winkler, C. AU - Chmiel, R. AU - Matzke, C. AU - Scholz, M. AU - Beyerlein, A. AU - Achenbach, P. AU - Bonifacio, E. AU - Ziegler, A.-G. C1 - 45679 C2 - 37423 SP - 2317-2323 TI - Islet autoantibody phenotypes and incidence in children at increased risk for type 1 diabetes. JO - Diabetologia VL - 58 IS - 10 PY - 2015 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: The therapeutic benefit of physical activity to prevent and treat type 2 diabetes is commonly accepted. However, the impact of the disease on the acute metabolic response is less clear. To this end, we investigated the effect of type 2 diabetes on exercise-induced plasma metabolite changes and the muscular transcriptional response using a complementary metabolomics/transcriptomics approach. METHODS: We analysed 139 plasma metabolites and hormones at nine time points, and whole genome expression in skeletal muscle at three time points, during a 60 min bicycle ergometer exercise and a 180 min recovery phase in type 2 diabetic patients and healthy controls matched for age, percentage body fat and maximal oxygen consumption ([Formula: see text]). RESULTS: Pathway analysis of differentially regulated genes upon exercise revealed upregulation of regulators of GLUT4 (SLC2A4RG, FLOT1, EXOC7, RAB13, RABGAP1 and CBLB), glycolysis (HK2, PFKFB1, PFKFB3, PFKM, FBP2 and LDHA) and insulin signal mediators in diabetic participants compared with controls. Notably, diabetic participants had normalised rates of lactate and insulin levels, and of glucose appearance and disappearance, after exercise. They also showed an exercise-induced compensatory regulation of genes involved in biosynthesis and metabolism of amino acids (PSPH, GATM, NOS1 and GLDC), which responded to differences in the amino acid profile (consistently lower plasma levels of glycine, cysteine and arginine). Markers of fat oxidation (acylcarnitines) and lipolysis (glycerol) did not indicate impaired metabolic flexibility during exercise in diabetic participants. CONCLUSIONS/INTERPRETATION: Type 2 diabetic individuals showed specific exercise-regulated gene expression. These data provide novel insight into potential mechanisms to ameliorate the disturbed glucose and amino acid metabolism associated with type 2 diabetes. AU - Hansen, J.S.* AU - Zhao, X.* AU - Irmler, M. AU - Liu, X.* AU - Hoene, M.* AU - Scheler, M. AU - Li, Y.* AU - Beckers, J. AU - Hrabě de Angelis, M. AU - Häring, H.-U. AU - Pedersen, B.K.* AU - Lehmann, R. AU - Xu, G.* AU - Plomgaard, P.* AU - Weigert, C. C1 - 45248 C2 - 37268 CY - New York SP - 1845-1854 TI - Type 2 diabetes alters metabolic and transcriptional signatures of glucose and amino acid metabolism during exercise and recovery. JO - Diabetologia VL - 58 IS - 8 PB - Springer PY - 2015 SN - 0012-186X ER - TY - JOUR AU - Heni, M.* AU - Kullmann, S. AU - Gallwitz, B.* AU - Häring, H.-U. AU - Preissl, H. AU - Fritsche, A. C1 - 46844 C2 - 37885 CY - New York SP - S305 TI - Associations of glucagon-like peptide 1 with food processing in the brain are present in lean and obese humans. JO - Diabetologia VL - 58 PB - Springer PY - 2015 SN - 0012-186X ER - TY - JOUR AU - Ivanova-Cederstroem, A. AU - Klymiuk, N.* AU - Kemter, E.* AU - Andree, C.* AU - Wuensch, A.* AU - Kurome, M.* AU - Kessler, B.* AU - Richter, D. AU - Müller, A. AU - Kurth, T.* AU - Bickle, M.* AU - Wolf, E.* AU - Solimena, M. C1 - 46842 C2 - 37886 CY - New York SP - S217 TI - Generation of the transgenic INS-SNAP (SOFIA) pig for the high-throughput high-content study of insulin granule biogenesis and turnover in isolated islets. JO - Diabetologia VL - 58 PB - Springer PY - 2015 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS:High intake of carbohydrates, particularly sucrose, in western societies is associated with the development of non-alcoholic fatty liver (NAFL) and diabetes mellitus. It is unclear whether this is related primarily to the carbohydrate quantity or to the hormonal responses, particularly glucose-dependent insulinotropic polypeptide (GIP), which is released in the proximal intestine. Therefore, we investigated the role of GIP by comparing two glucose-fructose dimers, sucrose and Palatinose (isomaltulose), resorbed proximally or distally. METHODS: The glycaemic and incretin responses to sucrose and Palatinose were studied by oral gavage and meal tests. We then analysed phenotypic and metabolic diet-induced changes in C57Bl/6J mice exposed to isoenergetic diets differing in carbohydrate type. Studies were repeated in GIP receptor knockout (Gipr -/-) mice and their wild-type littermates. RESULTS: Compared with sucrose, Palatinose intake resulted in slower glucose absorption and reduced postprandial insulin and GIP levels. After 22 weeks, Palatinose feeding prevented hepatic steatosis (48.5%) compared with sucrose and improved glucose tolerance, without differences in body composition and food intake. Ablation of GIP signalling in Gipr -/- mice completely prevented the deleterious metabolic effects of sucrose feeding. Furthermore, our microarray analysis indicated that sucrose increased 2.3-fold the hepatic expression of Socs2, which is involved in the growth hormone signalling pathway and participates in the development of NAFL. CONCLUSIONS/INTERPRETATION: Our results suggest that the site of glucose absorption and the GIP response determine liver fat accumulation and insulin resistance. GIP may play a role in sucrose induced fatty liver by regulating the expression of Socs2. AU - Keyhani-Nejad, F.* AU - Irmler, M. AU - Isken, F.* AU - Wirth, E.K.* AU - Beckers, J. AU - Birkenfeld, A.L.* AU - Pfeiffer, A.F.H.* C1 - 32641 C2 - 35190 CY - New York SP - 374-383 TI - Nutritional strategy to prevent fatty liver and insulin resistance independent from obesity by reducing glucose-dependent insulinotropic polypeptide responses in mice. JO - Diabetologia VL - 58 IS - 2 PB - Springer PY - 2015 SN - 0012-186X ER - TY - JOUR AB - Aims/hypothesis: The role of biomarkers of subclinical inflammation in the early deterioration of glycaemia before type 2 diabetes is largely unknown. We hypothesised that increased levels of circulating proinflammatory biomarkers and decreased circulating adiponectin would be associated with 7 year increases of HbA1c in non-diabetic individuals. Methods: This study was based on individuals who participated in the prospective Cooperative Health Research in the Region of Augsburg (KORA) S4 survey (1999–2001) and the 7 year follow-up KORA F4 (2006–2008) survey. Individuals with type 2 diabetes at baseline or with a diagnosis of diabetes in the period between both surveys were excluded, which left a sample of 850 men and women. Multivariable linear regression analyses were performed to assess associations among baseline values of leucocyte count and levels of acute-phase proteins (high-sensitivity C-reactive protein [hsCRP], serum amyloid A [SAA] and fibrinogen), IL-6 and adiponectin with changes in HbA1c between baseline and follow-up. Results: A high leucocyte count and high hsCRP, SAA and IL-6 levels were positively associated with changes in HbA1c after adjusting for age, sex, lifestyle factors and baseline HbA1c. In contrast, the adiponectin level was inversely associated with changes in HbA1c (p value between <0.0001 and 0.020). The associations of leucocyte count and levels of hsCRP and SAA with HbA1c changes remained significant after additional adjustment for waist circumference and circulating lipids at baseline and for the 7 year change in waist circumference (p value between 0.004 and 0.045). Conclusions/interpretation: An elevated leucocyte count and elevated hsCRP and SAA were associated with early deterioration of glycaemia before the diagnosis of type 2 diabetes. These associations were largely independent of baseline abdominal adiposity and increases in waist circumference. AU - Klüppelholz, B.* AU - Thorand, B. AU - Koenig, W.* AU - de Las Heras Gala, T. AU - Meisinger, C. AU - Huth, C. AU - Giani, G.* AU - Franks, P.W.* AU - Roden, M.* AU - Rathmann, W.* AU - Peters, A. AU - Herder, C.* C1 - 46412 C2 - 37686 SP - 2269-2277 TI - Association of subclinical inflammation with deterioration of glycaemia before the diagnosis of type 2 diabetes: The KORA S4/F4 study. JO - Diabetologia VL - 58 IS - 10 PY - 2015 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: Islet autoantibodies, in addition to elevated blood glucose, define type 1 diabetes. These autoantibodies are detectable for a variable period of time before diabetes onset. Thus, the occurrence of islet autoantibodies is associated with the beginning of the disease process. The age at, and order in, which autoantibodies appear may be associated with different genetic backgrounds or environmental exposures, or both. METHODS: Infants with HLA-DR high-risk genotypes (DR3/4, DR4/4, DR4/8 and DR3/3) were enrolled and prospectively followed with standardised autoantibody assessments quarterly throughout the first 4 years of life and then semi-annually thereafter. RESULTS: Autoantibodies appeared in 549/8,503 (6.5%) children during 34,091 person-years of follow-up. Autoantibodies at 3 (0.1%) and 6 (0.2%) months of age were rare. Of the 549, 43.7% had islet autoantibodies to insulin (IAA) only, 37.7% had glutamic acid decarboxylase autoantibodies (GADA) only, 13.8% had both GADA and IAA only, 1.6% had insulinoma antigen-2 only and 3.1% had other combinations. The incidence of IAA only peaked within the first year of life and declined over the following 5 years, but GADA only increased until the second year and remained relatively constant. GADA only were more common than IAA only in HLA-DR3/3 children but less common in HLA-DR4/8 children. CONCLUSIONS/INTERPRETATION: Islet autoantibodies can occur very early in life and the order of appearance was related to HLA-DR-DQ genotype. AU - Krischer, J.P.* AU - Lynch, K.F.* AU - Schatz, D.A.* AU - Ilonen, J.* AU - Lernmark, A.* AU - Hagopian, W.A.* AU - Rewers, M.J.* AU - She, J.X.* AU - Simell, O.G.* AU - Toppari, J.* AU - Ziegler, A.-G. AU - Akolkar, B.* AU - Bonifacio, E.* AU - TEDDY Study Group (Beyerlein, A. AU - Hummel, M. AU - Hummel, S. AU - Knopff, A. AU - Peplow, C. AU - Roth, R. AU - Stock, J. AU - Strauss, E. AU - Warncke, K. AU - Winkler, C.) C1 - 44014 C2 - 36697 CY - New York SP - 980-987 TI - The 6 year incidence of diabetes-associated autoantibodies in genetically at-risk children: The TEDDY study. JO - Diabetologia VL - 58 IS - 5 PB - Springer PY - 2015 SN - 0012-186X ER - TY - JOUR AB - The fluidity of cell membranes has been hypothesised as an important link in the association of fatty acids (FAs) with diabetes risk. The lipophilic index, which can be derived from the FA profile of blood or tissues, has recently been proposed as a novel measure of cell membrane FA fluidity. In this study we aimed to evaluate the lipophilic index in relation to the incidence of type 2 diabetes. We applied a nested case-cohort design (n = 1,740, including 362 cases) within the EPIC-Potsdam study, which involves 27,548 middle-aged men and women. Erythrocyte membrane FA proportions were measured at baseline and physician-confirmed incident diabetes was assessed during a mean follow-up of 7.0 years. The lipophilic index was calculated as the sum of the products of the FA proportions with the respective FA melting points. After multivariable adjustments, including body size measures, there was a positive association between the lipophilic index and diabetes risk (HR comparing top with bottom quartile 1.59 (95% CI 1.08, 2.34), p for trend across quartiles = 0.005). Adjustment for FAs, which are considered established diabetes risk markers, did not substantially attenuate this association. A high lipophilic index, reflecting lower membrane fluidity, may be associated with a higher risk of type 2 diabetes. Our data corroborate the hypothesis that membrane fluidity may be an important mediator that links intake and metabolism of FAs to diabetes risk. AU - Kröger, J.* AU - Jacobs, S.* AU - Jansen, E.H.J.M.* AU - Fritsche, A. AU - Boeing, H.* AU - Schulze, M.B.* C1 - 43291 C2 - 36546 CY - New York SP - 282-289 TI - Erythrocyte membrane fatty acid fluidity and risk of type 2 diabetes in the EPIC-Potsdam study. JO - Diabetologia VL - 58 IS - 2 PB - Springer PY - 2015 SN - 0012-186X ER - TY - JOUR AB - Aims/hypothesis: We selected the most informative protein biomarkers for the prediction of incident cardiovascular disease (CVD) in people with type 2 diabetes. Methods: In this nested case–control study we measured 42 candidate CVD biomarkers in 1,123 incident CVD cases and 1,187 controls with type 2 diabetes selected from five European centres. Combinations of biomarkers were selected using cross-validated logistic regression models. Model prediction was assessed using the area under the receiver operating characteristic curve (AUROC). Results: Sixteen biomarkers showed univariate associations with incident CVD. The most predictive subset selected by forward selection methods contained six biomarkers: N-terminal pro-B-type natriuretic peptide (OR 1.69 per 1 SD, 95% CI 1.47, 1.95), high-sensitivity troponin T (OR 1.29, 95% CI 1.11, 1.51), IL-6 (OR 1.13, 95% CI 1.02, 1.25), IL-15 (OR 1.15, 95% CI 1.01, 1.31), apolipoprotein C-III (OR 0.79, 95% CI 0.70, 0.88) and soluble receptor for AGE (OR 0.84, 95% CI 0.76, 0.94). The prediction of CVD beyond clinical covariates improved from an AUROC of 0.66 to 0.72 (AUROC for Framingham Risk Score covariates 0.59). In addition to the biomarkers, the most important clinical covariates for improving prediction beyond the Framingham covariates were estimated GFR, insulin therapy and HbA1c. Conclusions/interpretation: We identified six protein biomarkers that in combination with clinical covariates improved the prediction of our model beyond the Framingham Score covariates. Biomarkers can contribute to improved prediction of CVD in diabetes but clinical data including measures of renal function and diabetes-specific factors not included in the Framingham Risk Score are also needed. AU - Looker, H.C.* AU - Colombo, M.* AU - Agakov, F.V.* AU - Zeller, T.* AU - Groop, L.C.* AU - Thorand, B. AU - Palmer, C.N.* AU - Hamsten, A.* AU - dé Fairé, U.H.* AU - Nogoceke, E.* AU - Livingstone, S.J.* AU - Salomaa, V.V.* AU - Leander, K.* AU - Barbarini, N.N.* AU - Bellazzi, R.* AU - van Zuydam, N.* AU - McKeigue, P.M.* AU - Colhoun, H.M.* AU - SUMMIT Investigators (*) C1 - 43802 C2 - 36760 CY - New York SP - 1363-1371 TI - Protein biomarkers for the prediction of cardiovascular disease in type 2 diabetes. JO - Diabetologia VL - 58 IS - 6 PB - Springer PY - 2015 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: Epidemiological studies have found that a diet high in fibre and coffee, but low in red meat, reduces the risk for type 2 diabetes. We tested the hypothesis that these nutritional modifications differentially improve whole-body insulin sensitivity (primary outcome) and secretion. METHODS: Inclusion criteria were: age 18-69 years, BMI ≥30 kg/m(2), type 2 diabetes treated with diet, metformin or acarbose and known disease duration of ≤5 years. Exclusion criteria were: HbA1c >75 mmol/mol (9.0%), type 1 or secondary diabetes types and acute or chronic diseases including cancer. Patients taking any medication affecting the immune system or insulin sensitivity, other than metformin, were also excluded. Of 59 patients (randomised using randomisation blocks [four or six patients] with consecutive numbers), 37 (54% female) obese type 2 diabetic patients completed this controlled parallel-group 8-week low-energy dietary intervention. The participants consumed either a diet high in cereal fibre (whole grain wheat/rye: 30-50 g/day) and coffee (≥5 cups/day), and free of red meat (L-RISK, n = 17) or a diet low in fibre (≤10 g/day), coffee-free and high in red meat (≥150 g/day) diet (H-RISK, n = 20). Insulin sensitivity and secretion were assessed by hyperinsulinaemic-euglycaemic clamp and intravenous glucose tolerance tests with isotope dilution. Whole-body and organ fat contents were measured by magnetic resonance imaging and spectroscopy. RESULTS: Whole-body insulin sensitivity increased in both groups (mean [95% CI]) (H-RISK vs L-RISK: 0.8 [0.2, 1.4] vs 1.0 [0.4, 1.7] mg kg(-1) min(-1), p = 0.59), while body weight decreased (-4.8% [-6.1%, -3.5%] vs -4.6% [-6.0%, -3.3%], respectively). Hepatic insulin sensitivity remained unchanged, whereas hepatocellular lipid content fell in both groups (-7.0% [-9.6%, -4.5%] vs -6.7% [-9.5%, -3.9%]). Subcutaneous fat mass (-1,553 [-2,767, -340] cm(3) vs -751 [-2,047; 546] cm(3), respectively) visceral fat mass (-206 [-783, 371] cm(3) vs -241 [-856, 373] cm(3), respectively) and muscle fat content (-0.09% [-0.16%, -0.02%] vs -0.02% [-0.10%, 0.05%], respectively) decreased similarly. Insulin secretion remained unchanged, while the proinflammatory marker IL-18 decreased only after the L-RISK diet. CONCLUSIONS/INTERPRETATION: No evidence of a difference between both low-energy diets was identified. Thus, energy restriction per se seems to be key for improving insulin action in phases of active weight loss in obese type 2 diabetic patients, with a potential improvement of subclinical inflammation with the L-RISK diet. TRIAL REGISTRATION: Clinicaltrials.gov NCT01409330 FUNDING: This study was supported by the Ministry of Science and Research of the State of North Rhine-Westphalia (MIWF NRW), the German Federal Ministry of Health (BMG), the Federal Ministry for Research (BMBF) to the Center for Diabetes Research (DZD e.V.) and the Helmholtz Alliance Imaging and Curing Environmental Metabolic Diseases (ICEMED). AU - Nowotny, B.* AU - Zahiragic, L.* AU - Bierwagen, A.* AU - Kabisch, S.* AU - Groener, J.B.* AU - Nowotny, P.J.* AU - Fleitmann, A.K.* AU - Herder, C.* AU - Pacini, G.* AU - Erlund, I.* AU - Landberg, R.* AU - Häring, H.-U. AU - Pfeiffer, A.F.* AU - Nawroth, P.P.* AU - Roden, M.* C1 - 43183 C2 - 36070 CY - New York SP - 255-264 TI - Low-energy diets differing in fibre, red meat and coffee intake equally improve insulin sensitivity in type 2 diabetes: A randomised feasibility trial. JO - Diabetologia VL - 58 IS - 2 PB - Springer PY - 2015 SN - 0012-186X ER - TY - JOUR AU - Panse, M.* AU - Kaiser, G. AU - Gerst, F. AU - Häring, H.-U. AU - Ullrich, S. C1 - 46845 C2 - 37884 CY - New York SP - S232 TI - Downregulation of TxNIP under glucolipotoxic conditions in insulin secreting cells. JO - Diabetologia VL - 58 PB - Springer PY - 2015 SN - 0012-186X ER - TY - JOUR AU - Petzold, A. AU - Knoch, K.-P. AU - Sönmez, A. AU - Wegbrod, C. AU - Münster, C. AU - Friedrich, A. AU - Roivainen, M.* AU - Solimena, M. C1 - 46837 C2 - 37891 CY - New York SP - S229-S230 TI - Coxsackievirus B5 infection and CVB5 proteases 2A and 3C both increase caspase 3/7 activity independently from apoptosis and reduce insulin granule cargoes in beta cells. JO - Diabetologia VL - 58 PB - Springer PY - 2015 SN - 0012-186X ER - TY - JOUR AB - Aims/hypothesis: Oestrogens have previously been shown to exert beta cell protective, glucose-lowering effects in mouse models. Therefore, the recent development of a glucagon-like peptide-1 (GLP-1)–oestrogen conjugate, which targets oestrogen into cells expressing GLP-1 receptors, offers an opportunity for a cell-specific and enhanced beta cell protection by oestrogen. The purpose of this study was to compare the effects of GLP-1 and GLP-1–oestrogen during beta cell failure under glucolipotoxic conditions. Methods: Male New Zealand obese (NZO) mice were treated with daily s.c. injections of GLP-1 and GLP-1–oestrogen, respectively. Subsequently, the effects on energy homeostasis and beta cell integrity were measured. In order to clarify the targeting of GLP-1–oestrogen, transcription analyses of oestrogen-responsive genes in distinct tissues as well as microarray analyses in pancreatic islets were performed. Results: In contrast to GLP-1, GLP-1–oestrogen significantly decreased food intake resulting in a substantial weight reduction, preserved normoglycaemia, increased glucose tolerance and enhanced beta cell protection. Analysis of hypothalamic mRNA profiles revealed elevated expression of Pomc and Leprb. In livers from GLP-1–oestrogen-treated mice, expression of lipogenic genes was attenuated and hepatic triacylglycerol levels were decreased. In pancreatic islets, GLP-1–oestrogen altered the mRNA expression to a pattern that was similar to that of diabetes-resistant NZO females. However, conventional oestrogen-responsive genes were not different, indicating rather indirect protection of pancreatic beta cells. Conclusions/interpretation: GLP-1–oestrogen efficiently protects NZO mice against carbohydrate-induced beta cell failure by attenuation of hyperphagia. In this regard, targeted delivery of oestrogen to the hypothalamus by far exceeds the anorexigenic capacity of GLP-1 alone. AU - Schwenk, R.W.* AU - Baumeier, C.* AU - Finan, B. AU - Kluth, O.* AU - Brauer, C.* AU - Joost, H.G.* AU - DiMarchi, R.D.* AU - Tschöp, M.H. AU - Schürmann, A.* C1 - 43009 C2 - 35974 CY - New York SP - 604-614 TI - GLP-1–oestrogen attenuates hyperphagia and protects from beta cell failure in diabetes-prone New Zealand Obese (NZO) mice. JO - Diabetologia VL - 58 IS - 3 PB - Springer PY - 2015 SN - 0012-186X ER - TY - JOUR AU - Speier, S. AU - Chmelova, H. AU - Chouinard, J.A. AU - Cohrs, C.M. AU - Jahn, S. AU - Chen, C. C1 - 46839 C2 - 37889 CY - New York SP - S278 TI - Calcium independent functional compensation of beta cells predominates islet mass adaptation in diet induced insulin resistance. JO - Diabetologia VL - 58 PB - Springer PY - 2015 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: Lack of reversal of prediabetes (impaired glucose tolerance and/or impaired fasting glucose) to normal glucose regulation (NGR) during a lifestyle intervention is strongly associated with a higher incidence of diabetes later in life. In the Tübingen Lifestyle Intervention Program (TULIP) we hypothesised that an at-risk phenotype may exist at baseline that associates with this nonresponse to the intervention. METHODS: A total of 120 participants of TULIP with prediabetes at baseline were studied. Participants underwent 9 months of lifestyle intervention and had measurements of insulin secretion and insulin sensitivity during a 75 g OGTT, and measurements of liver fat content by proton magnetic resonance spectroscopy. RESULTS: During the lifestyle intervention, 55% of the participants did not revert to NGR. Even among participants with the largest body fat loss (upper quartile: -6.9 ± 3.3%, mean ± SD), 40% did not revert to NGR. In this regard, we identified at baseline a high-risk phenotype (n = 72) consisting of low disposition index or low insulin sensitivity + nonalcoholic fatty liver disease (NAFLD) and a low-risk phenotype (n = 48, all other traits). While the adjusted decrease in body fat was almost identical between these phenotypes (-5.7 ± 15.3% vs -7.7 ± 15.2%, p = 0.49), the high-risk phenotype had a smaller decrease in adjusted 2 h blood glucose levels (-3.7 ± 20.3% vs -18.5 ± 20.0%, p = 0.0009). In addition, only 31% of the participants with the high-risk phenotype, but 67% with the low-risk phenotype, reverted to NGR (p < 0.0001). The odds ratio for reaching the status NGR was 4.54 (95% CI 2.08, 9.94) for participants having the low-risk phenotype. CONCLUSIONS/INTERPRETATION: Stratification of individuals with prediabetes at baseline into a high-risk and a low-risk phenotype, based on corrected insulin secretion and insulin-resistant NAFLD, may help to determine the effectiveness of a lifestyle intervention to revert individuals to NGR.   AU - Stefan, N. AU - Staiger, H. AU - Wagner, R. AU - Machann, J. AU - Schick, F. AU - Häring, H.-U. AU - Fritsche, A. C1 - 46963 C2 - 39092 SP - 2877-2884 TI - A high-risk phenotype associates with reduced improvement in glycaemia during a lifestyle intervention in prediabetes. JO - Diabetologia VL - 58 IS - 12 PY - 2015 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: Ketogenic diets (KDs) have increasingly gained attention as effective means for weight loss and potential adjunctive treatment of cancer. The metabolic benefits of KDs are regularly ascribed to enhanced hepatic secretion of fibroblast growth factor 21 (FGF21) and its systemic effects on fatty-acid oxidation, energy expenditure (EE) and body weight. Ambiguous data from Fgf21-knockout animal strains and low FGF21 concentrations reported in humans with ketosis have nevertheless cast doubt regarding the endogenous function of FGF21. We here aimed to elucidate the causal role of FGF21 in mediating the therapeutic benefits of KDs on metabolism and cancer. METHODS: We established a dietary model of increased vs decreased FGF21 by feeding C57BL/6J mice with KDs, either depleted of protein or enriched with protein. We furthermore used wild-type and Fgf21-knockout mice that were subjected to the respective diets, and monitored energy and glucose homeostasis as well as tumour growth after transplantation of Lewis lung carcinoma cells. RESULTS: Hepatic and circulating, but not adipose tissue, FGF21 levels were profoundly increased by protein starvation, independent of the state of ketosis. We demonstrate that endogenous FGF21 is not essential for the maintenance of normoglycaemia upon protein and carbohydrate starvation and is therefore not needed for the effects of KDs on EE. Furthermore, the tumour-suppressing effects of KDs were independent of FGF21 and, rather, driven by concomitant protein and carbohydrate starvation. CONCLUSIONS/INTERPRETATION: Our data indicate that the multiple systemic effects of KD exposure in mice, previously ascribed to increased FGF21 secretion, are rather a consequence of protein malnutrition. AU - Stemmer, K. AU - Zani, F. AU - Habegger, K.M.* AU - Neff, C. AU - Kotzbeck, P. AU - Bauer, M. AU - Yalamanchilli, S. AU - Azad, A.* AU - Lehti, M.* AU - Martins, P.J.* AU - Müller, T.D. AU - Pfluger, P.T. AU - Seeley, R.J.* C1 - 45399 C2 - 37333 SP - 2414-2423 TI - FGF21 is not required for glucose homeostasis, ketosis or tumour suppression associated with ketogenic diets in mice. JO - Diabetologia VL - 58 IS - 10 PY - 2015 SN - 0012-186X ER - TY - JOUR AU - Stertmann, J. AU - Cohrs, C.M. AU - Chen, C. AU - Chmelova, H. AU - Solimena, M. AU - Speier, S. C1 - 46841 C2 - 37887 CY - New York SP - S251 TI - Comparative biology of porcine and human islets in situ and after xenotransplantation in vivo. JO - Diabetologia VL - 58 PB - Springer PY - 2015 SN - 0012-186X ER - TY - JOUR AU - van Waateringe, R.P.* AU - Mook-Kanamori, M.J.* AU - Slagter, S.N.* AU - van der Klauw, M.M.* AU - van Vliet-Ostaptchouk, J.V.* AU - Graaff, R.* AU - Lutgers, H.L.* AU - Suhre, K. AU - Selim, M.M.E.* AU - Takiddin, A.H.* AU - Al-Homsi, H.* AU - Al-Mahmoud, K.A.S.* AU - Wolffenbuttel, B.H.R.* AU - Mook-Kanamori, D.O.* C1 - 46836 C2 - 37892 CY - New York SP - S155-S156 TI - Skin autofluorescence is related to tobacco smoke and nicotine exposure. JO - Diabetologia VL - 58 PB - Springer PY - 2015 SN - 0012-186X ER - TY - JOUR AU - Wagner, R. AU - Heni, M. AU - Machann, J.* AU - Schick, F.* AU - Hatziagelaki, E.* AU - Machicao, F. AU - Staiger, H. AU - Häring, H.-U. AU - Fritsche, A. C1 - 46851 C2 - 37881 CY - New York SP - S142 TI - SNP x SNP interactions in the VPS13C/C2CD4A/C2CD4B locus modulate diabetes risk. JO - Diabetologia VL - 58 PB - Springer PY - 2015 SN - 0012-186X ER - TY - JOUR AB - Aims/hypothesis: Metabolomics has opened new avenues for studying metabolic alterations in type 2 diabetes. While many urine and blood metabolites have been associated individually with diabetes, a complete systems view analysis of metabolic dysregulations across multiple biofluids and over varying timescales of glycaemic control is still lacking. Methods: Here we report a broad metabolomics study in a clinical setting, covering 2,178 metabolite measures in saliva, blood plasma and urine from 188 individuals with diabetes and 181 controls of Arab and Asian descent. Using multivariate linear regression we identified metabolites associated with diabetes and markers of acute, short-term and long-term glycaemic control. Results: Ninety-four metabolite associations with diabetes were identified at a Bonferroni level of significance (p < 2.3 × 10−5), 16 of which have never been reported. Sixty-five of these diabetes-associated metabolites were associated with at least one marker of glycaemic control in the diabetes group. Using Gaussian graphical modelling, we constructed a metabolic network that links diabetes-associated metabolites from three biofluids across three different timescales of glycaemic control. Conclusions/interpretation: Our study reveals a complex network of biochemical dysregulation involving metabolites from different pathways of diabetes pathology, and provides a reference framework for future diabetes studies with metabolic endpoints. AU - Yousri, N.A.* AU - Mook-Kanamori, D.O.* AU - Selim, M.M.E.D.* AU - Takiddin, A.H.* AU - Al-Homsi, H.* AU - Al-Mahmoud, K.A.S.* AU - Karoly, E.D.* AU - Krumsiek, J. AU - Do, K.T. AU - Neumaier, U. AU - Mook-Kanamori, M.J.* AU - Rowe, J.* AU - Chidiac, O.M.* AU - McKeon, C.* AU - Al Muftah, W.A.* AU - Kader, S.A.* AU - Kastenmüller, G. AU - Suhre, K.* C1 - 45296 C2 - 37271 CY - New York SP - 1855-1867 TI - A systems view of type 2 diabetes-associated metabolic perturbations in saliva, blood and urine at different timescales of glycaemic control. JO - Diabetologia VL - 58 IS - 8 PB - Springer PY - 2015 SN - 0012-186X ER - TY - JOUR AU - Yousri, N.A.* AU - Mook-Kanamori, D.O.* AU - El-Din Selim, M.M.* AU - Takiddin, A.H.* AU - Al-Homsi, H.* AU - Al-Mahmoud, K.A.S.* AU - Karoly, E.D.* AU - Krumsiek, J. AU - Do, K.T. AU - Neumaier, U.* AU - Mook-Kanamori, M.J.* AU - Rowe, J.* AU - Chidiac, O.M.* AU - McKeon, C.* AU - Al Muftah, W.A.* AU - Kader, S.A.* AU - Kastenmüller, G. AU - Suhre, K.* C1 - 46283 C2 - 37433 CY - New York SP - 2199 TI - Erratum to: A systems view of type 2 diabetes-associated metabolic perturbations in saliva, blood and urine at different timescales of glycaemic control. JO - Diabetologia VL - 58 IS - 9 PB - Springer PY - 2015 SN - 0012-186X ER - TY - JOUR AB - Aims/hypothesis: Cardiac autonomic nervous dysfunction (CAND) raises the risk of mortality, but the glycaemic threshold at which it develops is unclear. We aimed to determine the prevalence of, risk factors for and impact of CAND in glucose intolerance and diabetes. Methods: Among 1,332 eligible participants aged 55–74 years in the population-based cross-sectional KORA S4 study, 130 had known diabetes mellitus (k-DM), and the remaining 1,202 underwent an OGTT. Heart rate variability (HRV) and QT variability were computed from supine 5 min ECGs. Results: In all, 565 individuals had normal glucose tolerance (NGT), 336 had isolated impaired fasting glucose (i-IFG), 72 had isolated impaired glucose tolerance (i-IGT), 151 had combined IFG–IGT (IFG–IGT) and 78 had newly detected diabetes mellitus (n-DM). Adjusted normal HRV limits were defined in the NGT population (5th and 95th percentiles). Three HRV measures were more frequently abnormal in those with k-DM, n-DM, IFG–IGT and i-IFG than in those with NGT (p < 0.05). The rates of CAND (≥2 of 4 HRV indices abnormal) were: NGT, 4.5%; i-IFG, 8.1%; i-IGT, 5.9%; IFG–IGT, 11.4%; n-DM, 11.7%; and k-DM, 17.5% (p < 0.05 vs NGT, except for i-IGT). Reduced HRV was associated with cardiovascular risk factors used to construct a simple screening score for CAND. Mortality was higher in participants with reduced HRV (p < 0.05 vs normal HRV). Conclusions/interpretation: In the general population aged 55–74 years, the prevalence of CAND is increased not only in individuals with diabetes, but also in those with IFG–IGT and, to a lesser degree, in those with i-IFG. It is associated with mortality and modifiable cardiovascular risk factors which may be used to screen for diminished HRV in clinical practice. AU - Ziegler, D.* AU - Voss, A.* AU - Rathmann, W.* AU - Strom, A.* AU - Perz, S. AU - Roden, M.* AU - Peters, A. AU - Meisinger, C. AU - KORA Study Group (Heinrich, J. AU - Gieger, C. AU - Grallert, H. AU - Holle, R. AU - Leidl, R. AU - Strauch, K.) C1 - 43793 C2 - 36762 CY - New York SP - 1118-1128 TI - Increased prevalence of cardiac autonomic dysfunction at different degrees of glucose intolerance in the general population: The KORA S4 survey. JO - Diabetologia VL - 58 IS - 5 PB - Springer PY - 2015 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: Subtyping GAD autoantibody (GADA) responses using affinity measurement allows the identification of GADA-positive children with a family history of type 1 diabetes who are at risk of developing diabetes. Here, we asked whether GADA affinity is a useful marker to stratify the risk of type 1 diabetes in GADA-positive schoolchildren from the general population. METHODS: GADA affinity was measured by competitive binding experiments with [(125)I]-labelled and unlabelled human 65 kDa isoform of GAD (GAD65) in sera from 97 GADA-positive children identified in the Karlsburg Type 1 Diabetes Risk Study of a general schoolchild population in north-eastern Germany. GADA epitope specificity was determined using radiobinding assays with [(35)S]-labelled GAD65/67 kDa isoform of GAD (GAD67) chimeric proteins. RESULTS: GADA affinity was high, ≥10(10) l/mol, in 33 of 35 multiple islet autoantibody-positive children. In contrast, the affinity ranged widely among 62 single GADA-positive children (median 3.1 × 10(9) l/mol; range 5.6 × 10(6) to >4.0 × 10(11) l/mol; p < 0.0001). High-affinity GADA were associated with HLA-DRB1*03 (p = 0.02) and predominantly directed against the C-terminal and/or middle part of the GAD65 protein. At follow-up, the affinity remained relatively constant. Five of the single GADA-positive children developed additional islet autoantibodies and had high-affinity GADA. Twenty-six children progressed to type 1 diabetes; among them, 23 had GADA affinities of ≥10(10) l/mol before disease onset. CONCLUSIONS/INTERPRETATION: Schoolchildren from the general population may develop heterogeneous GADA responses, and a high affinity can identify those GADA-positive children who are more likely to progress to type 1 diabetes. AU - Bender, C.* AU - Schlosser, M.* AU - Christen, U.* AU - Ziegler, A.-G. AU - Achenbach, P. C1 - 31676 C2 - 34644 CY - New York SP - 1911-1918 TI - GAD autoantibody affinity in schoolchildren from the general population. JO - Diabetologia VL - 57 IS - 9 PB - Springer PY - 2014 SN - 0012-186X ER - TY - JOUR AU - Breitfeld, J.* AU - Scholz, M.* AU - Marzi, C. AU - Grallert, H. AU - Ladenvall, C.* AU - Krause, K.* AU - Laurila, E.* AU - Isomaa, B.* AU - Groop, L.* AU - Prokopenko, I.* AU - Gieger, C. AU - Blueher, M.* AU - Stumvoll, M.* AU - Kovacs, P.* AU - Toenjes, A.* C1 - 43120 C2 - 36073 SP - S67-S68 TI - Genome wide meta-analysis highlights the role of genetic variation in RARRES2 in regulation of circulating serum chemerin. JO - Diabetologia VL - 57 PY - 2014 SN - 0012-186X ER - TY - JOUR AU - Gaulton, K.J.* AU - Morris, A.P.* AU - McCarthy, M.I.* AU - DIAGRAM Consortium (Gieger, C. AU - Grallert, H. AU - Klopp, N. AU - Illig, T. AU - Müller-Nurasyid, M. AU - Peters, A.) C1 - 43118 C2 - 36075 SP - S66 TI - FOXA2 bound sites are enriched for type 2 diabetes risk variants. JO - Diabetologia VL - 57 PY - 2014 SN - 0012-186X ER - TY - JOUR AU - Gerst, F. AU - Kaiser, G. AU - Stefan, N. AU - Häring, H.-U. AU - Ullrich, S. C1 - 43121 C2 - 36072 SP - S184 TI - The hepatokine fetuin-A triggers inflammation without inducing cell death but improves cAMP-dependent insulin secretion of pancreatic islets. JO - Diabetologia VL - 57 PY - 2014 SN - 0012-186X ER - TY - JOUR AB - Genome-wide association studies have revealed an association of the transcription factor ETS variant gene 5 (ETV5) with human obesity. However, its role in glucose homeostasis and energy balance is unknown. Etv5 knockout (KO) mice were monitored weekly for body weight (BW) and food intake. Body composition was measured at 8 and 16 weeks of age. Glucose metabolism was studied, and glucose-stimulated insulin secretion was measured in vivo and in vitro. Etv5 KO mice are smaller and leaner, and have a reduced BW and lower fat mass than their wild-type controls on a chow diet. When exposed to a high-fat diet, KO mice are resistant to diet-induced BW gain. Despite a greater insulin sensitivity, KO mice have profoundly impaired glucose tolerance associated with impaired insulin secretion. Morphometric analysis revealed smaller islets and a reduced beta cell size in the pancreatic islets of Etv5 KO mice. Knockdown of ETV5 in an insulin-secreting cell line or beta cells from human donors revealed intact mitochondrial and Ca2+ channel activity, but reduced insulin exocytosis. This work reveals a critical role for ETV5 in specifically regulating insulin secretion both in vitro and in vivo. AU - Gutierrez-Aguilar, R.* AU - Kim, D.* AU - Casimir, M.* AU - Dai, X.* AU - Pfluger, P.T. AU - Park, J.* AU - Haller, A.* AU - Donelan, E.* AU - D'Alessio, D.* AU - Woods, S.C.* AU - MacDonald, P.E.* AU - Seeley, R.J.* C1 - 29327 C2 - 33721 SP - 383-391 TI - The role of the transcription factor ETV5 in insulin exocytosis. JO - Diabetologia VL - 57 IS - 2 PB - Springer PY - 2014 SN - 0012-186X ER - TY - JOUR AU - Herder, C.* AU - Carstensen, M.* AU - Ouwens, D.M.* AU - Kowall, B.* AU - Peters, A. AU - Rathmann, W.* AU - Roden, M.* AU - Thorand, B. C1 - 43111 C2 - 36081 SP - S308 TI - Serum omentin is associated with lipid levels, but not with glucose tolerance and type 2: KORA F4 study. JO - Diabetologia VL - 57 PY - 2014 SN - 0012-186X ER - TY - JOUR AU - Kaiser, G. AU - Sabrautzki, S. AU - Gerst, F. AU - Przemeck, G.K.H. AU - Häring, H.-U. AU - Hrabě de Angelis, M. AU - Ullrich, S. C1 - 43115 C2 - 36078 SP - S172 TI - Defective compensatory insulin secretion causes HFD-induced glucose intolerance in mice with point mutation in free fatty acid receptor 1. JO - Diabetologia VL - 57 PY - 2014 SN - 0012-186X ER - TY - JOUR AU - Klingler, C.* AU - Wolf, M.* AU - Li, J.* AU - Chen, S.* AU - Zhao, X.* AU - Schleicher, E. AU - Häring, H.-U. AU - Xu, G.* AU - Lehmann, R. AU - Weigert, C. C1 - 43117 C2 - 36076 SP - S272 TI - Lysophosphatidylcholines as regulators of gene expression in human skeletal muscle. JO - Diabetologia VL - 57 PY - 2014 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: The DIRECT (Diabetes Research on Patient Stratification) Study is part of a European Union Framework 7 Innovative Medicines Initiative project, a joint undertaking between four industry and 21 academic partners throughout Europe. The Consortium aims to discover and validate biomarkers that: (1) predict the rate of glycaemic deterioration before and after type 2 diabetes onset; (2) predict the response to diabetes therapies; and (3) help stratify type 2 diabetes into clearly definable disease subclasses that can be treated more effectively than without stratification. This paper describes two new prospective cohort studies conducted as part of DIRECT. METHODS: Prediabetic participants (target sample size 2,200-2,700) and patients with newly diagnosed type 2 diabetes (target sample size ~1,000) are undergoing detailed metabolic phenotyping at baseline and 18 months and 36 months later. Abdominal, pancreatic and liver fat is assessed using MRI. Insulin secretion and action are assessed using frequently sampled OGTTs in non-diabetic participants, and frequently sampled mixed-meal tolerance tests in patients with type 2 diabetes. Biosamples include venous blood, faeces, urine and nail clippings, which, among other biochemical analyses, will be characterised at genetic, transcriptomic, metabolomic, proteomic and metagenomic levels. Lifestyle is assessed using high-resolution triaxial accelerometry, 24 h diet record, and food habit questionnaires. CONCLUSIONS/INTERPRETATION: DIRECT will yield an unprecedented array of biomaterials and data. This resource, available through managed access to scientists within and outside the Consortium, will facilitate the development of new treatments and therapeutic strategies for the prevention and management of type 2 diabetes. AU - Koivula, R.W.* AU - Heggie, A.* AU - Barnett, A.* AU - Cederberg, H.* AU - Hansen, T.H.* AU - Koopman, A.D.* AU - Ridderstråle, M.* AU - Rutters, F.* AU - Vestergaard, H.* AU - Gupta, R.* AU - Herrgård, S.* AU - Heymans, M.W.* AU - Perry, M.H.* AU - Rauh, S.* AU - Siloaho, M.* AU - Teare, H.J.* AU - Thorand, B. AU - Bell, J.* AU - Brunak, S.* AU - Frost, G.* AU - Jablonka, B.* AU - Mari, A.* AU - McDonald, T.J.* AU - Dekker, J.M.* AU - Hansen, T.* AU - Hattersley, A.* AU - Laakso, M.* AU - Pedersen, O.* AU - Koivisto, V.* AU - Ruetten, H.* AU - Walker, M.* AU - Pearson, E.* AU - Franks, P.W.* AU - DIRECT Consortium (*) C1 - 31036 C2 - 34108 CY - New York SP - 1132-1142 TI - Discovery of biomarkers for glycaemic deterioration before and after the onset of type 2 diabetes: Rationale and design of the epidemiological studies within the IMI DIRECT Consortium. JO - Diabetologia VL - 57 IS - 6 PB - Springer PY - 2014 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: Fetal programming plays an important role in the pathogenesis of type 2 diabetes. The aim of the present study was to investigate whether maternal metabolic changes during OGTT influence fetal brain activity. METHODS: Thirteen healthy pregnant women underwent an OGTT (75 g). Insulin sensitivity was determined by glucose and insulin measurements at 0, 60 and 120 min. At each time point, fetal auditory evoked fields were recorded with a fetal magnetoencephalographic device and response latencies were determined. RESULTS: Maternal insulin increased from a fasting level of 67 ± 25 pmol/l (mean ± SD) to 918 ± 492 pmol/l 60 min after glucose ingestion and glucose levels increased from 4.4 ± 0.3 to 7.4 ± 1.1 mmol/l. Over the same time period, fetal response latencies decreased from 297 ± 99 to 235 ± 84 ms (p = 0.01) and then remained stable until 120 min (235 ± 84 vs 251 ± 91 ms, p = 0.39). There was a negative correlation between maternal insulin sensitivity and fetal response latencies 60 min after glucose ingestion (r = 0.68, p = 0.02). After a median split of the group based on maternal insulin sensitivity, fetuses of insulin-resistant mothers showed a slower response to auditory stimuli (283 ± 79 ms) than those of insulin-sensitive mothers (178 ± 46 ms, p = 0.03). CONCLUSIONS/INTERPRETATION: Lower maternal insulin sensitivity is associated with slower fetal brain responses. These findings provide the first evidence of a direct effect of maternal metabolism on fetal brain activity and suggest that central insulin resistance may be programmed during fetal development. AU - Linder, K. AU - Schleger, F. AU - Ketterer, C. AU - Fritsche, L. AU - Kiefer-Schmidt, I.* AU - Hennige, A.M.* AU - Häring, H.-U. AU - Preissl, H. AU - Fritsche, A. C1 - 31039 C2 - 34111 CY - New York SP - 1192-1198 TI - Maternal insulin sensitivity is associated with oral glucose-induced changes in fetal brain activity. JO - Diabetologia VL - 57 IS - 6 PB - Springer PY - 2014 SN - 0012-186X ER - TY - JOUR AU - Morris, A.P.* AU - Teslovich, T.M.* AU - Ferreira, T.* AU - Mahajan, A.* AU - Lee, Y.* AU - Rayner, N.W.* AU - Mägi, R.* AU - DIAGRAM Consortium (Gieger, C. AU - Grallert, H. AU - Klopp, N. AU - Illig, T. AU - Müller-Nurasyid, M. AU - Peters, A.) C1 - 43114 C2 - 36079 SP - S50-S51 TI - Fine-mapping type 2 diabetes susceptibility loci with high-density imputation. JO - Diabetologia VL - 57 PY - 2014 SN - 0012-186X ER - TY - JOUR AU - Nejad, F.K.* AU - Isken, F.* AU - Osterhof, M.A.* AU - Nitz, B. AU - Ludwig, T. AU - Grallert, H. AU - Pfeifer, A.* AU - Kruse, M.* C1 - 43119 C2 - 36074 SP - S41 TI - A high fat diet during pregnancy and lactation affects the metabolic fate of Gipr-/- mice via hypothalamic insulin signalling and DNA-methylation of lipid metabolism genes. JO - Diabetologia VL - 57 PY - 2014 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: The common sequence variant I148M of the patatin-like phospholipase domain-containing protein 3 gene (PNPLA3) is associated with increased hepatic triacylglycerol (TAG) content, but not with insulin resistance, in humans. The PNPLA3 (I148M) variant was previously reported to alter the specificity of the encoded enzyme and subsequently affect lipid composition. METHODS: We analysed the fatty acid composition of five lipid fractions from liver tissue samples from 52 individuals, including 19 carriers of the minor PNPLA3 (I148M) variant. RESULTS: PNPLA3 (I148M) was associated with a strong increase (1.75-fold) in liver TAGs, but with no change in other lipid fractions. PNPLA3 (I148M) minor allele carriers had an increased n-3 polyunsaturated fatty acid (PUFA) α-linolenic acid content and reductions in several n-6 PUFAs in the liver TAG fraction. Furthermore, there was a strong inverse correlation between n-6 PUFA and TAG content independent of PNPLA3 genotype. In a multivariate model including liver fat content, PNPLA3 genotype and fatty acid composition, two significant differences could be exclusively attributed to the PNPLA3 (I148M) minor allele: reduced stearic acid and increased α-linolenic acid content in the hepatic TAG fraction. CONCLUSIONS: These changes therefore suggest a mechanism to explain the PNPLA3 (I148M)-dependent increase in liver fat content without causing insulin resistance. Stearic acid can induce insulin resistance, whereas α-linolenic acid may protect against it. AU - Peter, A. AU - Kovarova, M.* AU - Nadalin, S.* AU - Cermak, T.* AU - Königsrainer, A.* AU - Machicao, F. AU - Stefan, N. AU - Häring, H.-U. AU - Schleicher, E. C1 - 31766 C2 - 34725 CY - New York SP - 2103-2107 TI - PNPLA3 variant I148M is associated with altered hepatic lipid composition in humans. JO - Diabetologia VL - 57 IS - 10 PB - Springer PY - 2014 SN - 0012-186X ER - TY - JOUR AU - Peter, A. AU - Kantartzis, K. AU - Koenigsrainer, A. AU - Koenigsrainer, I. AU - Staiger, H. AU - Machicao, F. AU - Häring, H.-U. AU - Fritsche, A. AU - Stefan, N. C1 - 43112 C2 - 36287 SP - S294 TI - The hepatokine betatrophin is increased in nonalcoholic fatty liver disease and may affect insulin secretion in prediabetes. JO - Diabetologia VL - 57 PY - 2014 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: Vitamin D deficiency is common in people with type 1 diabetes, but its role in disease progression is unclear. Our aim was to assess the prevalence of vitamin D deficiency in prediabetes (defined as the presence of multiple islet autoantibodies), and investigate whether or not progression to type 1 diabetes is faster in children with vitamin D deficiency and multiple islet autoantibodies. METHODS: Levels of 25-hydroxyvitamin D [25(OH)D] were measured in 108 children with multiple islet autoantibodies within 2 years of islet autoantibody seroconversion, in 406 children who remained islet autoantibody-negative and in 244 patients with newly diagnosed type 1 diabetes. Children with multiple islet autoantibodies were prospectively followed for a median of 5.8 years (interquartile range 3.4-8.6 years) to monitor progression to type 1 diabetes. RESULTS: In the cross-sectional analysis, 25(OH)D levels were lower and the prevalence of vitamin D deficiency (<50 nmol/l) was higher in children with prevalent multiple islet autoantibodies than in islet autoantibody-negative children (59.9 ± 3.0 vs 71.9 ± 1.5 nmol/l; p < 0.001; 39.8% vs 28.3%; p = 0.021). The differences in vitamin D levels between the groups were greatest in summer. The cumulative incidence of type 1 diabetes at 10 years after seroconversion was similar between children with vitamin D deficiency and those with sufficient vitamin D levels (51.8% [95% CI 29.3, 74.3] vs 55.4% [95% CI 35.5, 72.3], p = 0.8). CONCLUSIONS/INTERPRETATION: Vitamin D levels were lower in children with multiple islet autoantibodies and in children with type 1 diabetes than in autoantibody-negative children. However, vitamin D deficiency was not associated with faster progression to type 1 diabetes in children with multiple islet autoantibodies.   AU - Raab, J. AU - Giannopoulou, E.Z. AU - Schneider, S. AU - Warncke, K. AU - Krasmann, M. AU - Winkler, C. AU - Ziegler, A.-G. C1 - 30645 C2 - 33764 CY - New York SP - 902-908 TI - Prevalence of vitamin D deficiency in pre-type 1 diabetes and its association with disease progression. JO - Diabetologia VL - 57 IS - 5 PB - Springer PY - 2014 SN - 0012-186X ER - TY - JOUR AU - Schlosser, M.* AU - Lampasona, V.* AU - Williams, A.J.K.* AU - Mueller, P.W.* AU - Pittman, D.L.* AU - Winter, W.E.* AU - Akolkar, B.* AU - Achenbach, P. C1 - 43116 C2 - 36077 SP - S145 TI - Combined appearance of autoantibodies against GAD, IA-2, insulin and ZnT8 in the islet autoantibody standardisation program 2013 proficiency workshop. JO - Diabetologia VL - 57 PY - 2014 SN - 0012-186X ER - TY - JOUR AU - Siegel-Axel, D. AU - Ullrich, S. AU - Stefan, N. AU - Rittig, K.* AU - Gerst, F. AU - Schmidt, U.* AU - Schreiner, B.* AU - Schaller, H.-E.* AU - Häring, H.-U. C1 - 43113 C2 - 36080 SP - S310 TI - The mRNA expression and release of (pro)-inflammatory and angiogenic factors in perivascular fat cells is influenced by fetuin-A via different signalling pathways. JO - Diabetologia VL - 57 PY - 2014 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: Fetuin-A (alpha2-Heremans-Schmid glycoprotein), a liver-derived circulating glycoprotein, contributes to lipid disorders, diabetes and cardiovascular diseases. In a previous study we found that perivascular fat cells (PVFCs) have a higher angiogenic potential than other fat cell types. The aim was to examine whether fetuin-A influences PVFC and vascular cell growth and the expression and secretion of proinflammatory and angiogenic proteins, and whether TLR4-independent pathways are involved. METHODS: Mono- and co-cultures of human PVFCs and endothelial cells were treated with fetuin-A and/or palmitate for 6-72 h. Proteins were quantified by ELISA and Luminex, mRNA expression by real-time PCR, and cell growth by BrDU-ELISA. Some PVFCs were preincubated with a nuclear factor κB NFκBp65 inhibitor, or the toll-like receptor 4 (TLR4) inhibitor CLI-095, or phosphoinositide 3-kinase (PI3K)/Akt inhibitors and/or stimulated with insulin. Intracellular forkhead box protein O1 (FoxO1), NFκBp65 and inhibitor of κB kinase β (IKKβ) localisation was visualised by immunostaining. RESULTS: PVFCs expressed and secreted IL-6, IL-8, plasminogen activator inhibitor 1 (PAI-1), basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF)-BB, monocyte chemotactic protein-1 (MCP-1), vascular endothelial growth factor (VEGF), placental growth factor (PLGF) and hepatocyte growth factor (HGF). Fetuin-A upregulated IL-6 and IL-8, and this was potentiated by palmitate and blocked by CLI-095. Immunostaining and electrophoretic mobility shift assay (EMSA) showed partial NFκBp65 activation. MCP-1 was upregulated and blocked by CLI-095, but not by palmitate. However, HGF was downregulated, which was slightly potentiated by palmitate. This effect persisted after TLR4 pathway blockade. Stimulation of insulin-PI3K-Akt signalling by insulin resulted in nuclear FoxO1 extrusion and HGF upregulation. Fetuin-A counteracted these insulin effects. CONCLUSIONS/INTERPRETATION: Fetuin-A and/or palmitate influence the expression of proinflammatory and angiogenic proteins only partially via TLR4 signalling. HGF downregulation seems to be mediated by interference with the insulin-dependent receptor tyrosine kinase pathway. Fetuin-A may also influence angiogenic and proinflammatory proteins involved in atherosclerosis. AU - Siegel-Axel, D.I. AU - Ullrich, S. AU - Stefan, N. AU - Rittig, K.* AU - Gerst, F. AU - Klingler, C.* AU - Schmidt, U.* AU - Schreiner, B.* AU - Randrianarisoa, E.* AU - Schaller, H.E.* AU - Stock, U.A.* AU - Weigert, C. AU - Königsrainer, A.* AU - Häring, H.-U. C1 - 30760 C2 - 33838 CY - New York SP - 1057-1066 TI - Fetuin-a influences vascular cell growth and production of proinflammatory and angiogenic proteins by human perivascular fat cells. JO - Diabetologia VL - 57 IS - 5 PB - Springer PY - 2014 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: Adequate evaluation of protein expression is a crucial prerequisite for functional studies. Commonly used strategies comprise detection of proteins by specific antibodies using western blotting and immunohistochemical staining, or detection of mRNA by in situ hybridisation and RT-PCR. We evaluated the tools for the detection of free fatty acid receptor 1 (FFAR1) expression. METHODS: Commercially available antibody preparations were used to detect endogenous expression of the FFAR1 receptor and this was compared with cell preparations deficient or overexpressing the mouse or human receptor. Concentrations of mRNA were evaluated by RT-PCR. RESULTS: All insulin-secreting cells, INS-1E, Min6 and mouse islets showed specific expression of Ffar1 at the mRNA level. However, none of the commercially available antibodies specifically detected rat, mouse or human FFAR1. CONCLUSIONS/INTERPRETATION: Proper positive and negative controls are an important prerequisite for the evaluation of FFAR1 expression. AU - Teutsch, C.A.* AU - Panse, M.* AU - Grundmann, M.* AU - Kaiser, G. AU - Kostenis, E.* AU - Häring, H.-U. AU - Ullrich, S. C1 - 30745 C2 - 33829 CY - New York SP - 776-780 TI - Detection of free fatty acid receptor 1 expression: The critical role of negative and positive controls. JO - Diabetologia VL - 57 IS - 4 PB - Springer PY - 2014 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: More than 40 regions of the human genome confer susceptibility for type 1 diabetes and could be used to establish population screening strategies. The aim of our study was to identify weighted sets of SNP combinations for type 1 diabetes prediction. METHODS: We applied multivariable logistic regression and Bayesian feature selection to the Type 1 Diabetes Genetics Consortium (T1DGC) dataset with genotyping of HLA plus 40 SNPs within other type 1 diabetes-associated gene regions in 4,574 cases and 1,207 controls. We tested the weighted models in an independent validation set (765 cases, 423 controls), and assessed their performance in 1,772 prospectively followed children. RESULTS: The inclusion of 40 non-HLA gene SNPs significantly improved the prediction of type 1 diabetes over that provided by HLA alone (p = 3.1 × 10(-25)), with a receiver operating characteristic AUC of 0.87 in the T1DGC set, and 0.84 in the validation set. Feature selection identified HLA plus nine SNPs from the PTPN22, INS, IL2RA, ERBB3, ORMDL3, BACH2, IL27, GLIS3 and RNLS genes that could achieve similar prediction accuracy as the total SNP set. Application of this ten SNP model to prospectively followed children was able to improve risk stratification over that achieved by HLA genotype alone. CONCLUSIONS: We provided a weighted risk model with selected SNPs that could be considered for recruitment of infants into studies of early type 1 diabetes natural history or appropriately safe prevention. AU - Winkler, C. AU - Krumsiek, J. AU - Buettner, F. AU - Angermüller, C. AU - Giannopoulou, E.Z. AU - Theis, F.J. AU - Ziegler, A.-G. AU - Bonifacio, E. C1 - 32099 C2 - 34962 SP - 2521-2529 TI - Feature ranking of type 1 diabetes susceptibility genes improves prediction of type 1 diabetes. JO - Diabetologia VL - 57 IS - 12 PY - 2014 SN - 0012-186X ER - TY - JOUR AU - Winkler, C. AU - Krumsiek, J. AU - Buettner, F. AU - Angermüller, C. AU - Giannopoulou, E.Z. AU - Theis, F.J. AU - Ziegler, A.-G. AU - Bonifacio, E. C1 - 42845 C2 - 35538 SP - 206 TI - Erratum to: Feature ranking of type 1 diabetes susceptibility genes improves prediction of type 1 diabetes. JO - Diabetologia VL - 58 IS - 1 PY - 2014 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: Islet autoantibody-positive children progress to type 1 diabetes at variable rates. In our study, we asked whether characteristic autoantibody and/or gene profiles could be defined for phenotypes showing extreme progression. METHODS: Autoantibodies to insulin (IAA), GAD (GADA), insulinoma-associated antigen-2 (IA-2A) and zinc transporter 8 (ZnT8A) were measured in follow-up sera, and genotyping for type 1 diabetes susceptibility genes (HLA-DR/HLA-DQ, INS variable number of tandem repeats [VNTR] and single nucleotide polymorphisms at PTPN22, PTPN2, ERBB3, IL2, SH2B3, CTLA4, IFIH1, KIAA0350 [also known as CLEC16A], CD25, IL18RAP, IL10, COBL) was performed on the DNA samples of children born to a parent with type 1 diabetes and prospectively followed from birth for up to 22 years. RESULTS: Of the 1,650 children followed, 23 developed multiple autoantibodies and progressed to diabetes within 3 years (rapid progressors), while 24 children developed multiple autoantibodies and remained non-diabetic for more than 10 years from seroconversion (slow progressors). Rapid and slow progressors were similar with respect to HLA-DR/HLA-DQ genotypes, development of IAA, GADA and ZnT8A, and progression to multiple autoantibodies. In contrast, IA-2A development was considerably delayed in the slow progressors. Furthermore, both groups were effectively distinguished by the combined presence or absence of type 1 diabetes susceptibility alleles of non-HLA genes, most notably IL2, CD25, INS VNTR, IL18RAP, IL10, IFIH1 and PTPN22, and discrimination was improved among children carrying high-risk HLA-DR/HLA-DQ genotypes. CONCLUSIONS/INTERPRETATION: Our data suggest that genotypes of non-HLA type 1 diabetes susceptibility genes influence the likelihood or rate of diabetes progression among children with multiple islet autoantibodies.   AU - Achenbach, P. AU - Hummel, M.* AU - Thümer, L.* AU - Boerschmann, H.* AU - Höfelmann, D. AU - Ziegler, A.-G. C1 - 24588 C2 - 31593 SP - 1615-1622 TI - Characteristics of rapid vs slow progression to type 1 diabetes in multiple islet autoantibody-positive children. JO - Diabetologia VL - 56 IS - 7 PB - Springer PY - 2013 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: Human complex metabolic traits are in part regulated by genetic determinants. Here we applied exome sequencing to identify novel associations of coding polymorphisms at minor allele frequencies (MAFs) >1% with common metabolic phenotypes. METHODS: The study comprised three stages. We performed medium-depth (8×) whole exome sequencing in 1,000 cases with type 2 diabetes, BMI >27.5 kg/m(2) and hypertension and in 1,000 controls (stage 1). We selected 16,192 polymorphisms nominally associated (p < 0.05) with case-control status, from four selected annotation categories or from loci reported to associate with metabolic traits. These variants were genotyped in 15,989 Danes to search for association with 12 metabolic phenotypes (stage 2). In stage 3, polymorphisms showing potential associations were genotyped in a further 63,896 Europeans. RESULTS: Exome sequencing identified 70,182 polymorphisms with MAF >1%. In stage 2 we identified 51 potential associations with one or more of eight metabolic phenotypes covered by 45 unique polymorphisms. In meta-analyses of stage 2 and stage 3 results, we demonstrated robust associations for coding polymorphisms in CD300LG (fasting HDL-cholesterol: MAF 3.5%, p = 8.5 × 10(-14)), COBLL1 (type 2 diabetes: MAF 12.5%, OR 0.88, p = 1.2 × 10(-11)) and MACF1 (type 2 diabetes: MAF 23.4%, OR 1.10, p = 8.2 × 10(-10)). CONCLUSIONS/INTERPRETATION: We applied exome sequencing as a basis for finding genetic determinants of metabolic traits and show the existence of low-frequency and common coding polymorphisms with impact on common metabolic traits. Based on our study, coding polymorphisms with MAF above 1% do not seem to have particularly high effect sizes on the measured metabolic traits. AU - Albrechtsen, A.* AU - Grarup, N.* AU - Li, Y.* AU - Sparsø, T.* AU - Tian, G.* AU - Cao, H.* AU - Jiang, T.* AU - Kim, S.Y.* AU - Korneliussen, T.* AU - Li, Q.* AU - Nie, C.* AU - Wu, R.* AU - Skotte, L.* AU - Morris, A.P.* AU - Ladenvall, C.* AU - Cauchi, S.* AU - Stancáková, A.* AU - Andersen, G.* AU - Astrup, A.* AU - Banasik, K.* AU - Bennett, A.J.* AU - Bolund, L.* AU - Charpentier, G.* AU - Chen, Y.* AU - Dekker, J.M.* AU - Doney, A.S.* AU - Dorkhan, M.* AU - Forsen, T.* AU - Frayling, T.M.* AU - Groves, C.J.* AU - Gui, Y.* AU - Hallmans, G.* AU - Hattersley, A.T.* AU - He, K.* AU - Hitman, G.A.* AU - Holmkvist, J.* AU - Huang, S.* AU - Jiang, H.* AU - Jin, X.* AU - Justesen, J.M.* AU - Kristiansen, K.* AU - Kuusisto, J.* AU - Lajer, M.* AU - Lantieri, O.* AU - Li, W.* AU - Liang, H.* AU - Liao, Q.* AU - Liu, X.* AU - Ma, T.* AU - Ma, X.* AU - Manijak, M.P.* AU - Marre, M.* AU - Mokrosiński, J.* AU - Morris, A.D.* AU - Mu, B.* AU - Nielsen, A.A.* AU - Nijpels, G.* AU - Nilsson, P.* AU - Palmer, C.N.* AU - Rayner, N.W.* AU - Renström, F.* AU - Ribel-Madsen, R.* AU - Robertson, N.* AU - Rolandsson, O.* AU - Rossing, P.* AU - Schwartz, T.W.* AU - D.E.S.I.R. Study Group (*) AU - Slagboom, P.E.* AU - Sterner, M.* AU - DIAGRAM Consortium (Huth, C. AU - Klopp, N. AU - Petersen, A.-K. AU - Grallert, H. AU - Gieger, C. AU - Wichmann, H.-E. AU - Meitinger, T. AU - Thorand, B. AU - Illig, T.) AU - Tang, M.* AU - Tarnow, L.* AU - Tuomi, T.* AU - van't Riet, E.* AU - van Leeuwen, N.* AU - Varga, T.V.* AU - Vestmar, M.A.* AU - Walker, M.* AU - Wang, B.* AU - Wang, Y.* AU - Wu, H.* AU - Xi, F.* AU - Yengo, L.* AU - Yu, C.* AU - Zhang, X.* AU - Zhang, J.* AU - Zhang, Q.* AU - Zhang, W.* AU - Zheng, H.* AU - Zhou, Y.* AU - Altshuler, D.* AU - 't Hart, L.M.* AU - Franks, P.W.* AU - Balkau, B.* AU - Froguel, P.* AU - McCarthy, M.I.* AU - Laakso, M.* AU - Groop, L.* AU - Christensen, C.* AU - Brandslund, I.* AU - Lauritzen, T.* AU - Witte, D.R.* AU - Linneberg, A.* AU - Jørgensen, T.* AU - Hansen, T.* AU - Wang, J.* AU - Nielsen, R.* AU - Pedersen, O.* C1 - 22998 C2 - 30977 SP - 298-310 TI - Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes. JO - Diabetologia VL - 56 IS - 2 PB - Springer PY - 2013 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: We previously identified the G6PC2 locus as a strong determinant of fasting plasma glucose (FPG) and showed that a common G6PC2 intronic single nucleotide polymorphism (SNP) (rs560887) and two common G6PC2 promoter SNPs (rs573225 and rs13431652) are highly associated with FPG. However, these promoter SNPs have complex effects on G6PC2 fusion gene expression, and our data suggested that only rs13431652 is a potentially causative SNP. Here we examine the effect of rs560887 on G6PC2 pre-mRNA splicing and the contribution of an additional common G6PC2 promoter SNP, rs2232316, to the association signal. METHODS: Minigene analyses were used to characterise the effect of rs560887 on G6PC2 pre-mRNA splicing. Fusion gene and gel retardation analyses characterised the effect of rs2232316 on G6PC2 promoter activity and transcription factor binding. The genetic association of rs2232316 with FPG variation was assessed using regression adjusted for age, sex and BMI in 4,220 Europeans with normal FPG. RESULTS: The rs560887-G allele was shown to enhance G6PC2 pre-mRNA splicing, whereas the rs2232316-A allele enhanced G6PC2 transcription by promoting Foxa2 binding. Genetic analyses provide evidence for association of the rs2232316-A allele with increased FPG (β = 0.04 mmol/l; p = 4.3 × 10(-3)) as part of the same signal as rs560887, rs573225 and rs13431652. CONCLUSIONS/INTERPRETATION: As with rs13431652, the in situ functional data with rs560887 and rs2232316 are in accord with the putative function of G6PC2 in pancreatic islets, and suggest that all three are potentially causative SNPs that contribute to the association between G6PC2 and FPG.   AU - Baerenwald, D.A.* AU - Bonnefond, A.* AU - Bouatia-Naji, N.* AU - Flemming, B.P.* AU - Umunakwe, O.C.* AU - Oeser, J.K.* AU - Pound, L.D.* AU - Conley, N.L.* AU - Cauchi, S.* AU - Lobbens, S.* AU - Eury, E.* AU - Balkau, B.* AU - Lantieri, O.* AU - MAGIC Investigators (Grallert, H. AU - Gieger, C. AU - Meisinger, C. AU - Thorand, B. AU - Wichmann, H.-E. AU - Illig, T.) AU - Dadi, P.K.* AU - Jacobson, D.A.* AU - Froguel, P.* AU - O'Brien, R.M.* C1 - 28185 C2 - 32998 SP - 1306-1316 TI - Multiple functional polymorphisms in the G6PC2 gene contribute to the association with higher fasting plasma glucose levels. JO - Diabetologia VL - 56 IS - 6 PB - Springer PY - 2013 SN - 0012-186X ER - TY - JOUR AU - Boehm, A.A. AU - Halama, A. AU - Adamski, J. AU - Häring, H.-U. AU - Hrabě de Angelis, M. AU - Staiger, H. C1 - 29278 C2 - 33662 SP - S331 TI - Metabolic profiling of cultured human adipocytes from metabolically malign versus benign obese individuals. JO - Diabetologia VL - 56 PB - Springer PY - 2013 SN - 0012-186X ER - TY - JOUR AU - Brady, I.* AU - Looker, H.C.* AU - Colombo, M.* AU - Zeller, T.* AU - Thorand, B. AU - Groop, L.* AU - Palmer, C.N.A.* AU - Hamsten, A.* AU - de Faire, U.* AU - Nogoceke, E.* AU - Barbarini, N.* AU - Agakov, F.V.* AU - McKeigue, P.M.* AU - Colhoun, H.M.* C1 - 29269 C2 - 33696 SP - S10-S11 TI - Biomarkers for prediction of CVD in type 2 diabetes. JO - Diabetologia VL - 56 PB - Springer PY - 2013 SN - 0012-186X ER - TY - JOUR AU - Colombo, M.* AU - Agakov, F.V.* AU - Brady, I.* AU - Looker, H.C.* AU - Groop, L.* AU - Thorand, B. AU - Hamsten, A.* AU - de Faire, U.* AU - Palmer, C.N.A.* AU - Nogoceke, E.* AU - Gan, L.-M.* AU - Salomaa, V.* AU - McKeigue, P.M.* AU - Colhoun, H.M.* C1 - 29276 C2 - 33664 SP - S539 TI - Metabolic predictors of CVD in type 2 diabetes. JO - Diabetologia VL - 56 PB - Springer PY - 2013 SN - 0012-186X ER - TY - JOUR AU - Heni, M. AU - Kullmann, S. AU - Veit, R.* AU - Ketterer, C.* AU - Machicao, F. AU - Staiger, H. AU - Häring, H.-U. AU - Preissl, H. AU - Fritsche, A. C1 - 29270 C2 - 33695 SP - S294 TI - Variation in the obesity risk gene FTO determines the postprandial cerebral processing of food stimuli. JO - Diabetologia VL - 56 PB - Springer PY - 2013 SN - 0012-186X ER - TY - JOUR AU - Herder, C.* AU - Bongaerts, B.W.C.* AU - Rathmann, W.* AU - Heier, M. AU - Kowall, B.* AU - Koenig, W.* AU - Thorand, B. AU - Roden, M.* AU - Meisinger, C. AU - Ziegler, D.* C1 - 29273 C2 - 33692 SP - S500 TI - Association of subclinical inflammation with polyneuropathy in the older population: KORA F4 study. JO - Diabetologia VL - 56 PB - Springer PY - 2013 SN - 0012-186X ER - TY - JOUR AB - In steroid diabetes insulin secretion does not adequately compensate for enhanced hepatic gluconeogenesis and peripheral insulin resistance. Previous studies suggest that activation of the transcription factor forkhead box O1 (FOXO1) contributes to glucocorticoid-induced beta cell death. This study examines the role and regulation of FOXO1 in insulin-secreting cells. INS-1E cells and mouse islet cells were cultured in the presence of dexamethasone. Signalling pathways were modified pharmacologically or by small interfering (si)RNA-mediated inhibition of protein synthesis. Changes in protein abundance and phosphorylation were analysed by western blotting, and subcellular localisation was assessed using confocal microscopy. Transcript levels were examined by RT-PCR. Surprisingly, downregulation of FOXO1 by siRNA did not affect dexamethasone-induced apoptosis or Bim expression, but it prevented the effects of the pan protein kinase B (AKT) inhibitor (Akti-1/2). Indeed, dexamethasone and Akti-1/2 synergistically increased beta cell death and Bim expression. Akti-1/2 triggered dephosphorylation and nuclear translocation of FOXO1. Glucocorticoid-receptor activation stimulated Foxo1 transcription, but FOXO1 phosphorylation was unchanged and the cytosolic concentration of FOXO1 remained high in relation to its nuclear concentration. However, subcellular fractionation revealed a significant increase in both cytosolic and nuclear FOXO1 compared with untreated cells. Dexamethasone diminished Pdx1 mRNA level, an effect which was not reversed by siRNA against Foxo1. Downregulation of AKT isoforms and serum/glucocorticoid-regulated kinase 1 (SGK1) suggests that only sustained suppression of all three AKT isoforms caused dephosphorylation and nuclear accumulation of FOXO1. This study reveals that FOXO1 is not the main mediator of glucocorticoid-receptor-induced beta cell apoptosis, but rather that it escalates beta cell death when AKT activity is inhibited by distinct pathways. AU - Kaiser, G. AU - Gerst, F. AU - Michael, D.* AU - Berchtold, S.* AU - Friedrich, B.* AU - Strutz-Seebohm, N.* AU - Lang, F.* AU - Häring, H.-U. AU - Ullrich, S. C1 - 25728 C2 - 31924 SP - 1587-1595 TI - Regulation of Forkhead box O1 (FOXO1) by protein kinase B and glucocorticoids: Different mechanisms of induction of beta cell death in vitro. JO - Diabetologia VL - 56 IS - 7 PB - Springer PY - 2013 SN - 0012-186X ER - TY - JOUR AU - Kantartzis, K. AU - Rettig, I.* AU - Machann, J.* AU - Schick, F.* AU - Fritsche, A.* AU - Scheja, L.* AU - Häring, H.-U.* AU - Stefan, N.* C1 - 29272 C2 - 33693 SP - S323 TI - The change in plasma triglycerides during an OGTT strongly predicts nonalcoholic fatty liver disease and the effectiveness of a lifestyle intervention to reduce liver fat. JO - Diabetologia VL - 56 PB - Springer PY - 2013 SN - 0012-186X ER - TY - JOUR AU - Keyhani-Nejad, F.* AU - Isken, F.* AU - Birkenfeld, A.L.* AU - Irmler, M. AU - Beckers, J. AU - Pfeiffer, A.F.H.* C1 - 29271 C2 - 33694 CY - New York SP - S267 TI - High glycaemic index (GI) diet induced hepatic fat accumulation and insulin resistance is associated with high glucose-dependent insulinotropic polypeptide (GIP) secretion. JO - Diabetologia VL - 56 PB - Springer PY - 2013 SN - 0012-186X ER - TY - JOUR AB - Type 2 diabetes was less prevalent in studies of the offspring of centenarians and a separate study of nonagenarian siblings. We examined whether this reduction would also be found when less extreme criteria of parental longevity (a lifespan of at least 80 years) were applied. Moreover, we looked for an association between parental longevity and incidence of dysglycaemia, which has not yet been reported for a population-based study group. Baseline and 7-year follow-up data on 55-74-year-old participants in the population-based German Cooperative Health Research in the Region of Augsburg (KORA) S4/F4 cohort study were used for the analyses. Participants whose parents had died from traumatic causes were excluded. Diabetes was assessed by validated physician diagnosis or OGTTs. Using logistic regression models, adjusted OR and 95% CIs were calculated for the associations between parental longevity and the prevalence or incidence of dysglycaemia, which was defined as including either type 2 diabetes or prediabetes (defined in this study as comprising impaired glucose tolerance [IGT] and impaired fasting glucose [IFG]). In age- and sex-adjusted models, the prevalence of type 2 diabetes was lower in individuals with one (OR 0.63, 95% CI 0.43, 0.93) or two (OR 0.46, 95% CI 0.25, 0.85) long-lived parents. Among participants with normal glucose tolerance at baseline, the odds of incident dysglycaemia were lower in those with one (OR 0.65, 95% CI 0.40, 1.03) or two long-lived parents (OR 0.46, 95% CI 0.22, 0.96) after adjustment for age and sex. This study showed that longevity of the parents, defined by a lifespan of at least 80 years, was associated with a lower prevalence and incidence of dysglycaemia in their offspring in an older German population. AU - Kowall, B.* AU - Peters, A. AU - Thorand, B. AU - Rathmann, W.* AU - Meisinger, C. C1 - 22398 C2 - 30870 SP - 268-274 TI - Associations between longevity of parents and glucose regulation in their offspring: The KORA S4/F4 study. JO - Diabetologia VL - 56 IS - 2 PB - Springer PY - 2013 SN - 0012-186X ER - TY - JOUR AU - Kowall, B.* AU - Rathmann, W.* AU - Bongaerts, B.* AU - Meisinger, C. AU - Peters, A. AU - Huth, C. AU - Zierer, A. AU - Ladwig, K.-H. AU - Holle, R. C1 - 29300 C2 - 33699 SP - S171 TI - In the grey zone of type 2 diabetes prediction: Can we separate poorly discriminated incident cases and non-cases? JO - Diabetologia VL - 56 PB - Springer PY - 2013 SN - 0012-186X ER - TY - JOUR AU - Lagou, V.* AU - Maegi, R.* AU - Surakka, I.* AU - Sarin, A.-P.* AU - Horikoshi, M.* AU - Thorleifsson, G.* AU - Hägg, S.* AU - Beekman, M.* AU - Ladenvall, C.* AU - Hottenga, J.-J.* AU - Ried, J.S. AU - McCarthy, M.I.* AU - Morris, A.* AU - Ripatti, S.* AU - Prokopenko, I.* C1 - 29268 C2 - 33697 SP - S60 TI - Pleiotropic effects on lipid levels and obesity identified in multi-trait meta-analysis of genome-wide association studies (GWAS) of type 2 diabetes related traits. JO - Diabetologia VL - 56 PB - Springer PY - 2013 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: Viruses are candidate causative agents in the pathogenesis of autoimmune (type 1) diabetes. We hypothesised that children with a rapid onset of type 1 diabetes may have been exposed to such agents shortly before the initiation of islet autoimmunity, possibly at high dose, and thus study of these children could help identify viruses involved in the development of autoimmune diabetes. METHODS: We used next-generation sequencing to search for viruses in plasma samples and examined the history of infection and fever in children enrolled in The Environmental Determinants of Diabetes in the Young (TEDDY) study who progressed to type 1 diabetes within 6 months from the appearance of islet autoimmunity, and in matched islet-autoantibody-negative controls. RESULTS: Viruses were not detected more frequently in plasma from rapid-onset patients than in controls during the period surrounding seroconversion. In addition, infection histories were found to be similar between children with rapid-onset diabetes and control children, although episodes of fever were reported less frequently in children with rapid-onset diabetes. CONCLUSIONS/INTERPRETATION: These findings do not support the presence of viraemia around the time of seroconversion in young children with rapid-onset type 1 diabetes.   AU - Lee, H.S.* AU - Briese, T.* AU - Winkler, C. AU - Rewers, M.* AU - Bonifacio, E.* AU - Hyoty, H.* AU - Pflueger, M. AU - Simell, O.* AU - She, J.X.* AU - Hagopian, W.* AU - Lernmark, A.* AU - Akolkar, B.* AU - Krischer, J.P.* AU - Ziegler, A.-G. AU - TEDDY Study Group (*) C1 - 24573 C2 - 31585 SP - 1705-1711 TI - Next-generation sequencing for viruses in children with rapid-onset type 1 diabetes. JO - Diabetologia VL - 56 IS - 8 PB - Springer PY - 2013 SN - 0012-186X ER - TY - JOUR AU - Linder, K.* AU - Schleger, F.* AU - Ketterer, C.* AU - Fritsche, L.* AU - Kiefer-Schmidt, I.* AU - Hennige, A.M. AU - Häring, H.-U. AU - Preissl, H. AU - Fritsche, A. C1 - 29280 C2 - 33660 SP - S71-S72 TI - Maternal insulin resistance affects foetal brain activity. JO - Diabetologia VL - 56 PB - Springer PY - 2013 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: Diabetic retinopathy is a major complication of type 2 diabetes and the leading cause of blindness in adults of working age. Neuronal defects are known to occur early in disease, but the source of this dysfunction is unknown. The aim of this study was to examine differences in the retinal membrane proteome among non-diabetic mice and mouse models of diabetes either with or without metformin treatment. METHODS: Alterations in the retinal membrane proteome of 10-week-old diabetic db/db mice, diabetic db/db mice orally treated with the anti-hyperglycaemic metformin, and congenic wild-type littermates were examined using label-free mass spectrometry. Pathway enrichment analysis was completed with Genomatix and Ingenuity. Alterations in Slc17a7 mRNA and vesicular glutamate transporter 1 (VGLUT1) protein expression were evaluated using real-time quantitative PCR and immunofluorescence. RESULTS: A total of 98 proteins were significantly differentially abundant between db/db and wild-type animals. Pathway enrichment analysis indicated decreases in levels of proteins related to synaptic transmission and cell signalling. Metformin treatment produced 63 differentially abundant proteins compared with untreated db/db mice, of which only 43 proteins were found to occur in both datasets, suggesting that treatment only partially normalises the alterations induced by diabetes. VGLUT1, which is responsible for loading glutamate into synaptic vesicles, was found to be differentially abundant in db/db mice and was not normalised by metformin. The decrease in Slc17a7/VGLUT1 was confirmed by transcriptomic and immunocytochemical analysis. CONCLUSIONS/INTERPRETATION: These findings expand the knowledge of the protein changes in diabetic retinopathy and suggest that membrane-associated signalling proteins are susceptible to changes that are partially ameliorated by treatment.   AU - Ly, A. AU - Scheerer, M.F. AU - Zukunft, S. AU - Muschet, C. AU - Merl, J. AU - Adamski, J. AU - Hrabě de Angelis, M. AU - Neschen, S. AU - Hauck, S.M. AU - Ueffing, M. C1 - 27586 C2 - 32734 SP - 192-203 TI - Retinal proteome alterations in a mouse model of type 2 diabetes. JO - Diabetologia VL - 57 IS - 1 PB - Springer PY - 2013 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: Most genetic variants identified for type 2 diabetes have been discovered in European populations. We performed genome-wide association studies (GWAS) in a Chinese population with the aim of identifying novel variants for type 2 diabetes in Asians. METHODS: We performed a meta-analysis of three GWAS comprising 684 patients with type 2 diabetes and 955 controls of Southern Han Chinese descent. We followed up the top signals in two independent Southern Han Chinese cohorts (totalling 10,383 cases and 6,974 controls), and performed in silico replication in multiple populations. RESULTS: We identified CDKN2A/B and four novel type 2 diabetes association signals with p < 1 × 10(-5) from the meta-analysis. Thirteen variants within these four loci were followed up in two independent Chinese cohorts, and rs10229583 at 7q32 was found to be associated with type 2 diabetes in a combined analysis of 11,067 cases and 7,929 controls (p meta = 2.6  × 10(-8); OR [95% CI] 1.18 [1.11, 1.25]). In silico replication revealed consistent associations across multiethnic groups, including five East Asian populations (p meta = 2.3 × 10(-10)) and a population of European descent (p = 8.6 × 10(-3)). The rs10229583 risk variant was associated with elevated fasting plasma glucose, impaired beta cell function in controls, and an earlier age at diagnosis for the cases. The novel variant lies within an islet-selective cluster of open regulatory elements. There was significant heterogeneity of effect between Han Chinese and individuals of European descent, Malaysians and Indians. CONCLUSIONS/INTERPRETATION: Our study identifies rs10229583 near PAX4 as a novel locus for type 2 diabetes in Chinese and other populations and provides new insights into the pathogenesis of type 2 diabetes.   AU - Ma, R.C.* AU - Hu, C.* AU - Tam, C.H.* AU - Zhang, R.* AU - Kwan, P.* AU - Leung, T.F.* AU - Thomas, G.N.* AU - Go, M.J.* AU - Hara, K.* AU - Sim, X.* AU - Ho, J.S.* AU - Wang, C.* AU - Li, H.* AU - Lu, L.* AU - Wang, Y.* AU - Li, J.W.* AU - Lam, V.K.* AU - Wang, J.* AU - Yu, W.* AU - Kim, Y.J.* AU - Ng, D.P.* AU - Fujita, H.* AU - Panoutsopoulou, K.* AU - Day-Williams, A.G.* AU - Lee, H.M.* AU - Ng, A.C.* AU - Fang, Y.J.* AU - Kong, A.P.* AU - Jiang, F.* AU - Ma, X.* AU - Hou, X.* AU - Tang, S.* AU - Lu, J.* AU - Yamauchi, T.* AU - Tsui, S.K.* AU - Woo, J.* AU - Leung, P.C.* AU - Zhang, X.* AU - Tang, N.L.* AU - Sy, H.Y.* AU - Liu, J.* AU - Wong, T.Y.* AU - Lee, J.Y.* AU - Maeda, S.* AU - Xu, G.* AU - Cherny, S.S.* AU - Chan, T.F.* AU - Ng, M.C.* AU - Xiang, K.* AU - Morris, A.P.* AU - DIAGRAM Consortium (Huth, C. AU - Grallert, H. AU - Klopp, N. AU - Illig, T. AU - Petersen, A.-K. AU - Meitinger, T. AU - Thorand, B. AU - Gieger, C. AU - Wichmann, H.-E.) AU - Keildson, S.* AU - MuTHER Consortium (*) AU - Hu, R.* AU - Ji, L.* AU - Lin, X.* AU - Cho, Y.S.* AU - Kadowaki, T.* AU - Tai, E.S.* AU - Zeggini, E.* AU - McCarthy, M.I.* AU - Hon, K.L.* AU - Baum, L.* AU - Tomlinson, B.* AU - So, W.Y.* AU - Bao, Y.* AU - Chan, J.C.* AU - Jia, W.* C1 - 28108 C2 - 32942 SP - 1291-1305 TI - Genome-wide association study in a Chinese population identifies a susceptibility locus for type 2 diabetes at 7q32 near PAX4. JO - Diabetologia VL - 56 IS - 6 PB - Springer PY - 2013 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: Evidence suggests that low serum potassium concentrations or hypokalaemia induced by the intake of diuretics are associated with incident diabetes and increased risk for diabetes in persons with hypertension. We examined a possible association between serum potassium and prediabetes (defined as isolated impaired fasting glucose [i-IFG], isolated impaired glucose tolerance [i-IGT] or combined IFG/IGT), as well as known and newly diagnosed diabetes (NDD), in 32- to 81-year-old men and women with and without hypertension. METHODS: This cross-sectional analysis was based on 2,948 participants in the Cooperative Health Research in the Region of Augsburg (KORA) F4 study conducted in 2006-2008 in southern Germany. Serum concentrations of potassium were measured by indirect potentiometry. RESULTS: In the total sample there was no association between serum potassium concentrations and prediabetes. In hypertensive persons however serum potassium levels in the first and second quartile compared with the highest quartile were independently significantly associated with prediabetes after multivariable adjustment (OR for prediabetes, 2.02 [95% CI 1.27, 3.21] for quartile 2 and 2.00 [95% CI 1.27, 3.15] for quartile 1), while in persons without hypertension no association was found. In multinomial logistic regression analysis these findings could be confirmed. In hypertensive participants after multivariable adjustment the associations were statistically significant for i-IGT and NDD (i-IGT OR 1.23; NDD OR 1.41). However, in non-hypertensive persons, all associations between serum potassium levels and each of the categories of impaired glucose regulation were non-significant. CONCLUSIONS/INTERPRETATION: Serum potassium levels were independently associated with prediabetes and NDD in hypertensive adults from the general population. AU - Meisinger, C. AU - Stöckl, D. AU - Rückert, I.-M. AU - Döring, A. AU - Thorand, B. AU - Heier, M. AU - Huth, C. AU - Belcredi, P. AU - Kowall, B.* AU - Rathmann, W.* C1 - 22996 C2 - 30976 SP - 484-491 TI - Serum potassium is associated with prediabetes and newly diagnosed diabetes in hypertensive adults from the general population: The KORA F4-study. JO - Diabetologia VL - 56 IS - 3 PB - Springer PY - 2013 SN - 0012-186X ER - TY - JOUR AU - Sartorius, T. AU - Heni, M.* AU - Schoepfer, P.* AU - Peter, A.* AU - Fritsche, A. AU - Synofzik, M.* AU - Häring, H.-U. AU - Maetzler, W.* AU - Hennige, A.M.* C1 - 29277 C2 - 33663 SP - S297 TI - Insulin action in the brain depends on whole-body insulin sensitivity. JO - Diabetologia VL - 56 PB - Springer PY - 2013 SN - 0012-186X ER - TY - JOUR AU - Schipf, S.* AU - Ittermann, T.* AU - Tamayo, T.* AU - Maier, W. AU - Meisinger, C. AU - Greiser, K.H.* AU - Mueller, G.* AU - Moebus, S.* AU - Voelzke, H.* C1 - 29267 C2 - 33698 SP - S126-S127 TI - Regional differences in the incidence of known type 2 diabetes mellitus in 45-74 years old individuals: Results from five population-based studies in Germany. JO - Diabetologia VL - 56 PB - Springer PY - 2013 SN - 0012-186X ER - TY - JOUR AU - Schunk, M. AU - Reitmeir, P. AU - Meisinger, C. AU - Kluttig, A.* AU - Hartwig, S.* AU - Schipf, S.* AU - Voelzke, H.* AU - Peters, A. AU - Holle, R. C1 - 29275 C2 - 33665 SP - S57 TI - Health-related quality of life in adults with and without type 2 diabetes: Results of a pooled analysis of German population-based cohort studies. JO - Diabetologia VL - 56 PY - 2013 SN - 0012-186X ER - TY - JOUR AB - Expansion of adipose tissue mass, predominantly in the visceral depot, strongly associates with the development of metabolic complications that are often observed in obesity. In addition, in obesity, an increased prevalence of nonalcoholic fatty liver disease and reduced cardiorespiratory fitness are observed. However, not all obese individuals develop metabolic abnormalities. To better understand the molecular mechanisms that predispose obese humans to the development of metabolic diseases, comparing the metabolically healthy obese (MHO) vs an unhealthy obese phenotype (MUO) may be of great value. A new study by Esser et al (DOI: 10.1007/s00125-013-3023-9 ) now provides important evidence that the MHO phenotype is associated with a lower activation of the NOD-like receptor family pyrin domain containing-3 (NLPR3) inflammasome in macrophages of visceral adipose tissue and a more favourable inflammatory profile as compared with the MUO phenotype. This finding could promote novel studies in humans to decipher stimuli and mechanisms leading to increased inflammasome activity, not only in adipose tissue, but also in other organs that are involved in the regulation of metabolism. AU - Stienstra, R.* AU - Stefan, N. C1 - 29064 C2 - 33617 SP - 2343-2346 TI - Tipping the inflammatory balance: Inflammasome activation distinguishes metabolically unhealthy from healthy obesity. JO - Diabetologia VL - 56 IS - 11 PY - 2013 SN - 0012-186X ER - TY - JOUR AB - Epidemiological studies that have examined associations between long-term exposure to traffic-related air pollution and type 2 diabetes mellitus in adults are inconsistent, and studies on insulin resistance are scarce. We aimed to assess the association between traffic-related air pollution and insulin resistance in children. Fasting blood samples were collected from 397 10-year-old children in two prospective German birth cohort studies. Individual-level exposures to traffic-related air pollutants at the birth address were estimated by land use regression models. The association between air pollution and HOMA of insulin resistance (HOMA-IR) was analysed using a linear model adjusted for several covariates including birthweight, pubertal status and BMI. Models were also further adjusted for second-hand smoke exposure at home. Sensitivity analyses that assessed the impact of relocating, study design and sex were performed. In all crude and adjusted models, levels of insulin resistance were greater in children with higher exposure to air pollution. Insulin resistance increased by 17.0% (95% CI 5.0, 30.3) and 18.7% (95% CI 2.9, 36.9) for every 2SDs increase in ambient NO2 and particulate matter a parts per thousand currency sign10 mu m in diameter, respectively. Proximity to the nearest major road increased insulin resistance by 7.2% (95% CI 0.8, 14.0) per 500 m. Traffic-related air pollution may increase the risk of insulin resistance. Given the ubiquitous nature of air pollution and the high incidence of insulin resistance in the general population, the associations examined here may have potentially important public health effects despite the small/moderate effect sizes observed. AU - Thiering, E. AU - Cyrys, J. AU - Kratzsch, J.* AU - Meisinger, C. AU - Hoffmann, B.* AU - Berdel, D.* AU - von Berg, A.* AU - Koletzko, S.* AU - Bauer, C.P.* AU - Heinrich, J. C1 - 24489 C2 - 31548 SP - 1696-1704 TI - Long-term exposure to traffic-related air pollution and insulin resistance in children: Results from the GINIplus and LISAplus birth cohorts. JO - Diabetologia VL - 56 IS - 8 PB - Springer PY - 2013 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: Prediabetes is a collective term for different subphenotypes (impaired glucose tolerance [IGT] and/or impaired fasting glucose [IFG]) with different pathophysiologies. A positive family history for type 2 diabetes (FHD) is associated with increased risk for type 2 diabetes. We assumed that it would also associate with prediabetes, but wondered whether all subphenotypes are related to a positive family history. METHODS: In a study population of 8,106 non-diabetic individuals of European origin collected from four study centres (normal glucose tolerance, NGT n = 5,482, IFG and/or IGT n = 2,624), we analysed whether having at least one first degree relative with diabetes is associated with prediabetes. The analyses were performed using the same models in each population separately. Afterwards, a meta-analysis was performed. RESULTS: FHD was significantly associated with the risk for prediabetes (IFG and/or IGT, OR 1.40; 95% CI 1.27, 1.54). This association remained significant in multivariable logistic regression models including sex, age and BMI (OR 1.26; 95% CI 1.14, 1.40). When different prediabetic outcomes were considered separately, the association was found for isolated IFG (OR 1.37; 95% CI 1.20, 1.57), isolated IGT (OR 1.25; 95% CI 1.07, 1.46) as well as for the combination IFG+IGT (OR 1.64; 95% CI 1.40, 1.93). After stratification on BMI, association between FHD and prediabetes was seen only in non-obese individuals (BMI < 30 kg/m(2)). CONCLUSIONS/INTERPRETATION: We found that FHD is an important risk factor for prediabetes, especially for combined IGT and IFG. Its relevance seems to be more evident in the non-obese. AU - Wagner, R. AU - Thorand, B. AU - Osterhoff, M.A. AU - Müller, G. AU - Böhm, A. AU - Meisinger, C. AU - Kowall, B. AU - Rathmann, W. AU - Kronenberg, F.* AU - Staiger, H. AU - Stefan, N. AU - Roden, M. AU - Schwarz, P.E. AU - Pfeiffer, A.F. AU - Häring, H.-U. AU - Fritsche, A. C1 - 27449 C2 - 32675 SP - 2176-2180 TI - Family history of diabetes is associated with higher risk for prediabetes: A multicentre analysis from the German Center for Diabetes Research. JO - Diabetologia VL - 56 IS - 10 PB - Springer PY - 2013 SN - 0012-186X ER - TY - JOUR AU - Williams, A.J.K.* AU - Lampasona, V.* AU - Schlosser, M.* AU - Mueller, P.W.* AU - Pittman, D.* AU - Winter, W.E.* AU - Wyatt, R.* AU - Akolkar, B.* AU - Bingley, P.J.* AU - Achenbach, P. C1 - 29279 C2 - 33661 SP - S17 TI - N-terminally truncated GAD discriminates progression in GAD antibody positive relatives of patients with type 1 diabetes. JO - Diabetologia VL - 56 PB - Springer PY - 2013 SN - 0012-186X ER - TY - JOUR AU - Ziegler, D.* AU - Voss, A.* AU - Nowak, S.* AU - Scheer, M.* AU - Rathmann, W.* AU - Perz, S. AU - Roden, M.* AU - Peters, A. AU - Meisinger, C. C1 - 29274 C2 - 33691 SP - S492 TI - Prevalence and risk factors of cardiac autonomic nerve dysfunction in the elderly population with diabetes and prediabetes: The KORA S4 survey. JO - Diabetologia VL - 56 PB - Springer PY - 2013 SN - 0012-186X ER - TY - JOUR AB - Impaired insulin sensitivity is a major factor leading to type 2 diabetes. Animal studies suggest that the brain is involved in the regulation of insulin sensitivity. We investigated whether insulin action in the human brain regulates peripheral insulin sensitivity and examined which brain areas are involved. Insulin and placebo were given intranasally. Plasma glucose, insulin and C-peptide were measured in 103 participants at 0, 30 and 60 min. A subgroup ( = 12) was also studied with functional MRI, and blood sampling at 0, 30 and 120 min. For each time-point, the HOMA of insulin resistance (HOMA-IR) was calculated as an inverse estimate of peripheral insulin sensitivity. Plasma insulin increased and subsequently decreased. This excursion was accompanied by slightly decreased plasma glucose, resulting in an initially increased HOMA-IR. At 1 h after insulin spray, the HOMA-IR subsequently decreased and remained lower up to 120 min. An increase in hypothalamic activity was observed, which correlated with the increased HOMA-IR at 30 min post-spray. Activity in the putamen, right insula and orbitofrontal cortex correlated with the decreased HOMA-IR at 120 min post-spray. Central insulin action in specific brain areas, including the hypothalamus, may time-dependently regulate peripheral insulin sensitivity. This introduces a potential novel mechanism for the regulation of peripheral insulin sensitivity and underlines the importance of cerebral insulin action for the whole organism. AU - Heni, M.* AU - Kullmann, S. AU - Ketterer, C.* AU - Guthoff, M.* AU - Linder, K.* AU - Wagner, R.* AU - Stingl, K.T.* AU - Veit, R.* AU - Staiger, H. AU - Häring, H.-U. AU - Preissl, H. AU - Fritsche, A. C1 - 8004 C2 - 29986 SP - 1773-1782 TI - Nasal insulin changes peripheral insulin sensitivity simultaneously with altered activity in homeostatic and reward-related human brain regions. JO - Diabetologia VL - 55 IS - 6 PB - Springer PY - 2012 SN - 0012-186X ER - TY - JOUR AB - Autoantibodies to zinc transporter 8 (ZnT8A) are associated with risk of type 1 diabetes. Apart from the SLC30A8 gene itself, little is known about the genetic basis of ZnT8A. We hypothesise that other loci in addition to SLC30A8 are associated with ZnT8A. The levels of ZnT8A were measured in 2,239 British type 1 diabetic individuals diagnosed before age 17 years, with a median duration of diabetes of 4 years. Cases were tested at over 775,000 loci genome wide (including 53 type 1 diabetes associated regions) for association with positivity for ZnT8A. ZnT8A were also measured in an independent dataset of 855 family members with type 1 diabetes. Only FCRL3 on chromosome 1q23.1 and the HLA class I region were associated with positivity for ZnT8A. rs7522061T > C was the most associated single nucleotide polymorphism (SNP) in the FCRL3 region (p = 1.13 x 10(-16)). The association was confirmed in the family dataset (p a parts per thousand currency signaEuro parts per thousand 9.20 x 10(-4)). rs9258750A > G was the most associated variant in the HLA region (p = 2.06 x 10(-9) and p = 0.0014 in family cases). The presence of ZnT8A was not associated with HLA-DRB1, HLA-DQB1, HLA-A, HLA-B or HLA-C (p > 0.05). Unexpectedly, the two loci associated with the presence of ZnT8A did not alter risk of having type 1 diabetes, and the 53 type 1 diabetes risk loci did not influence positivity for ZnT8A, despite them being disease specific. ZnT8A are not primary pathogenic factors in type 1 diabetes. Nevertheless, ZnT8A testing in combination with other autoantibodies facilitates disease prediction, despite the biomarker not being under the same genetic control as the disease. AU - Howson, J.M.M.* AU - Krause, S.* AU - Stevens, H.* AU - Smyth, D.J.* AU - Wenzlau, J.M.* AU - Bonifacio, E.* AU - Hutton, J.* AU - Ziegler, A.-G. AU - Todd, J.A.* AU - Achenbach, P. C1 - 7590 C2 - 29854 SP - 1978-1984 TI - Genetic association of zinc transporter 8 (ZnT8) autoantibodies in type 1 diabetes cases. JO - Diabetologia VL - 55 IS - 7 PB - Springer PY - 2012 SN - 0012-186X ER - TY - JOUR AB - The aim of this study was to prospectively examine the association between body iron stores and risk of type 2 diabetes. We designed a case-cohort study among 27,548 individuals within the population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study. During 7 years of follow-up, 849 incident cases of type 2 diabetes were identified. Of these, 607 remained for analyses after exclusion of participants with missing data or abnormal glucose levels at baseline. A sub-cohort of 2,500 individuals was randomly selected from the full cohort, comprising 1,969 individuals after applying the same exclusion criteria. After adjustment for age, sex, BMI, waist circumference, sports activity, bicycling, education, occupational activity, smoking habit, alcohol consumption and circulating levels of gamma-glutamyltransferase, alanine aminotransferase, fetuin-A, high-sensitivity C-reactive protein, adiponectin, HDL-cholesterol and triacylglycerol, higher serum ferritin concentrations were associated with a higher risk of type 2 diabetes (RR in the highest vs lowest quintile, 1.73; 95% CI 1.15, 2.61; p (trend) = 0.002). No significant association was observed for soluble transferrin receptor (RR 1.33; 95% CI 0.85, 2.09; p (trend) = 0.50). The soluble transferrin receptor-to-ferritin ratio was significantly inversely related to risk (RR 0.61; 95% CI 0.41, 0.91; p (trend) = 0.02). High ferritin levels are associated with higher risk of type 2 diabetes independently of established diabetes risk factors and a range of diabetes biomarkers whereas soluble transferrin receptor concentrations are not related to risk. These results support the hypothesis that higher iron stores below the level of haemochromatosis are associated with risk of type 2 diabetes. AU - Montonen, J.* AU - Boeing, H.* AU - Steffen, A.* AU - Lehmann, R. AU - Fritsche, A. AU - Joost, H.G.* AU - Schulze, M.B.* AU - Pischon, T.* C1 - 8616 C2 - 29602 SP - 2613-2621 TI - Body iron stores and risk of type 2 diabetes: Results from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study. JO - Diabetologia VL - 55 IS - 10 PB - Springer PY - 2012 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: We have previously found that the mass of perivascular adipose tissue (PVAT) correlates negatively with insulin sensitivity and post-ischaemic increase in blood flow. To understand how PVAT communicates with vascular vessels, interactions between perivascular, subcutaneous and visceral fat cells with endothelial cells (ECs) were examined with regard to inflammatory, metabolic and angiogenic proteins. To test for possible in vivo relevance of these findings, circulating levels of the predominant secretion product, hepatocyte growth factor (HGF), was measured in individuals carefully phenotyped for fat distribution patterns. METHODS: Mono- and co-cultures of human primary fat cells with ECs were performed. mRNA expression and protein production were studied using Luminex, cytokine array, RealTime Ready and ELISA systems. Effects of HGF on vascular cells were determined by WST assays. In patients, HGF levels were measured by ELISA, and the mass of different fat compartments was determined by whole-body MRI. RESULTS: In contrast with other fat cell types, PVAT cells released higher amounts of angiogenic factors, e.g. HGF, acidic fibroblast growth factor, thrombospondin-1, serpin-E1, monocyte chemotactic protein-1 and insulin-like growth factor-binding protein -3. Cocultures showed different expression profiles from monocultures, and mature adipocytes differed from pre-adipocytes. HGF was preferentially released by PVAT cells and stimulated EC growth and smooth muscle cell cytokine release. Finally, in 95 patients, only PVAT, not visceral or subcutaneous mass, correlated independently with serum HGF levels (p = 0.03; r = 0.225). CONCLUSIONS: Perivascular (pre-)adipocytes differ substantially from other fat cells with regard to mRNA expression and protein production of angiogenic factors. This may contribute to fat tissue growth and atherosclerotic plaque complications. Higher levels of angiogenic factors, such as HGF, in patients with increased perivascular fat mass may have pathological relevance. AU - Rittig, K.* AU - Dolderer, J.H.* AU - Balletshofer, B.* AU - Machann, J. AU - Schick, F. AU - Meile, T.* AU - Küper, M.* AU - Stock, U.A.* AU - Staiger, H. AU - Machicao, F. AU - Schaller, H.E.* AU - Königsrainer, A.* AU - Häring, H.-U. AU - Siegel-Axel, D.I.* C1 - 7942 C2 - 29926 SP - 1514-1525 TI - The secretion pattern of perivascular fat cells is different from that of subcutaneous and visceral fat cells. JO - Diabetologia VL - 55 IS - 5 PB - Springer PY - 2012 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: The aim of this study was to compare estimates of body fat content, i.e. body adiposity index (BAI), BMI and waist and hip circumferences, with respect to their ability to predict the percentage of body fat (PBF; confirmed by magnetic resonance tomography) and incident type 2 diabetes. METHODS: Associations between anthropometric measurements and PBF were evaluated in the Tübingen Lifestyle Intervention Program (TULIP; 138 men, 222 women), and between these measurements and incident type 2 diabetes in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study (9,729 men, 15,438 women) and the Cooperative Health Research in the Region of Augsburg (KORA) study (5,573 men, 5,628 women), using correlation and multivariate Cox regression analyses. RESULTS: BMI more strongly correlated with PBF (men: r = 0.81, women: r = 0.84) than BAI (r = 0.68 and 0.81, respectively), while waist circumference among men (r = 0.84) and hip circumference among women (r = 0.88) showed the strongest correlations. BAI overestimated PBF among men (mean difference -3.0%), and this error was dependent on the value of PBF. BAI was more weakly associated with diabetes risk (RRs for 1 SD, EPIC-Potsdam men: 1.62 [95% CI 1.52, 1.72], women: 1.67 [95% CI 1.55, 1.80]; KORA men: 1.62 [95% CI 1.48, 1.78], women: 1.82 [95% CI 1.65, 2.02]) compared with BMI (RRs, EPIC-Potsdam men: 1.95 [95% CI 1.83, 2.09], women 1.88 [95% CI 1.76, 2.02], KORA men 1.75 [95% CI 1.62, 1.89], women 2.00 [95% CI 1.81, 2.22]), while waist circumference showed the strongest associations (RRs: 2.17 [95% CI 2.01, 2.35], 2.33 [95% CI 2.15, 2.53], 1.81 [95% CI 1.66, 1.96] and 2.29 [95% CI 2.05, 2.57] for EPIC-Potsdam men and women and KORA men and women, respectively). CONCLUSIONS/INTERPRETATION: Waist circumference in men and hip circumference in women are better predictors of PBF than BAI and BMI. BAI was not as strong a predictor of diabetes as BMI, while waist circumference was the strongest predictor. AU - Schulze, M.B.* AU - Thorand, B. AU - Fritsche, A.* AU - Häring, H.-U. AU - Schick, F.* AU - Zierer, A. AU - Rathmann, W.* AU - Kröger, J.* AU - Peters, A. AU - Boeing, H.* AU - Stefan, N.* C1 - 7454 C2 - 29719 SP - 1660-1667 TI - Body adiposity index, body fat content and incidence of type 2 diabetes. JO - Diabetologia VL - 55 IS - 6 PB - Springer PY - 2012 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: The aim of this study was to examine the association between age at menarche and prediabetes as well as diabetes, considering confounding factors and the possible mediating role of adult obesity. METHODS: This cross-sectional study analysed data on 1,503 women aged 32-81 years from the German population-based KORA (Cooperative Health Research in the Region of Augsburg, South Germany) F4 Study (2006-2008). Data were collected by standardised interviews, physical examinations, and whole blood and serum measurements, including administration of an OGTT in non-diabetic participants. RESULTS: Of the 1,503 women, 226 showed a prediabetic state (impaired fasting glucose and/or impaired glucose tolerance) and 140 persons had diabetes (45 participants with previously undiagnosed diabetes and 95 with known diabetes). In Poisson regression analysis, age at menarche was significantly inversely associated with prediabetes or diabetes after adjustment for year of birth (RR 0.88; 95% CI 0.82, 0.94, p < 0.0001 per additional year of menarche) and after additional adjustment for a number of confounding factors (RR 0.88; 95% CI 0.83, 0.94, p = 0.0001). Further adjustment for current BMI slightly attenuated the association with prediabetes or diabetes (RR 0.89; 95% CI 0.83, 0.95, p = 0.0009), but the association remained clearly significant. CONCLUSIONS/INTERPRETATION: Age at menarche seems to be inversely associated with prediabetes and diabetes independent of confounding factors including current BMI. Women at risk for diabetes might be identified by a history of young age at menarche. AU - Stöckl, D. AU - Döring, A. AU - Peters, A. AU - Thorand, B. AU - Heier, M. AU - Huth, C. AU - Stöckl, H.* AU - Rathmann, W.* AU - Kowall, B.* AU - Meisinger, C. C1 - 7212 C2 - 29564 SP - 681-688 TI - Age at menarche is associated with prediabetes and diabetes in women (aged 32-81 years) from the general population: The KORA F4 study. JO - Diabetologia VL - 55 IS - 3 PB - Springer PY - 2012 SN - 0012-186X ER - TY - JOUR AB - Microalbuminuria represents an established surrogate marker of early diabetic nephropathy and glomerular microangiopathy. Increasing evidence is emerging of a role of perivascular adipose tissue (PVAT) as an important link between obesity, insulin resistance and both macro- and microangiopathy. It is not known whether perivascular renal sinus fat (RSF) has an impact on microalbuminuria in the prediabetic stage. We investigated whether RSF quantified by MRI is associated with microalbuminuria before or after exercise. Non-diabetic individuals at increased risk of type 2 diabetes were recruited into the Tubingen Lifestyle Intervention Program (TULIP); 146 participants took part in the analysis. RSF was measured in axial MRI sections at the level of the renal artery. Urine was collected before and after exercise stress testing. Participants (age 47 +/- 12 years; mean +/- SD) reached a mean exercise load of 176 +/- 49 W, with a mean arterial peak pressure (MAPP) of 112 +/- 14 mmHg. After adjusting for sex, age, visceral adipose tissue (VAT) and MAPP during exercise, RSF was significantly associated with postexercise albumin/creatinine ratio (ACR; p = 0.006). No association between RSF and baseline BP could be observed after adjusting for confounders (p = 0.26), and there was no association between RSF and baseline ACR either (p = 0.2). RSF is associated with exercise-induced albuminuria independently of sex, age, VAT and MAPP in a non-diabetic cohort at diabetic risk. We conclude that PVAT in the renal sinus may play a role in the pathogenesis of microalbuminuria. AU - Wagner, R.* AU - Machann, J.* AU - Lehmann, R. AU - Rittig, K.* AU - Schick, F.* AU - Lenhart, J.* AU - Artunc, F.* AU - Linder, K.* AU - Claussen, C.D.* AU - Schleicher, E.D. AU - Fritsche, A. AU - Häring, H.-U. AU - Weyrich, P.* C1 - 7969 C2 - 29955 SP - 2054-2058 TI - Exercise-induced albuminuria is associated with perivascular renal sinus fat in individuals at increased risk of type 2 diabetes. JO - Diabetologia VL - 55 IS - 7 PB - Springer PY - 2012 SN - 0012-186X ER - TY - JOUR AB - Aim/hypothesis Seroconversion to islet autoantibodies precedes type 1 diabetes. This study aimed to identify periods of high seroconversion incidence, which could be targeted for mechanistic and therapeutic studies. Methods Incidence of islet autoantibodies was calculated in 1,650 genetically at-risk children followed with measurements of islet autoantibodies and thyroid autoantibodies at age 9 months and 2, 5, 8, 11, 14 and 17 years. Peak incidence periods were confirmed in a second cohort of 150 children followed until age 6 years with three-monthly samples up to age 3 years. Results Islet autoantibody incidence (per 1,000 person-years) was 18.5 until age 9 months, 21 from 9 months to 2 years and < 10 for intervals after age 2 years. The second cohort confirmed peak incidence around age 9 months and demonstrated an absence of seroconversion before this age. Seroconversion to insulin autoantibodies occurred earlier than other autoantibodies (p < 0.01 against glutamic acid decarboxylase [GAD]-, insulinoma-associated protein 2 [IA-2]- and zinc transporter 8 [ZnT8]-autoantibodies). Early peak seroconversion incidence was most evident in children with high-risk HLA DR3/4-DQ8 or DR4/4-DQ8 genotypes. Conclusion The age period 9 months to 2 years is associated with a high incidence of activation of type 1 diabetes-associated autoimmunity in genetically at-risk children and should be targeted for effective primary prevention strategies. AU - Ziegler, A.-G. AU - Bonifacio, E.* AU - BABYDIAB-BABYDIET Study Group (*) C1 - 7598 C2 - 29897 SP - 1937-1943 TI - Age-related islet autoantibody incidence in offspring of patients with type 1 diabetes. JO - Diabetologia VL - 55 IS - 7 PB - Springer PY - 2012 SN - 0012-186X ER - TY - JOUR AB - Lower adiponectin levels are associated with higher risk of incident type 2 diabetes. Most analyses have been adjusted for confounding factors, but few have taken into account insulin resistance per se. We tested the hypothesis that the association of adiponectin levels with incident type 2 diabetes differs between insulin-resistant and insulin-sensitive individuals. We studied two prospective cohorts: the Framingham Offspring Study (n = 2,023) and the Cooperative Health Research in the Region of Augsburg (KORA) S4/F4 study (n = 887) cohorts. Insulin resistance was estimated by HOMA-insulin resistance (HOMA-IR). We used logistic regression analysis to test the association between adiponectin and incident type 2 diabetes overall and in insulin-resistant vs insulin-sensitive individuals (defined by ≥ vs <75th percentile of HOMA-IR).At baseline, Framingham's participants were 60 ± 9 years old and 56% were women; KORA's participants were 63 ± 5 years old and 49% were women. Type 2 diabetes incidence was 5.4% over 6.5 years (n = 109) in Framingham and 10.5% over 8 years (n = 93) in KORA. Lower adiponectin levels were associated with type 2 diabetes incidence in both cohorts. In insulin-resistant individuals, lower adiponectin levels were associated with higher risk of type 2 diabetes incidence (OR 1.60 [95% CI 1.10-2.31] per SD decrease in Framingham, p = 0.01; and OR 2.34 [95% CI 1.16-4.73] in KORA, p = 0.02); while this was not observed in insulin-sensitive individuals (OR 1.10 [95% CI 0.73-1.67] in Framingham, p = 0.64; and OR 1.34 [95%CI: 0.88-2.03] in KORA, p = 0.18).We conclude that lower adiponectin levels are associated with higher risk of type 2 diabetes in insulin-resistant but not in insulin-sensitive individuals. This suggests that some level of insulin resistance is needed to see deleterious effects of low adiponectin. AU - Hivert, M.F.* AU - Sullivan, L.M.* AU - Shrader, P.* AU - Fox, C.S.* AU - Nathan, D.M.* AU - D'Agostino, R.B, Sr.* AU - Wilson, P.W.* AU - Kowall, B.* AU - Herder, C.* AU - Meisinger, C. AU - Thorand, B. AU - Rathmann, W.* AU - Meigs, J.B.* C1 - 6325 C2 - 28507 CY - New York, USA SP - 1019-1024 TI - Insulin resistance influences the association of adiponectin levels with diabetes incidence in two population-based cohorts: The Cooperative Health Research in the Region of Augsburg (KORA) S4/F4 study and the Framingham Offspring Study. JO - Diabetologia VL - 54 IS - 5 PB - Springer PY - 2011 SN - 0012-186X ER - TY - JOUR AB - Rare mutations in the gene HNF4A, encoding the transcription factor hepatocyte nuclear factor 4α (HNF-4A), account for ~5% of cases of MODY and more frequent variants in this gene may be involved in multifactorial forms of diabetes. Two low-frequency, non-synonymous variants in HNF4A (V255M, minor allele frequency [MAF] ~0.1%; T130I, MAF ~3.0%)-known to influence downstream HNF-4A target gene expression-are of interest, but previous type 2 diabetes association reports were inconclusive. We aimed to evaluate the contribution of these variants to type 2 diabetes susceptibility through large-scale association analysis. METHODS: We genotyped both variants in at least 5,745 cases and 14,756 population controls from the UK and Denmark. We also undertook an expanded association analysis that included previously reported and novel genotype data obtained in Danish, Finnish, Canadian and Swedish samples. A meta-analysis incorporating all published association studies of the T130I variant was subsequently carried out in a maximum sample size of 14,279 cases and 26,835 controls. RESULTS: We found no association between V255M and type 2 diabetes in either the initial (p = 0.28) or the expanded analysis (p = 0.44). However, T130I demonstrated a modest association with type 2 diabetes in the UK and Danish samples (additive per allele OR 1.17 [95% CI 1.08-1.28]; p = 1.5 × 10⁻⁴), which was strengthened in the meta-analysis (OR 1.20 [95% CI 1.10-1.30]; p = 2.1 × 10⁻⁵). CONCLUSIONS/INTERPRETATION: Our data are consistent with T130I as a low-frequency variant influencing type 2 diabetes risk, but are not conclusive when judged against stringent standards for genome-wide significance. This study exemplifies the difficulties encountered in association testing of low-frequency variants. AU - Jafar-Mohammadi, B.* AU - Groves, C.J.* AU - Gjesing, A.P.* AU - Herrera, BM.* AU - Winckler, W.* AU - Stringham, H.M.* AU - Morris, A.P.* AU - Lauritzen, T.* AU - Doney, A.S.* AU - Morris, A.D.* AU - Weedon, M.N.* AU - Swift, AJ.* AU - Kuusisto, J.* AU - Laakso, M.* AU - Altshuler, D.* AU - Hattersley, A.T.* AU - Collins, F.S.* AU - Boehnke, M.* AU - Hansen, T.* AU - Pedersen, O.* AU - Palmer, C.N.* AU - Frayling, T.M.* AU - DIAGRAM Consortium (Huth, C. AU - Grallert, H. AU - Gieger, C. AU - Klopp, N. AU - Meitinger, T. AU - Petersen, A.-K. AU - Thorand, B. AU - Wichmann, H.-E. AU - Illig, T.) AU - Gloyn, AL.* AU - McCarthy, M.I.* C1 - 5143 C2 - 28567 SP - 111-119 TI - A role for coding functional variants in HNF4A in type 2 diabetes susceptibility. JO - Diabetologia VL - 54 IS - 1 PB - Springer PY - 2011 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: Obesity is strongly associated with the development of non-alcoholic fatty liver disease (NAFLD). The cytokine osteopontin (OPN) was recently shown to be involved in obesity-induced adipose tissue inflammation and reduced insulin response. Accumulating evidence links OPN to the pathogenesis of NAFLD. Here we aimed to identify the role of OPN in obesity-associated hepatic steatosis and impaired hepatic glucose metabolism. METHODS: Wild-type (WT) and Opn (also known as Spp1) knockout (Opn (-/-)) mice were fed a high-fat or low-fat diet to study OPN effects in obesity-driven hepatic alterations. RESULTS: We show that genetic OPN deficiency protected from obesity-induced hepatic steatosis, at least in part, by downregulating hepatic triacylglycerol synthesis. Conversely, absence of OPN promoted fat storage in adipose tissue thereby preventing the obesity-induced shift to ectopic fat accumulation in the liver. Euglycaemic-hyperinsulinaemic clamp studies revealed that insulin resistance and excess hepatic glucose production in obesity were significantly attenuated in Opn (-/-) mice. OPN deficiency markedly improved hepatic insulin signalling as shown by enhanced insulin receptor substrate-2 phosphorylation and prevented upregulation of the major hepatic transcription factor Forkhead box O1 and its gluconeogenic target genes. In addition, obesity-driven hepatic inflammation and macrophage accumulation was blocked by OPN deficiency. CONCLUSIONS/INTERPRETATION: Our data strongly emphasise OPN as mediator of obesity-associated hepatic alterations including steatosis, inflammation, insulin resistance and excess gluconeogenesis. Targeting OPN action could therefore provide a novel therapeutic strategy to prevent obesity-related complications such as NAFLD and type 2 diabetes. AU - Kiefer, F.W.* AU - Neschen, S. AU - Pfau, B.* AU - Legerer, B.* AU - Neuhofer, A.* AU - Kahle-Stephan, M. AU - Hrabě de Angelis, M. AU - Schlederer, M.* AU - Mair, M.* AU - Kenner, L.* AU - Plutzky, J.* AU - Zeyda, M.* AU - Stulnig, T.M.* C1 - 6480 C2 - 28778 SP - 2132-2142 TI - Osteopontin deficiency protects against obesity-induced hepatic steatosis and attenuates glucose production in mice. JO - Diabetologia VL - 54 IS - 8 PB - Springer PY - 2011 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: By combining multiple genome-wide association (GWA) studies and comprehensive replication efforts, 12 novel type 2 diabetes associated loci have recently been discovered. Here we evaluate the effect of lead variants of these loci on estimates of insulin release and insulin resistance derived from an oral glucose tolerance test. METHODS: We examined 12 lead variants in or near HMGA2, CENTD2 (also known as ARAP1), KLF14, PRC1, TP53INP1, ZBED3, ZFAND6, CHCHD9, DUSP9, KCNQ1, BCL11A and HNF1A in 5,722 middle-aged people from the population-based Inter99 sample. RESULTS: Carriers of the major diabetogenic allele of rs1552224 in CENTD2 had increased 30-min plasma glucose values (2.0%, p = 2 × 10(-5)) as well as 4.2% reduced insulin release 30 min after an oral glucose load (p = 0.001). Risk allele carriers also had decreased BIGTT-acute insulin release (AIR), which is a surrogate measure of insulin release where sex, BMI, plasma glucose and serum insulin are integrated (5.3%, p = 8 × 10(-7)). In addition, a decreased corrected insulin response (CIR; 9.9%, p = 3 × 10(-8)) was observed. For rs5945326 near DUSP9 on the X-chromosome we stratified according to sex. Male carriers of the risk allele showed nominally decreased BIGTT-AIR (2.6%, p = 0.01). No associations with intermediate metabolic traits were found in women. For the remaining ten lead variants no consistent associations were demonstrated. CONCLUSIONS/INTERPRETATION: Of the lead variants from 12 novel type 2 diabetes associated loci, CENTD2 significantly associated with increased plasma glucose values and decreased glucose-stimulated insulin release, suggesting that the diabetogenic effect of this locus is mediated through an impaired pancreatic beta cell function. AU - Nielsen, T.* AU - Sparsø, T.* AU - Grarup, N.* AU - Jørgensen, T.* AU - Pisinger, C.* AU - Witte, D.R* AU - Hansen, T.* AU - Pedersen, O.* AU - DIAGRAM Consortium (Huth, C. AU - Grallert, H. AU - Gieger, C. AU - Klopp, N. AU - Meitinger, T. AU - Petersen, A.-K. AU - Thorand, B. AU - Wichmann, H.-E. AU - Illig, T.) C1 - 5635 C2 - 29387 SP - 1052-1056 TI - Type 2 diabetes risk allele near CENTD2 is associated with decreased glucose-stimulated insulin release. JO - Diabetologia VL - 54 IS - 5 PB - Springer PY - 2011 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: We report a genome-wide association study of type 2 diabetes in an admixed sample from Mexico City and describe the results of a meta-analysis of this study and another genome-wide scan in a Mexican-American sample from Starr County, TX, USA. The top signals observed in this meta-analysis were followed up in the Diabetes Genetics Replication and Meta-analysis Consortium (DIAGRAM) and DIAGRAM+ datasets. METHODS: We analysed 967 cases and 343 normoglycaemic controls. The samples were genotyped with the Affymetrix Genome-wide Human SNP array 5.0. Associations of genotyped and imputed markers with type 2 diabetes were tested using a missing data likelihood score test. A fixed-effects meta-analysis including 1,804 cases and 780 normoglycaemic controls was carried out by weighting the effect estimates by their inverse variances. RESULTS: In the meta-analysis of the two Hispanic studies, markers showing suggestive associations (p < 10(-5)) were identified in two known diabetes genes, HNF1A and KCNQ1, as well as in several additional regions. Meta-analysis of the two Hispanic studies and the recent DIAGRAM+ dataset identified genome-wide significant signals (p < 5 × 10(-8)) within or near the genes HNF1A and CDKN2A/CDKN2B, as well as suggestive associations in three additional regions, IGF2BP2, KCNQ1 and the previously unreported C14orf70. CONCLUSIONS/INTERPRETATION: We observed numerous regions with suggestive associations with type 2 diabetes. Some of these signals correspond to regions described in previous studies. However, many of these regions could not be replicated in the DIAGRAM datasets. It is critical to carry out additional studies in Hispanic and American Indian populations, which have a high prevalence of type 2 diabetes. AU - Parra, E.J.* AU - Below, J.E.* AU - Krithika, S.* AU - Valladares, A.* AU - Barta, J.L.* AU - Cox, N.J.* AU - Hanis, C.L.* AU - Wacher, N.* AU - Garcia-Mena, J.* AU - Hu, P.* AU - Shriver, M.D* AU - DIAGRAM Consortium (Huth, C. AU - Grallert, H. AU - Gieger, C. AU - Klopp, N. AU - Meitinger, T. AU - Petersen, A.-K. AU - Thorand, B. AU - Wichmann, H.-E. AU - Illig, T.) AU - Kumate, J.* AU - McKeigue, P.M.* AU - Escobedo, J.* AU - Cruz, M.* C1 - 6891 C2 - 29406 SP - 2038-2046 TI - Genome-wide association study of type 2 diabetes in a sample from Mexico City and a meta-analysis of a Mexican-American sample from Starr County, Texas. JO - Diabetologia VL - 54 IS - 8 PB - Springer PY - 2011 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: The aim of this study was to examine human enteroviruses (HEVs) and other intestinal viruses derived from children who participated in the Babydiet intervention study and to analyse the findings according to the appearance of islet autoantibodies, dietary intervention, maternal type 1 diabetes and clinical symptoms. METHODS: In the Babydiet study the influence of first gluten exposure (6 or 12 months) on the development of islet autoimmunity was investigated in 150 children with increased genetic and familial risk for type 1 diabetes. Blood and stool samples were collected at 3 monthly intervals until the age of 3 years and yearly thereafter. Infections and clinical symptoms were recorded daily for the first year. In the present study, 339 stool samples collected from 104 children during the first year of life were analysed for HEVs and a certain proportion of the samples were analysed for other intestinal viruses. RESULTS: HEV was detected in 32 (9.4%) samples from 24 (23.1%) children. Altogether 13 serotypes were identified, with HEV-A species being the most common. Children with gastrointestinal symptoms had norovirus (3/11) and sapovirus (1/11) infections in addition to HEV (1/11). Of the 104 children, 22 developed islet autoantibodies. HEV infections were detected in 18% (4/22) and 24% (20/82) of islet-autoantibody-positive and -negative children, respectively (p = 0.5). The prevalence of HEV was similar in the gluten-exposed groups and in children from mothers with type 1 diabetes or from affected fathers and/or siblings (p = 1.0 and 0.6, respectively). CONCLUSIONS/INTERPRETATION: No correlation was found between the presence of HEV in the first year of life and the development of islet autoantibodies. There was no association between HEV infections and dietary intervention, maternal diabetes or clinical symptoms. AU - Simonen-Tikka, M.-L.* AU - Pflueger, M. AU - Klemola, P.* AU - Savolainen-Kopra, C.* AU - Smura, T.* AU - Hummel, S. AU - Kaijalainen, S.* AU - Nuutila, K.* AU - Natri, O.* AU - Roivainen, M.* AU - Ziegler, A.-G. C1 - 6857 C2 - 29360 SP - 2995-3002 TI - Human enterovirus infections in children at increased risk for type 1 diabetes: The Babydiet study. JO - Diabetologia VL - 54 IS - 12 PB - Springer PY - 2011 SN - 0012-186X ER - TY - JOUR AB - Autoantibodies are a hallmark feature of type 1 diabetes and have proved useful markers for disease prediction and classification [1]. New autoantibodies are of interest since they may strengthen disease relevance in autoantibody-positive individuals [2, 3]. Recently, autoantibodies against the inducible chemokine CCL3 were reported to be associated with type 1 diabetes [4], and commercial kits for the measurement of anti-CCL3 autoantibodies are now available. CCL3 is produced during inflammation and is suggested to be produced by beta cells under stress. We had the opportunity to evaluate this commercial kit and here report our findings. Sera from patients with new or recent onset of type 1 diabetes (n = 54; median age 10 years; IQR 7.5–13.5 years), controls (n = 40; median age 11.2 years; IQR 4.7–16.3 years), first-degree relatives of patients with type 1 diabetes (n = 33; median age 10.5 years; IQR 7.7–11.2 years) and participants with other autoimmune diseases (n = 17; median age 1 AU - Ziegler, A.-G.* AU - Mollenhauer, U. AU - Achenbach, P. AU - Bonifacio, E.* C1 - 3997 C2 - 28064 CY - Berlin ; Heidelberg SP - 699-700 TI - Anti-CCL3 autoantibodies are not markers of type 1 diabetes when measured by a commercial ELISA method. JO - Diabetologia VL - 54 IS - 3 PB - Springer PY - 2011 SN - 0012-186X ER - TY - JOUR AB - Our aim was to determine the relationships between autoantibodies to zinc transporter 8 (ZnT8), genotypes of the ZnT8-encoding gene SLC30A8 and type 1 diabetes risk. ZnT8 autoantibodies (ZnT8A) were measured in sera of 1,633 children with a first-degree family history of type 1 diabetes and who were prospectively followed from birth. Antibodies were measured by Protein A-based radiobinding assays and COOH-terminal (R325, W325 or Q325 variants) or NH2-terminal constructs of human ZnT8. SLC30A8 genotyping at single-nucleotide polymorphism (SNP) rs13266634 was performed on 1,170 children. Antibodies against COOH-terminal ZnT8 constructs (ZnT8A-COOH) developed in 58 children as early as 9 months of age (median 3 years). They were detected in 55 of 128 (43%) children with autoantibodies to insulin, GAD and/or insulinoma-associated protein 2 and 34 of 42 (81%) who progressed to diabetes. The additional presence of ZnT8A-COOH stratified diabetes risk in islet autoantibody-positive children (p < 0.0001). SLC30A8 genotype strongly influenced ZnT8A type and diabetes risk in ZnT8A-COOH-positive children. Antibody binding against the ZnT8 R325 variant was strictly correlated with the number of the corresponding SLC30A8 R325-encoding alleles, whereas binding against the W325 variant was highest in children who had SLC30A8 W325-encoding alleles (p = 0.001). Moreover, ZnT8A-COOH-positive children who carried homozygous SLC30A8 SNP rs13266634 genotypes progressed faster to diabetes than those who were heterozygous (59% [95% CI 42.3-75.7%] vs 22% [95% CI 0-44.3%] within 5 years; p = 0.01). Autoimmunity against the COOH-terminal region of ZnT8 is a highly relevant prognostic feature in childhood type 1 diabetes. Risk stratification in ZnT8A-COOH-positive children is further improved by SLC30A8 genotyping. AU - Achenbach, P. AU - Lampasona, V.* AU - Landherr, U. AU - Koczwara, K. AU - Krause, S.* AU - Grallert, H. AU - Winkler, C. AU - Pflüger, M. AU - Illig, T. AU - Bonifacio, E.* AU - Ziegler, A.-G. C1 - 2083 C2 - 26563 SP - 1881-1888 TI - Autoantibodies to zinc transporter 8 and SLC30A8 genotype stratify type 1 diabetes risk. JO - Diabetologia VL - 52 IS - 9 PB - Springer PY - 2009 SN - 0012-186X ER - TY - JOUR AB - One major objective of the St Vincent Declaration was to reduce the excess risk of myocardial infarction in patients with diabetes mellitus. We estimated the trend of the incidence and relative risk of myocardial infarction in the diabetic and non-diabetic populations in southern Germany from 1985 to 2006. Using data from the Monitoring Trends and Determinants on Cardiovascular Diseases (MONICA)/Cooperative Health Research in the Region of Augsburg (KORA) Project in southern Germany, we ascertained all fatal and non-fatal first myocardial infarctions between 1985 and 2006 (n = 14,891, age 25-74 years). We estimated the diabetic and the non-diabetic populations using data on diabetes prevalence from surveys, and evaluated incidence of myocardial infarction in the two estimated populations. To test for time trends, we fitted Poisson regression models. Of individuals with first myocardial infarction, 71% were male and 28% known to have diabetes. In the non-diabetic population, myocardial infarction incidence decreased by about 1.5% to 2.0% per year. A comparable decrease was seen in the population of diabetic women. However, in the population of diabetic men, incidence of myocardial infarction increased by about 1% per year. Over the whole study period, myocardial infarction incidence decreased by 34% and 27% in non-diabetic men and women respectively (RR 0.66, 95% CI 0.59-0.74 and 0.73, 0.62-0.87 respectively). In diabetic women, it decreased by 27% (RR 0.73, 0.61-0.88), whereas in diabetic men, it increased by 25% (RR 1.25, 1.07-1.45). Our results suggest that the St Vincent goal of reducing excess cardiovascular morbidity in diabetic individuals has not been achieved and that the situation in men has actually got worse. AU - Icks, A.* AU - Dickhaus, T.* AU - Hörmann, A. AU - Heier, M. AU - Giani, G.* AU - Kuch, B.* AU - Meisinger, C. C1 - 1591 C2 - 26706 SP - 1836-1841 TI - Differences in trends in estimated incidence of myocardial infarction in non-diabetic and diabetic people: Monitoring Trends and Determinants on Cardiovascular Diseases (MONICA)/Cooperative Health Research in the Region of Augsburg (KORA) registry. JO - Diabetologia VL - 52 IS - 9 PB - Springer PY - 2009 SN - 0012-186X ER - TY - JOUR AB - Macrophage migration inhibitory factor (MIF) is a central mediator of innate immunity. Our aim was to investigate the triangular association between MIF genotypes, circulating MIF concentrations and incident type 2 diabetes, and to use a Mendelian randomisation approach to assess the causal role of MIF. METHODS: Using a case-cohort design within the population-based MONICA/KORA Augsburg Study, based on 502 individuals with incident type 2 diabetes (293 men, 209 women) and 1,632 non-cases (859 men, 773 women), we determined MIF serum levels at baseline and genotyped four MIF single nucleotide polymorphisms (SNPs). RESULTS: The C allele of SNP rs1007888 (3.8 kb 3' of the translation termination codon) was associated with increased circulating MIF. MIF genotype rs1007888CC was associated with an increased risk of type 2 diabetes in women [hazard ratio (95% CI) 1.74 (1.02-2.97)], but not in men [1.17 (0.75-1.81)]. Elevated MIF serum levels were associated with higher type 2 diabetes risk also only in women [HR (95% CI) 1.95 (1.15-3.29) comparing extreme quartiles after multiple adjustment], but not in men (p for interaction 0.039). The association between MIF levels and incident type 2 diabetes was significantly higher in obese women (111 cases, 147 non-cases) compared with non-obese women (98 cases, 626 non-cases; p for BMI interaction 0.0002). CONCLUSIONS/INTERPRETATION: The consistent triangular relationship between genotypes, serum levels and incident type 2 diabetes in women indicates that MIF may play a causal role in the aetiology of type 2 diabetes and that elevated MIF levels confer a higher disease risk. AU - Herder, C.* AU - Klopp, N. AU - Baumert, J.J. AU - Müller-Nurasyid, M. AU - Khuseyinova, N.* AU - Meisinger, C. AU - Martin, S.* AU - Illig, T. AU - Koenig, W.* AU - Thorand, B. C1 - 2156 C2 - 25254 SP - 276-284 TI - Effect of macrophage migration inhibitory factor (MIF) gene variants and MIF serum concentrations on the risk of type 2 diabetes: Results from the MONICA/KORA Augsburg Case-Cohort Study, 1984-2002. JO - Diabetologia VL - 51 IS - 2 PB - Springer PY - 2008 SN - 0012-186X ER - TY - JOUR AB - The aim was to identify type 2 diabetes susceptibility regions in 250 German families. SUBJECTS AND METHODS: We conducted a genome-wide linkage scan using 439 short tandem repeat polymorphisms at an average resolution of 7.76 +/- 3.80 cM (Marshfield). In an affected-only-design (affected sib pairs), we performed nonparametric multipoint linkage analyses. Conditional analyses were applied where linkage signals were found in the baseline analyses. RESULTS: We identified two loci with nominal evidence for linkage on chromosomes 1p36.13 and 16p12.2 (D1S3669, 37.05 cM, logarithmic odds ratio [LOD] = 1.49, p = 0.004; D16S403, 43.89 cM, LOD = 1.85, p = 0.002). D16S403 crossed the empirically obtained threshold of genome-wide suggestive significance of LOD = 1.51. Positive findings in those regions have been reported by the following other linkage studies on: (1) symptomatic/clinical gall bladder disease with type 2 diabetes in Mexican Americans from the San Antonio Family Diabetes/Gallbladder Study (LOD = 3.7, D1S1597-D1S407, 29.93-33.75 cM); (2) body size-adiposity in another Mexican American population (D1S1597, LOD = 2.53, 29.93 cM); (3) lipid abnormalities (LOD = 3.1, D1S2826-D1S513, 41.92-60.01 cM); and (4) hypertension in Australian sib pairs (LOD = 3.1, D1S2834-D1S2728, 31.02-33.75 cM); as well as (5) a meta-analysis of four European type 2 diabetes-related genome scans (LOD = 1.09, D16S412, 42.81 cM). In linkage analyses conditional on evidence for linkage at D16S403 we identified a LOD increase (Delta LOD) of 1.55 (p = 0.0075) at D17S2180. Similar conditioning on D17S2180 revealed evidence for interaction with D1S3669 (Delta LOD = 1.67, p = 0.0055), D16S403 (Delta LOD = 1.48, p = 0.0091) and another locus on chromosome 1 where several genome scans have reported evidence for linkage ( approximately 200 cM, Delta LOD = 1.60, p = 0.0066). CONCLUSIONS/INTERPRETATION: Our results and the findings of other studies are consistent with the presence of a locus for a complex metabolic syndrome on chromosome 1p36.13. AU - Hoffmann, K.* AU - Mattheisen, M.* AU - Dahm, S.* AU - Nürnberg, P.* AU - Roe, C.* AU - Johnson, J.* AU - Cox, N.J.* AU - Wichmann, H.-E. AU - Wienker, T.F.* AU - Schulze, J.* AU - Schwarz, P.E.* C1 - 2201 C2 - 24587 SP - 418-1422 TI - A German genome-wide linkage scan for type 2 diabetes supports the existence of a metabolic syndrome locus on chromosome 1p36.13 and a type 2 diabetes locus on chromosome 16p12.2. JO - Diabetologia VL - 50 IS - 7 PB - Springer PY - 2007 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: Previous studies have shown an inverse association between soluble thrombomodulin (sTM) and incident CHD, but there is a lack of data on the association between sTM and type 2 diabetes. Since CHD and type 2 diabetes share many risk factors, the aim of this study was to assess whether elevated sTM levels are associated with a lower incidence of type 2 diabetes. MATERIALS AND METHODS: A case-cohort study was performed in initially healthy middle-aged men and women based on data from the Monitoring of Trends and Determinants in Cardiovascular Disease/Cooperative Health Research in the Region of Augsburg (MONICA/KORA) studies conducted between 1984 and 1998. Levels of sTM were measured with an ELISA in serum samples from 138 men and 86 women who developed type 2 diabetes during follow-up (cases) and 534 men and 446 women who did not develop type 2 diabetes (non-cases). RESULTS: An inverse association was found between sTM and type 2 diabetes risk after multivariable adjustment for diabetes risk factors, including several other markers of inflammation and endothelial dysfunction. Markers of inflammation and endothelial dysfunction were particularly strong confounders of the observed association. In the fully adjusted model, a 1 SD increase in sTM was associated with a 27% decrease in the risk of type 2 diabetes (hazard ratio = 0.73, 95% CI 0.58-0.91) in the total study population. We did not observe significant risk differences between men and women. CONCLUSIONS/INTERPRETATION: These data suggest that, in initially healthy middle-aged men and women, levels of sTM are inversely associated with the risk of type 2 diabetes. AU - Thorand, B. AU - Baumert, J.J. AU - Herder, C.* AU - Meisinger, C. AU - König, W.* C1 - 4064 C2 - 24500 SP - 545-548 TI - Soluble thrombomodulin as a predictor of type 2 diabetes: Results from the MONICA/KORA Augsburg case-cohort study, 1984-1998. JO - Diabetologia VL - 50 IS - 3 PB - Springer PY - 2007 SN - 0012-186X ER - TY - JOUR AB - Aims/hypothesis: The chemokines monocyte chemoattractant protein-1 (MCP-1), IL-8 and interferon-γ-inducible protein-10 (IP-10) are released by adipocytes and appear to be involved in atherosclerosis. We hypothesised that these chemokines may be risk factors for the development of type 2 diabetes. Subjects and methods: Using a case-cohort design based on data from the population-based Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA)/Kooperative Gesundheitsforschung in der Region Augsburg/Cooperative Health Research in the Region of Augsburg (KORA Augsburg) study, chemokine levels at baseline were analysed in 526 individuals with and 1,695 individuals without incident type 2 diabetes. The mean follow-up time was 10.8 years. Results: MCP-1 was associated with type 2 diabetes, largely independently of classic risk factors, whereas various clinical and metabolic parameters as well as lifestyle factors were major confounders of the association of IL-8 and IP-10 with type 2 diabetes. Further adjustment for C-reactive protein (CRP) and IL-6 had no impact on the observed associations. The hazard ratio (HR) for subjects with systemic concentrations of all three chemokines (MCP-1, IL-8 and IP-10) above the respective median compared with those with all chemokines below or equal to the median was 1.79 (95% CI 1.18-2.72) and was comparable with the HR for elevated CRP and IL-6 together (adjusted for age, sex, survey, BMI, systolic blood pressure, total cholesterol:HDL cholesterol ratio, physical activity, alcohol intake, smoking and parental history of diabetes). Conclusions/ interpretation: Elevated concentrations of MCP-1, IL-8 and IP-10 are associated with incident type 2 diabetes. Whereas the association of IL-8 and IP-10 with diabetes was attenuated by multivariable adjustment, high MCP-1 levels contributed to diabetes risk independently of previously described clinical, metabolic and immunological risk factors. © Springer-Verlag 2006. AU - Herder, C.* AU - Baumert, J.J. AU - Thorand, B. AU - König, W.* AU - de Jager, W.* AU - Meisinger, C. AU - Illig, T. AU - Martin, S.* AU - Kolb, H.* C1 - 3166 C2 - 23697 SP - 921-929 TI - Chemokines as risk factors for the type 2 diabetes: Results from the MONICA/KORA Augsburg study, 1984-2002. JO - Diabetologia VL - 49 IS - 5 PY - 2006 SN - 0012-186X ER - TY - JOUR AU - Meisinger, C. AU - Döring, A. AU - Thorand, B. AU - Löwel, H. C1 - 4823 C2 - 23841 SP - 1770-1776 TI - Association of cigarette smoking and tar and nicotine intake with development of type 2 diabetes mellitus in men and woman from the general population: The MONICA/KORA Augsburg Cohort study. JO - Diabetologia VL - 49 PY - 2006 SN - 0012-186X ER - TY - JOUR AB - Aims/hypothesis The aim of this study was to examine sex-specific associations between leisure time physical activity and incident type 2 diabetes in a representative population sample in Germany. Methods The study was based on 4,069 men and 4,034 women (aged 25 to 74 years) who participated in one of the three MONICA Augsburg surveys between 1984 and 1995. Subjects were free of diabetes at baseline. Incident cases of type 2 diabetes were assessed in 1998 using a follow-up questionnaire. Sex-specific hazard ratios (HRs) were estimated from Cox proportional hazard models. Results A total of 145 cases of incident type 2 diabetes among men and 82 among women were registered during the mean follow-up period of 7.4 years. In both sexes, a high leisure time physical activity level was associated with a reduced risk of incident type 2 diabetes. After adjustment for confounding factors, the HR in highly active men (more than 2 h physical activity per week in summer and winter) was 0.83 (95% CI: 0.50–1.36). In contrast, highly active women had the lowest risk of type 2 diabetes even after multivariable adjustment (HR 0.24; 95% CI: 0.06–0.98). In subgroup analyses, after multivariable adjustment, the protective effect of moderate to high physical activity was significant in women with a BMI below 30 kg/m2 (HR 0.24; 95% CI: 0.09–0.65) but not in women with a BMI of 30 kg/m2 or higher (HR 0.97; 95% CI: 0.44–2.11). Conclusions/interpretation Leisure time physical activity is effective in preventing type 2 diabetes, especially in nonobese women, in the general population.   AU - Meisinger, C. AU - Löwel, H. AU - Thorand, B. AU - Döring, A. C1 - 3603 C2 - 22621 SP - 27-34 TI - Leisure time physical activity and the risk of type 2 diabetes in men and woman from the general population: The MONICA/KORA Augsburg Cohort Study. JO - Diabetologia VL - 48 IS - 1 PY - 2005 SN - 0012-186X ER - TY - JOUR AB - Aims/hypothesis To examine gender specific associations between sleep disturbance and incident type 2 diabetes mellitus in a representative population sample in Germany. Methods The study was based on 4,140 men and 4,129 women (aged 25–74 years) who participated in one of the three MONICA Augsburg surveys between 1984 and 1995, and who were free of diabetes at baseline. Incident cases of type 2 diabetes were assessed using a follow-up questionnaire in 1998. Gender specific hazard ratios were estimated from Cox proportional hazard models. Results A total of 119 cases of incident type 2 diabetes among men and 69 among women were registered during the mean follow-up period of 7.5 years. In both sexes, difficulty maintaining sleep was associated with a higher risk of type 2 diabetes. After adjustment for age, survey, hypertension, dyslipidemia, parental history of diabetes, history of angina pectoris, regular smoking, physical activity, alcohol intake, body mass index and education, the hazard ratio in men was 1.60 (95% CI: 1.05–2.45) and the hazard ratio in women was 1.98 (95% CI: 1.20–3.29). In contrast, difficulty initiating sleep was not associated with a significantly increased risk of developing type 2 diabetes mellitus after multivariable adjustment in both sexes in the present study. Conclusions/interpretation Difficulty maintaining sleep was associated with an increased risk of type 2 diabetes in men and women from the general population. Although, the causal pathway is not entirely clear, it seems that both insulin resistance and chronic low-grade systemic inflammation may be involved.   AU - Meisinger, C. AU - Heier, M. AU - Löwel, H. C1 - 4718 C2 - 22680 SP - 235-241 TI - Sleep disturbance as a predictor of type 2 diabetes mellitus in men and woman from the general population. JO - Diabetologia VL - 48 IS - 2 PY - 2005 SN - 0012-186X ER - TY - JOUR AB - AIMS/HYPOTHESIS: To estimate the prevalence of undiagnosed diabetes mellitus, impaired glucose tolerance (IGT) and impaired fasting glucose (IFG), and their relations with cardiovascular risk factors in the general population aged 55 to 74 years in Southern Germany. METHODS: Oral glucose tolerance tests were carried out in a random sample of 1353 subjects aged 55 to 74 years participating in the KORA (Cooperative Health Research in the Region of Augsburg) Survey 2000. Prevalences of glucose tolerance categories (1999 WHO criteria) were adjusted for sample probabilities. The numbers needed to screen (NNTS) to identify one person with undiagnosed diabetes were estimated from age-adjusted logistic regression models. RESULTS: Sample design-based prevalences of known and unknown diabetes, IGT, and IFG were 9.0%, 9.7%, 16.8%, 9.8% in men, and 7.9%, 6.9%, 16.0%, 4.5% in women, respectively. In both sexes, participants with undiagnosed diabetes had higher BMI, waist circumference, systolic blood pressure, triglycerides, uric acid, and lower HDL-cholesterol than normoglycaemic subjects. A combination of abdominal adiposity, hypertension, and parental diabetes in men resulted in a NNTS of 2.9 (95%CI: 2.0-4.6). In women, the combination of increased triglycerides, hypertension and parental diabetes history yielded a NNTS of 3.2 (95%CI: 2.2-5.1). CONCLUSION/INTERPRETATION: About 40% of the population aged 55 to 74 years in the Augsburg region have disturbed glucose tolerance or diabetes. Half of the total cases with diabetes are undiagnosed. Cardiovascular risk factors worsen among glucose tolerance categories, indicating the need for screening and prevention. Screening for undiagnosed diabetes could be most efficient in individuals with abdominal adiposity (men), hypertriglyceridaemia (women), hypertension, and parental diabetes history. AU - Rathmann, W.* AU - Haastert, B.* AU - Icks, A. AU - Löwel, H. AU - Meisinger, C. AU - Holle, R. AU - Giani, G.* C1 - 24013 C2 - 31374 SP - 182-189 TI - High prevalence of undiagnosed diabetes mellitus in Southern Germany: Target populations for efficient screening. The KORA survey 2000. JO - Diabetologia VL - 46 IS - 2 PB - Springer PY - 2003 SN - 0012-186X ER - TY - JOUR AB - Aims/hypothesis. A population-based sample was studied to define immune abnormalities in individuals at risk of Type II (non-insulin-dependent) diabetes mellitus because of impaired glucose tolerance. Methods. A total of 1653 individuals aged 55 to 74 years participated in a population based survey in Southern Germany (KORA Survey 2000). Those without a history of diabetes were subjected to an OGTT. Randomly selected subjects with IGT (n=80) were compared with non-diabetic control subjects (n=77) and patients with Type II diabetes (n=152) of the same population-based sample after matching for age and sex. Immune parameters were analysed in serum with rigidly evaluated ELISA. Results. Serum pro-inflammatory cytokine interleukin 6 (IL-6) concentrations were higher in subjects with IGT and Type II diabetes than in the control subjects (median 1.8 and 2.5 vs 0.8 pg/ml, p<0.0001). Soluble IL-6 receptors potentiate IL-6 bioactivity and their concentrations were mildly increased in Type II diabetes (p<0.05). These immune changes seem relevant because IL-6 dependent acute-phase proteins C-reactive protein, serum amyloid A protein and fibrinogen were also increased in IGT and Type II diabetes. Circulating concentrations of TNF-α and its two receptors sTNF-R60 and sTNF-R80 were not increased in IGT subjects compared with the control subjects. Conclusion/interpretation. Our study shows systemic up-regulation of selected inflammatory mediators in patients with Type II diabetes and IGT. The pattern observed is non-random and fits with an IL-6 associated rather than TNF-α associated response. Type II diabetes impaired glucose tolerance systemic inflammation interleukin 6 tumour necrosis factor α C-reactive protein serum amyloid A protein innate immunity cytokine acute-phase protein AU - Müller, S.* AU - Martin, S.* AU - Koenig, W.* AU - Hanifi-Moghaddam, P.* AU - Rathmann, W.* AU - Haastert, B.* AU - Giani, G.* AU - Illig, T. AU - Thorand, B. AU - Kolb, H.* C1 - 10245 C2 - 20742 SP - 805-812 TI - Impaired glucose tolerance is associated with increased serum concentrations of interleukin 6 and co-regulated acute-phase proteins but not TNF-alpha or its receptors. JO - Diabetologia VL - 45 IS - 6 PY - 2002 SN - 0012-186X ER - TY - JOUR AB - Aims/hypothesis. Mortality of diabetic patients after myocardial infarction remains high despite recent improvement in their management. This study population-based evaluates the impact of cardiovascular drug therapy on mortality within 28 days and during 5-year follow-up in diabetic compared with non-diabetic patients.¶Methods. Using the MONICA Augsburg register from 1985 to 1992, 2210 inpatients with incident Q-wave myocardial infarction aged 25–74 years were included, of whom 468 had diabetes. Primary end point was mortality within 28 days and over 5 years. General linear model procedures were used for age-adjustment, controlling for sex, and testing significance; hazard risk ratios were calculated using multivariable Cox proportional hazards model procedures.¶Results. During the 5-year follow-up, 598 subjects died (396 diabetic, 202 non-diabetic). The mortality rate within 28 days was 12.6 % in diabetic patients (women 18.0 %, men 9.9 %) and 7.3 % in non-diabetic patients (p = 0.001). Mortality in diabetic patients over 5 years was increased by 64 % (95 % confidence interval 1.39–1.95) compared with non-diabetic patients. This was considerably reduced (p < 0.001) in patients treated with thrombolytic drugs (risk ratio: diabetes 0.57, no diabetes 0.65) and with beta blockers (0.62 and 0.64) and antiplatelets (0.76 and 0.74) at hospital discharge. Mortality of diabetic patients treated with these drugs was reduced to that of non-diabetic patients without such treatment (risk ratio 1.01 to 1.27; p > 0.1).¶Conclusion/interpretation. Diabetic patients after myocardial infarction are at particularly high risk of dying, but benefit clearly from treatment with thrombolytics, beta blockers and antiplatelets. This study does not, however, allow any inferences to be drawn for treatment with angiotensin converting enzyme inhibitors or the impact of left ventricular function. AU - Löwel, H. AU - König, W.* AU - Engel, S.* AU - Hörmann, A. AU - Keil, U. C1 - 21315 C2 - 19430 SP - 218-226 TI - The impact of diabetes mellitus on survival after myocardial infarction: can it be modified by drug treatment ? : Results of a population-based myocardial infarction register follow-up study. JO - Diabetologia VL - 43 IS - 2 PY - 2000 SN - 0012-186X ER - TY - JOUR AB - The 10-year follow-up of the Munich General Practitioner Project was designed as a long-term prospective study to evaluate factors predicting macrovascular and overall mortality in a random cohort of non-insulin-dependent diabetic (NIDDM) patients. Of the original 290 patients (103 males, 187 females, median age 65 years) 92.5% could be assessed, 103 subjects had died, 58 from macrovascular causes. In an univariate analysis of baseline data, deceased patients, and especially those who died from macrovascular causes had significantly higher fasting blood glucose, HbA1c, von Willebrand-factor protein, urine albumin excretion, and serum beta 2-microglobulin, were significantly older, exhibited significantly more ischaemic heart disease (abnormal ECG Minnesota codes), carotid artery and peripheral vascular disease (both determined by ultrasound-Doppler), and had significantly inferior knowledge about diabetes and its treatment. No significant differences were seen for gender, blood pressure, smoking, total cholesterol, triglycerides, HDL-cholesterol, or the use of antidiabetic, antihypertensive or coronary drugs. In a multiple logistic regression analysis, the risk factors for macrovascular death were age, HbA1c and von Willebrand-factor protein. When baseline macrovascular disease was taken into account, carotid artery disease was also a determinant. The main variables from the metabolic syndrome (blood pressure, dyslipidaemia, body mass index) did not enter a multiple logistic regression analysis. The data suggest that age and haemoglobin A1c are major determinants, and that in addition von Willebrand-factor associated endothelial damage is a risk factor for macrovascular mortality in NIDDM patients. AU - Standl, E.* AU - Balletshofer, B.* AU - Dahl, B.* AU - Weichenhain, B.* AU - Stiegler, H.* AU - Hörmann, A. AU - Holle, R. C1 - 24204 C2 - 31471 SP - 1540-1545 TI - Predictors of 10-year macrovascular and overall mortality in patients with NIDDM: The Munich General Practitioner Project. JO - Diabetologia VL - 39 IS - 12 PB - Springer PY - 1996 SN - 0012-186X ER -