TY - JOUR AB - UNLABELLED: Survivors of childhood cancers who received high doses (40-60 Gy) of cranial irradiation (CI) have increased risks of developing obesity, type 2 diabetes, and metabolic syndrome (MetS). Here, we subjected mice to CI of 0, 0.5, or 2 Gy directed to the hypothalamus to explore the effects of low-to-moderate doses of CI on MetS risks. Despite targeting the hypothalamus as a major metabolic control center, we did not detect hypothalamic astrocyte or microglia activation at 2 or 7 days, or at 3 months post-CI. Indirect calorimetry at 2 months post-CI showed no metabolic alterations between groups, yet female mice subjected to CI were unresponsive to leptin compared with sham. Follow-up monitoring over 2 years revealed accelerated weight gain in the 2-Gy female group and glucose intolerance in both sexes following CI. Insulin sensitivity, plasma insulin, and triglycerides remained unaltered, but both male and female 2-Gy groups showed elevated VLDL and lowered HDL cholesterol levels and aberrant hypothalamic mRNA levels of genes involved in synaptic and neuronal function, neuroinflammation, and endoplasmic reticulum stress. Mortality remained unaffected by all doses of CI. These data strongly suggest a significant risk for developing MetS following low-to-moderate doses of CI, and they support tailored clinical risk assessment and monitoring strategies for patients undergoing CI, especially when the hypothalamus is included. ARTICLE HIGHLIGHTS: High-dose cranial irradiation (CI) during early developmental stages has been linked to metabolic abnormalities in later life, but causal evidence at low-to-moderate doses has been elusive. Monitoring mice for 2 years post-2-Gy CI to the hypothalamus, we found increased risks of leptin resistance, dyslipidemia, glucose intolerance, and weight gain, identifying the hypothalamus as the likely responsible region. Our findings suggest that low-to-moderate doses of CI may be a risk factor for developing metabolic syndrome. Future clinical risk assessment and monitoring strategies are needed for patients undergoing CI of hypothalamic centers governing glucose and energy metabolism. AU - Harrison, L. AU - Schriever, S.C. AU - Bernecker, M. AU - Mallet, N. AU - Mencias Castillejo, C. AU - Ameli, H. AU - Baumann, P. AU - Contreras, R. AU - Stolz, J. AU - Lindner, R. AU - Bartzsch, S. AU - Schmid, T.E. AU - Combs, S.E. AU - Rosemann, M. AU - Pfluger, P.T. C1 - 75304 C2 - 58263 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 1775-1786 TI - Low-to-moderate dosed cranial irradiation in young mice induces sex-specific metabolic disturbances later in life. JO - Diabetes VL - 74 IS - 10 PB - Amer Diabetes Assoc PY - 2025 SN - 0012-1797 ER - TY - JOUR AB - This study compares novel type 1 diabetes-related autoantibody assays developed to improve upon the standard radiobinding assay (RBA). Samples from 1505 individuals, followed for 5 years or to clinical type 1 diabetes, originally tested by RBA were aliquoted and sent blindly to 5 laboratories (BDC, IDR, DRI, MSD, Enable) to be tested by electrochemiluminescence (ECL) assays, Luciferase Immuno Precipitation System (LIPS) assays, multiplex antibody detection by agglutination-PCR (ADAP) assays, and N-terminally truncated GAD65 or IA2β autoantibody RBAs (tGADA/IA2βA). Findings: The fraction of samples that were concordant for negative/positive interpretations across all assays were 79.7% (GADA), 65.2% (IA-2A), 36.2% (IAA), and 67.5% (ZnT8A). The assays with the highest Youden index for predicting the previous RBA results differed by autoantibody: 0.65 LIPS(IDR) for IAA, 0.91 ECL(BDC) for ZnT8A, 0.82 tGADA RBA(IDR) for GADA, 0.91 ECL(MSD and BDC) for IA-2A. The Youden index for predicting 5-year type 1 diabetes varied significantly across assays and was highest for LIPS(DRI) for all autoantibody combinations, with little variation in the respective maximum Youden index. The discordance between assays makes it problematic to interpret positivity when comparing results from different assays. Longitudinal autoantibody assessments should be tested with the same assay. AU - Krischer, J.P.* AU - Muller, S.* AU - You, L.* AU - Achenbach, P. AU - Bazzigaluppi, E.* AU - Brigatti, C.* AU - Lampasona, V.* AU - Mathew, A.* AU - Robinson, P.N.* AU - Seftel, D.* AU - Sigal, G.* AU - Tsai, C.T.* AU - Wang, M.* AU - Yu, L.* C1 - 73637 C2 - 57150 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 1535-1546 TI - A comparative analysis of the sensitivity, specificity, concordance, and the 5-year predictive power of diabetes-related autoantibody assays. JO - Diabetes VL - 74 IS - 9 PB - Amer Diabetes Assoc PY - 2025 SN - 0012-1797 ER - TY - JOUR AU - Ussar, S. C1 - 75374 C2 - 58003 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 1464-1465 TI - Targeting adipose inflammation and energy expenditure to sustain metabolic health after weight loss. JO - Diabetes VL - 74 IS - 9 PB - Amer Diabetes Assoc PY - 2025 SN - 0012-1797 ER - TY - JOUR AB - UNLABELLED: Over the last two decades, increased availability of human pancreatic tissues has allowed for major expansions in our understanding of islet biology in health and disease. Indeed, studies of fixed and frozen pancreatic tissues, as well as efforts using viable isolated islets obtained from organ donors, have provided significant insights toward our understanding of diabetes. However, the procedures associated with islet isolation result in distressed cells that have been removed from any surrounding influence. The pancreas tissue slice technology was developed as an in situ approach to overcome certain limitations associated with studies on isolated islets or fixed tissue. In this Perspective, we discuss the value of this novel platform and review how pancreas tissue slices, within a short time, have been integrated in numerous studies of rodent and human islet research. We show that pancreas tissue slices allow for investigations in a less perturbed organ tissue environment, ranging from cellular processes, over peri-islet modulations, to tissue interactions. Finally, we discuss the considerations and limitations of this technology in its future applications. We believe the pancreas tissue slices will help bridge the gap between studies on isolated islets and cells to the systemic conditions by providing new insight into physiological and pathophysiological processes at the organ level. ARTICLE HIGHLIGHTS: Human pancreas tissue slices represent a novel platform to study human islet biology in close to physiological conditions. Complementary to established technologies, such as isolated islets, single cells, and histological sections, pancreas tissue slices help bridge our understanding of islet physiology and pathophysiology from single cell to intact organ. Diverse sources of viable human pancreas tissue, each with distinct characteristics to be considered, are available to use in tissue slices for the study of diabetes pathogenesis. AU - Cohrs, C.M. AU - Chen, C. AU - Atkinson, M.A.* AU - Drotar, D.M.* AU - Speier, S. C1 - 69059 C2 - 53836 SP - 11-22 TI - Bridging the Gap: Pancreas tissue slices from organ and tissue donors for the study of diabetes pathogenesis. JO - Diabetes VL - 73 IS - 1 PY - 2024 SN - 0012-1797 ER - TY - JOUR AB - We investigated whether characterisation of full-length (f-)GADA responses could identify early insulin requirement in adult-onset diabetes. In 179 f-GADA positive participants diagnosed with type 2 diabetes, we assessed associations of truncated (t-)GADA positivity, f-GADA IgG subclasses, and f-GADA affinity with early insulin requirement (<5 years), type 1 diabetes genetic risk score (T1D GRS), and C-peptide. t-GADA positivity was lower in f-GADA positive without early insulin in comparison to f-GADA positive type 2 diabetes requiring insulin within 5 years, and type 1 diabetes (75% vs. 91% and 95% respectively, p<0.0001). t-GADA positivity (in those f-GADA positive) identified a group with a higher type 1 diabetes genetic susceptibility (mean T1D GRS 0.248 vs. 0.225, p=0.003), lower C-peptide (1156 pmol/L vs. 4289 pmol/L, p=1x10-7), and increased IA-2A positivity (23% vs. 6%, p=0.03). In survival analysis, t-GADA positivity was associated with early insulin requirement compared with those only positive for f-GADA, independently from age of diagnosis, f-GADA titre and duration of diabetes [adjusted HR 5.7 (95% CI 1.4, 23.5), p=0.017]. The testing of t-GADA in f-GADA positive individuals with type 2 diabetes identifies those who have genetic and clinical characteristics comparable to type 1 diabetes and stratifies those at higher risk of early insulin requirement. AU - Grace, S.L.* AU - Gillespie, K.M.* AU - Williams, C.L.* AU - Lampasona, V.* AU - Achenbach, P. AU - Pearson, E.R.* AU - Williams, A.J.K.* AU - Long, A.E.* AU - McDonald, T.J.* AU - Jones, A.G.* C1 - 71060 C2 - 55995 SP - 1583-1591 TI - Autoantibodies to truncated GAD(96-585) antigen stratify risk of early insulin requirement in adult-onset diabetes. JO - Diabetes VL - 73 IS - 10 PY - 2024 SN - 0012-1797 ER - TY - JOUR AB - Genetic determinants of inter-individual differences in energy expenditure (EE) are largely unknown. Sphingolipids, such as ceramides, have been implicated in the regulation of human EE via mitochondrial uncoupling. In this study, we investigated whether genetic variants within enzymes involved in sphingolipid synthesis and degradation affect EE and insulin-related traits in a cohort of American Indians informative for 24-hour EE and glucose disposal rates during a hyperinsulinemic-euglycemic clamp. Association analysis of 10,084 genetic variants within 28 genes involved in sphingolipid pathways identified a missense variant (rs267738, A>C, E115A) in exon 4 of CERS2 that was associated with higher sleeping EE (+116 kcal/day) and increased rates of endogenous glucose production during basal (+5%) and insulin-stimulated (+43%) conditions, both indicators of hepatic insulin resistance. The rs267738 variant did not affect ceramide synthesis in HepG2 cells but resulted in a 30% decrease in basal mitochondrial respiration. In conclusion, we provide evidence that the CERS2 rs267738 missense variant may influence hepatic glucose production and post-absorptive sleeping metabolic rate. AU - Heinitz, S. AU - Traurig, M.* AU - Krakoff, J.* AU - Rabe, P.* AU - Stäubert, C.* AU - Kobes, S.* AU - Hanson, R.L.* AU - Stumvoll, M. AU - Blüher, M. AU - Bogardus, C.* AU - Baier, L.J.* AU - Piaggi, P.* C1 - 70724 C2 - 55863 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 1361-1371 TI - An E115A missense variant in CERS2 is associated with increased sleeping energy expenditure and hepatic insulin resistance in American Indians. JO - Diabetes VL - 73 IS - 8 PB - Amer Diabetes Assoc PY - 2024 SN - 0012-1797 ER - TY - JOUR AB - Type 1 diabetes treatment stands at a crucial and exciting crossroad since the 2022 U.S. Food and Drug Administration (FDA) approval of teplizumab to delay disease development. In this Perspective article, we discuss four major conceptual and practical issues that emerged as key to further advance type 1 diabetes research and therapies. First, collaborative networks leveraging the synergy between the type 1 diabetes research and care community members are key to fostering innovation, know-how and translation into the clinical arena worldwide. Second, recent clinical trials in presymptomatic stage 2 and recent-onset stage 3 disease have shown the promise, and potential pitfalls, of using immunomodulatory and/or beta-cell protective agents to achieve sustained remission or prevention. Third, the increasingly appreciated heterogeneity of clinical, immunological, and metabolic phenotypes and disease trajectories is of critical importance to advance the decision-making process for tailored type 1 diabetes care and therapy. Fourth, the clinical benefits of early diagnosis of beta-cell autoimmunity warrant consideration of general population screening for islet autoantibodies, which requires further efforts to address the technical, organizational and ethical challenges inherent to a sustainable program. Efforts are underway to integrate these four concepts into the future directions of type 1 diabetes research and therapy. AU - Mallone, R.* AU - Sims, E.* AU - Achenbach, P. AU - Mathieu, C.* AU - Pugliese, A.* AU - Atkinson, M.* AU - Dutta, S.* AU - Evans-Molina, C.* AU - Klatzmann, D.* AU - Koralova, A.* AU - Long, S.A.* AU - Overbergh, L.* AU - Rodriguez-Calvo, T. AU - Ziegler, A.-G. AU - You, S.H.* C1 - 72140 C2 - 56502 TI - Emerging concepts and success stories in type 1 diabetes research: A roadmap for a bright future. JO - Diabetes VL - 74 IS - 1 PY - 2024 SN - 0012-1797 ER - TY - JOUR AB - Lesioned fascicles (LF) in the sciatic nerves of individuals with diabetic neuropathy (DN) correlate with clinical symptom severity. This study aimed to characterize the structural and molecular composition of these lesions to better understand DN pathogenesis. Sciatic nerves from amputees with and without type 2 diabetes (T2D) were examined using ex vivo magnetic resonance neurography, in vitro imaging, and proteomic analysis. Lesions were only found in T2D donors and exhibited significant structural abnormalities, including axonal degeneration, demyelination, and impaired blood nerve barrier (BNB). While non-lesioned fascicles from T2D donors showed activation of neuroprotective pathways, lesioned fascicles lacked this response and instead displayed increased complement activation via the classical pathway. The detection of liver-derived acute-phase proteins suggests that BNB disruption facilitates harmful inter-organ communication between the liver and nerves. These findings reveal key molecular mechanisms contributing to DN and highlight potential targets for therapeutic intervention. AU - Schwarz, D.* AU - Marois, M.L.* AU - Sturm, V.* AU - Peters, A.S.* AU - Longuespée, R.* AU - Helm, D.* AU - Schneider, M.* AU - Eichmüller, B.* AU - Hidmark, A.S.* AU - Fischer, M.* AU - Kender, Z. AU - Schwab, C.* AU - Hausser, I.* AU - Weis, J.* AU - Dihlmann, S.* AU - Böckler, D.* AU - Bendszus, M.* AU - Heiland, S.* AU - Herzig, S. AU - Nawroth, P.P.* AU - Szendroedi, J. AU - Fleming, T. C1 - 72050 C2 - 56551 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 65-74 TI - Exploring structural and molecular features of sciatic nerve lesions in diabetic neuropathy: Unveiling pathogenic pathways and targets. JO - Diabetes VL - 74 IS - 1 PB - Amer Diabetes Assoc PY - 2024 SN - 0012-1797 ER - TY - JOUR AB - Autoantibodies to glutamate decarboxylase (GADA) are widely used in the prediction and classification of type 1 diabetes. GADA radiobinding assays (RBAs) using N-terminally truncated antigens offer improved specificity but radioisotopes limit the high-throughput potential for population screening. Luciferase-based Immunoprecipitation System (LIPS) assays are sensitive and specific alternatives to RBAs with the potential to improve risk stratification. The performance of assays using the Luciferase (Nluc-) conjugated GAD65 constructs, Nluc-GAD65(96-585) and full length Nluc-GAD65(1-585) were evaluated in 434 well-characterised sera from recent-onset type 1 diabetes patients and first-degree relatives. Non-radioactive, high-throughput LIPS assays are quicker and require less serum than RBAs. Of 171 relatives previously tested single autoantibody positive for autoantibodies to full-length GAD65 by RBA but had not progressed to diabetes, fewer retested positive by LIPS using either truncated (n=72) or full-length (n=111) antigen. The Nluc-GAD65(96-585) truncation demonstrated the highest specificity in LIPS assays overall but in contrast to RBA, N-terminus truncations did not result in a significant increase in disease-specificity compared with the full-length antigen. This suggests that binding of non-specific antibodies is affected by the conformational changes resulting from addition of the Nluc antigen. Nluc-GAD65(96-585) LIPS assays offer low blood volume, high specificity GADA tests for screening and diagnostics. AU - Wyatt, R.C.* AU - Grace, S.L.* AU - Brigatti, C.* AU - Marzinotto, I.* AU - Gillard, B.T.* AU - Shoemark, D.K.* AU - Chandler, K.* AU - Achenbach, P. AU - Piemonti, L.* AU - Long, A.E.* AU - Gillespie, K.M.* AU - Lampasona, V.* AU - Williams, A.J.K.* C1 - 69826 C2 - 55269 SP - 565-571 TI - Improved specificity of glutamate decarboxylase 65 autoantibody measurement using luciferase-based immunoprecipitation system (LIPS) assays. JO - Diabetes VL - 73 IS - 4 PY - 2024 SN - 0012-1797 ER - TY - JOUR AB - UNLABELLED: Prediabetes is a metabolic condition associated with gut microbiome composition, although mechanisms remain elusive. We searched for fecal metabolites, a readout of gut microbiome function, associated with impaired fasting glucose (IFG) in 142 individuals with IFG and 1,105 healthy individuals from the UK Adult Twin Registry (TwinsUK). We used the Cooperative Health Research in the Region of Augsburg (KORA) cohort (318 IFG individuals, 689 healthy individuals) to replicate our findings. We linearly combined eight IFG-positively associated metabolites (1-methylxantine, nicotinate, glucuronate, uridine, cholesterol, serine, caffeine, and protoporphyrin IX) into an IFG-metabolite score, which was significantly associated with higher odds ratios (ORs) for IFG (TwinsUK: OR 3.9 [95% CI 3.02-5.02], P < 0.0001, KORA: OR 1.3 [95% CI 1.16-1.52], P < 0.0001) and incident type 2 diabetes (T2D; TwinsUK: hazard ratio 4 [95% CI 1.97-8], P = 0.0002). Although these are host-produced metabolites, we found that the gut microbiome is strongly associated with their fecal levels (area under the curve >70%). Abundances of Faecalibacillus intestinalis, Dorea formicigenerans, Ruminococcus torques, and Dorea sp. AF24-7LB were positively associated with IFG, and such associations were partially mediated by 1-methylxanthine and nicotinate (variance accounted for mean 14.4% [SD 5.1], P < 0.05). Our results suggest that the gut microbiome is linked to prediabetes not only via the production of microbial metabolites but also by affecting intestinal absorption/excretion of host-produced metabolites and xenobiotics, which are correlated with the risk of IFG. Fecal metabolites enable modeling of another mechanism of gut microbiome effect on prediabetes and T2D onset. ARTICLE HIGHLIGHTS: Prediabetes is a metabolic condition associated with gut microbiome composition, although mechanisms remain elusive. We investigated whether there is a fecal metabolite signature of impaired fasting glucose (IFG) and the possible underlying mechanisms of action. We identified a fecal metabolite signature of IFG associated with prevalent IFG in two independent cohorts and incident type 2 diabetes in a subanalysis. Although the signature consists of metabolites of nonmicrobial origin, it is strongly correlated with gut microbiome composition. Fecal metabolites enable modeling of another mechanism of gut microbiome effect on prediabetes by affecting intestinal absorption or excretion of host compounds and xenobiotics. AU - Nogal, A.* AU - Tettamanzi, F.* AU - Dong, Q. AU - Louca, P.* AU - Visconti, A.* AU - Christiansen, C.* AU - Breuninger, T.A.* AU - Linseisen, J.* AU - Grallert, H. AU - Wawro, N. AU - Asnicar, F.* AU - Wong, K.* AU - Baleanu, A.F.* AU - Michelotti, G.A.* AU - Segata, N.* AU - Falchi, M.* AU - Peters, A. AU - Franks, P.W.* AU - Bagnardi, V.* AU - Spector, T.D.* AU - Bell, J.T.* AU - Gieger, C. AU - Valdes, A.M.* AU - Menni, C.* C1 - 68608 C2 - 54708 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 1870-1880 TI - A faecal metabolite signature of impaired fasting glucose: Results from twoindependent population-based cohorts. JO - Diabetes VL - 72 IS - 12 PB - Amer Diabetes Assoc PY - 2023 SN - 0012-1797 ER - TY - JOUR AB - We aimed to investigate the characteristics and longitudinal course of sensory phenotypes identified through Quantitative Sensory Testing in the frame of diabetic polyneuropathy (DSPN). 316 individuals with diabetes mellitus (DM) were examined (78.8% T2DM), of which 250 were follow-up visits 1, 2 and/or 4 (2.88±1.27) years. Allocation into four sensory phenotypes (healthy, thermal hyperalgesia-TH, mechanical hyperalgesia-MH, and sensory loss-SL) at every timepoint was based on QST profiles of the right foot. Cross-sectional analyses demonstrated a gradual worsening of clinical and electrophysiological sensory findings, and increased DSPN prevalence across the groups culminating in SL. Motor nerve impairment was observed solely in SL. Longitudinal analysis revealed a distinct pattern of the phenotype's developmental course (healthy to TH, to MH, to SL). Baseline MH exhibited the highest risk of transition to SL. Regression to healthy was uncommon and mostly observed in TH. Among those without DSPN initially, presence or future occurrence of SL was associated with a three- to fivefold higher likelihood of DSPN development. Our comprehensive longitudinal study of phenotyped patients with DM elucidates the natural course of DSPN. QST-based sensory examination together with other tools for phenotyping may perhaps be useful to determine the natural course of diabetic neuropathy, to identify patients at high risk for DSPN and guide preventive and therapeutic interventions. AU - Tsilingiris, D.* AU - Schimpfle, L.* AU - Rauchhaupt, E.V.* AU - Sulaj, A.* AU - Seebauer, L.* AU - Herzig, S. AU - Szendrödi, J. AU - Kopf, S.* AU - Kender, Z.* C1 - 68714 C2 - 54923 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 135-146 TI - Sensory phenotypes provide insight into the natural course of diabetic polyneuropathy. JO - Diabetes VL - 73 IS - 1 PB - Amer Diabetes Assoc PY - 2023 SN - 0012-1797 ER - TY - JOUR AB - The objective of this work was to investigate whether impaired insulin secretion can be restored by lifestyle intervention in specific subphenotypes of prediabetes. One thousand forty-five participants from the Prediabetes Lifestyle Intervention Study (PLIS) were assigned to 6 recently established prediabetes clusters. Insulin secretion was assessed by a C-peptide-based index derived from oral glucose tolerance tests and modeled from three time-points during a 1-yr intervention. We also analyzed the change of glycemia, insulin sensitivity and liver fat. All pre-diabetes high-risk clusters (cluster 3, 5 and 6) had improved glycemic traits during lifestyle intervention, whereas insulin secretion only increased in clusters 3 and 5 (p<0.001); however, high liver fat in cluster 5 was associated with a failure to improve insulin secretion (pinteraction<0.001). Thus, interventions to reduce liver fat have the potential to improve insulin secretion in a defined subgroup of prediabetes. Prediabetes is a heterogenous condition comprising subphenotypes with different risks of diabetes and its complications (1). From its two key features, insulin resistance and impaired insulin secretion, insulin resistance can be clearly improved by lifestyle intervention (LI); however, it is not known, if LI can improve insulin secretion in specific subphenotypes of reduced insulin secretion (2). Recently, we described 6 clusters of prediabetic metabolism (1). Two of these clusters (cluster 3 and 5) have high risk of progression to diabetes. Another group (cluster 6) has an intermediate risk of diabetes as these persons are capable of compensating insulin resistance via hyperinsulinemia over years. In this study, we retrospectively stratified participants of a large multi-center study into these novel clusters of prediabetic metabolism (1) and investigated whether LI improved their insulin secretion and other glycemic traits. AU - Wagner, R. AU - Heni, M. AU - Kantartzis, K. AU - Sandforth, A. AU - Machann, J.* AU - Schick, F.* AU - Peter, A. AU - Fritsche, L. AU - Szendrödi, J. AU - Pfeiffer, A.F.* AU - Schürmann, A.* AU - Blüher, M.* AU - Hauner, H.* AU - Seissler, J.* AU - Bornstein, S.* AU - Roden, M.* AU - Stefan, N. AU - Birkenfeld, A.L. AU - White, M.F.* AU - Häring, H.-U. AU - Fritsche, A. C1 - 66977 C2 - 53392 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 362-366 TI - Lower hepatic fat is associated with improved insulin secretion in a high-risk prediabetes subphenotype during lifestyle intervention. JO - Diabetes VL - 72 IS - 3 PB - Amer Diabetes Assoc PY - 2023 SN - 0012-1797 ER - TY - JOUR AB - Type 1 diabetes in children is heralded by a preclinical phase defined by circulating autoantibodies to pancreatic islet antigens. How islet autoimmunity is initiated and then progresses to clinical diabetes remains poorly understood. Only one study has reported gene expression in specific immune cells of at-risk children, associated with progression to islet autoimmunity. We analysed gene expression by RNAseq in CD4+ and CD8+ T cells, NK cells and B cells, and chromatin accessibility by ATACseq in CD4+ T cells, in five genetically at-risk children with islet autoantibodies who progressed to diabetes over a median of 3 years ('Progressors') compared to five children matched for sex, age and HLA-DR who had not progressed ('Non-progressors). In Progressors, differentially expressed genes (DEGs) were largely confined to CD4+ T cells and enriched for cytotoxicity-related genes/pathways. Several top-ranked DEGs were validated in a semi-independent cohort of 13 Progressors and 11 Non-progressors. Flow cytometry confirmed progression was associated with expansion of CD4+ cells with a cytotoxic phenotype. By ATAC-seq, progression was associated with reconfiguration of regulatory chromatin regions in CD4+ T cells, some linked to differentially expressed cytotoxicity-related genes. Our findings suggest that cytotoxic CD4+ T cells play a role in promoting progression to type 1 diabetes. AU - Bediaga, N.G.* AU - Garnham, A.L.* AU - Naselli, G.* AU - Bandala-Sanchez, E.* AU - Stone, N.L.* AU - Cobb, J.* AU - Harbison, J.E.* AU - Wentworth, J.M.* AU - Ziegler, A.-G. AU - Couper, J.J.* AU - Smyth, G.K.* AU - Harrison, L.C.* C1 - 63992 C2 - 51792 SP - 566-577 TI - Cytotoxicity-related gene expression and chromatin accessibility define a subset of CD4+ T cells that mark progression to type 1 diabetes. JO - Diabetes VL - 71 IS - 3 PY - 2022 SN - 0012-1797 ER - TY - JOUR AB - Progressive dysfunction and failure of insulin-releasing β-cells is a hallmark of type 2 diabetes (T2D). To study mechanisms of β-cell loss in T2D, we performed islet single-cell RNA-sequencing of two obese mouse strains differing in their diabetes susceptibility. On a control diet, we identified six β-cell clusters with similar abundance in both strains. However, after feeding a diabetogenic diet for two days, β-cell cluster composition markedly differed between strains. Islets of diabetes-resistant mice developed into a protective β-cell cluster (Beta4), whereas those of diabetes-prone mice progressed towards stress-related clusters with a strikingly different expression pattern. Interestingly, the protective cluster showed indications of reduced β-cell identity, such as downregulation of GLUT2, GLP1R and MafA, and in-vitro knockdown of GLUT2 in β-cells to mimick its phenotype decreased stress response and apoptosis. This might explain enhanced β-cell survival of diabetes-resistant islets. In contrast, β-cells of diabetes-prone mice responded with expression changes indicating metabolic pressure and ER stress, presumably leading to later β-cell loss. In conclusion, failure of diabetes-prone mice to adapt gene expression towards a more dedifferentiated state in response to rising blood glucose levels leads to β-cell failure and diabetes development. AU - Gottmann, P.* AU - Speckmann, T.* AU - Stadion, M.* AU - Zuljan, E.* AU - Aga, H.* AU - Sterr, M. AU - Büttner, M. AU - Santos, P.M.* AU - Jähnert, M.* AU - Bornstein, S.R.* AU - Theis, F.J. AU - Lickert, H. AU - Schürmann, A.* C1 - 65677 C2 - 52885 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 1962-1978 TI - Heterogeneous development of β-cell populations In diabetes-resistant and -susceptible mice. JO - Diabetes VL - 71 IS - 9 PB - Amer Diabetes Assoc PY - 2022 SN - 0012-1797 ER - TY - JOUR AB - In our previous data-driven analysis of evolving patterns of islet autoantibodies (IAb) against insulin (IAA), GAD (GADA), and islet antigen 2 (IA-2A), we discovered three trajectories, characterized according to multiple IAb (TR1), IAA (TR2), or GADA (TR3) as the first appearing autoantibodies. Here we examined the evolution of IAb levels within these trajectories in 2,145 IAb-positive participants followed from early life and compared those who progressed to type 1 diabetes (n = 643) with those remaining undiagnosed (n = 1,502). With use of thresholds determined by 5-year diabetes risk, four levels were defined for each IAb and overlaid onto each visit. In diagnosed participants, high IAA levels were seen in TR1 and TR2 at ages <3 years, whereas IAA remained at lower levels in the undiagnosed. Proportions of dwell times (total duration of follow-up at a given level) at the four IAb levels differed between the diagnosed and undiagnosed for GADA and IA-2A in all three trajectories (P < 0.001), but for IAA dwell times differed only within TR2 (P < 0.05). Overall, undiagnosed participants more frequently had low IAb levels and later appearance of IAb than diagnosed participants. In conclusion, while it has long been appreciated that the number of autoantibodies is an important predictor of type 1 diabetes, consideration of autoantibody levels within the three autoimmune trajectories improved differentiation of IAb-positive children who progressed to type 1 diabetes from those who did not. AU - Kwon, B.C.* AU - Achenbach, P. AU - Anand, V.* AU - Frohnert, B.I.* AU - Hagopian, W.* AU - Hu, J.* AU - Koski, E.* AU - Lernmark, Å.* AU - Lou, O.* AU - Martin, F.* AU - Ng, K.* AU - Toppari, J.* AU - Veijola, R.* C1 - 67021 C2 - 53368 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 2632-2641 TI - Islet autoantibody levels differentiate progression trajectories in individuals with presymptomatic type 1 diabetes. JO - Diabetes VL - 71 IS - 12 PB - Amer Diabetes Assoc PY - 2022 SN - 0012-1797 ER - TY - JOUR AB - Death rate is increased in type 2 diabetes. Unraveling biomarkers of novel pathogenic pathways capable to identify high-risk patients is instrumental to tackle this burden. We investigated the association between serum metabolites and all-cause mortality in type 2 diabetes and then, whether the associated metabolites mediate the effect of inflammation on mortality risk and improve ENFORCE and RECODe, two well-established all-cause mortality prediction models in diabetes. Two cohorts comprising 856 individuals (279 all-cause deaths) were analyzed. Serum metabolites (n=188) and pro- and anti-inflammatory cytokines (n=7) were measured. In the pooled analysis, hexanoylcarnitine, kynurenine and tryptophan were significantly and independently associated with mortality (HRs, [95%CIs] 1.60, [1.43-1.80]; 1.53, [1.37-1.71]; 0.71, [0.62-0.80] per 1SD). The kynurenine/tryptophan ratio (KTR-a proxy of indoleamine-2,3-dioxygenase which degrades tryptophan to kynurenine and contribute to a pro-inflammatory status) mediated 42% of the significant association between the anti-atherogenic IL-13 and mortality. Adding the three metabolites improved discrimination and reclassification (all P<0.01) of both mortality prediction models. In type 2 diabetes, hexanoylcarnitine, tryptophan and kynurenine are associated to and improve the prediction of all-cause mortality. Further studies are needed to investigate whether interventions aimed at reducing KTR, also reduce the risk of death especially in patients with low IL-13. AU - Scarale, M.G.* AU - Mastroianno, M.* AU - Prehn, C. AU - Copetti, M.* AU - Salvemini, L.* AU - Adamski, J. AU - De Cosmo, S.* AU - Trischitta, V.* AU - Menzaghi, C.* C1 - 64819 C2 - 51976 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 1363-1370 TI - Circulating metabolites associate with and improve the prediction of all-cause mortality in type 2 diabetes. JO - Diabetes VL - 71 IS - 6 PB - Amer Diabetes Assoc PY - 2022 SN - 0012-1797 ER - TY - JOUR AB - Most screening programs to identify individuals at risk for type 1 diabetes have targeted relatives of people living with the disease to improve yield and feasibility. However, ∼90% of those who develop type 1 diabetes do not have a family history. Recent successes in disease-modifying therapies to impact the course of early-stage disease have ignited the consideration of the need for and feasibility of population screening to identify those at increased risk. Existing population screening programs rely on genetic or autoantibody screening, and these have yielded significant information about disease progression and approaches for timing for screening in clinical practice. At the March 2021 Type 1 Diabetes TrialNet Steering Committee meeting, a session was held in which ongoing efforts for screening in the general population were discussed. This report reviews the background of these efforts and the details of those programs. Additionally, we present hurdles that need to be addressed for successful implementation of population screening and provide initial recommendations for individuals with positive screens so that standardized guidelines for monitoring and follow-up can be established. AU - Sims, E.K.* AU - Besser, R.E.J.* AU - Dayan, C.* AU - Geno Rasmussen, C.* AU - Greenbaum, C.J.* AU - Griffin, K.J.* AU - Hagopian, W.* AU - Knip, M.* AU - Long, A.E.* AU - Martin, F.* AU - Mathieu, C.* AU - Rewers, M.* AU - Steck, A.K.* AU - Wentworth, J.M.* AU - Rich, S.S.* AU - Kordonouri, O.* AU - Ziegler, A.-G. AU - Herold, K.C.* C1 - 64618 C2 - 51968 SP - 610-623 TI - Screening for type 1 diabetes in the general population: A status report and perspective. JO - Diabetes VL - 71 IS - 4 PY - 2022 SN - 0012-1797 ER - TY - JOUR AB - Fat accumulation in the liver, pancreas, skeletal muscle, and visceral bed relates to type-2 diabetes (T2D). However, the distribution of fat among these compartments is heterogenous and it is unclear whether specific distribution patterns indicate high T2D risk. We therefore investigated fat-distribution patterns and their link to future T2D. From 2168 individuals without diabetes who underwent computed tomography in Japan, this case-cohort study included 658 randomly selected individuals and 146 incident cases of T2D over 6 years of follow-up. Using data-driven analysis (k-means) based on fat content in the liver, pancreas, muscle, and visceral bed, we identified four fat-distribution clusters: Hepatic steatosis, Pancreatic steatosis, Trunk myosteatosis, and Steatopenia. Compared with the Steatopenia cluster, the adjusted hazard ratios (95% CIs) for incident T2D were 4.02 (2.27-7.12) for the Hepatic steatosis cluster, 3.38 (1.65-6.91) for the Pancreatic steatosis cluster, and 1.95 (1.07-3.54) for the Trunk myosteatosis cluster. The clusters were replicated in 319 German individuals without diabetes who underwent magnetic resonance imaging and metabolic phenotyping. The distribution of AUC-glucose across the four clusters found in Germany was similar to the distribution of T2D risk across the four clusters in Japan. Insulin sensitivity and insulin secretion differed across the four clusters. Thus, we identified patterns of fat distribution with different T2D risks presumably due to differences in insulin sensitivity and insulin secretion. AU - Yamazaki, H.* AU - Tauchi, S.* AU - Machann, J. AU - Haueise, T. AU - Yamamoto, Y.* AU - Dohke, M.* AU - Hanawa, N.* AU - Kodama, Y.* AU - Katanuma, A.* AU - Stefan, N. AU - Fritsche, A. AU - Birkenfeld, A.L. AU - Wagner, R. AU - Heni, M. C1 - 65550 C2 - 52304 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 1937-1945 TI - Fat-distribution patterns and future type-2 diabetes. JO - Diabetes VL - 71 IS - 9 PB - Amer Diabetes Assoc PY - 2022 SN - 0012-1797 ER - TY - JOUR AB - Bone morphogenetic proteins (BMPs) are a group of signaling molecules that belong to the TGF-β superfamily. Initially discovered for their ability to induce bone formation, BMPs are known to play a diverse and critical array of biological roles. We here focus on recent evidence showing that BMP4 is an important regulator of white/beige adipogenic differentiation with important consequences for thermogenesis, energy homeostasis, and development of obesity in vivo. BMP4 is highly expressed in, and released by, human adipose tissue, and serum levels are increased in obesity. Recent studies have now shown BMP4 to play an important role not only for white/beige/brown adipocyte differentiation and thermogenesis but also in regulating systemic glucose homeostasis and insulin sensitivity. It also has important suppressive effects on hepatic glucose production and lipid metabolism. Cellular BMP4 signaling/action is regulated by both ambient cell/systemic levels and several endogenous and systemic BMP antagonists. Reduced BMP4 signaling/action can contribute to the development of obesity, insulin resistance, and associated metabolic disorders. In this article, we summarize the pleiotropic functions of BMP4 in the pathophysiology of these diseases and also consider the therapeutic implications of targeting BMP4 in the prevention/treatment of obesity and its associated complications. AU - Baboota, R.K.* AU - Blüher, M. AU - Smith, U.* C1 - 61076 C2 - 50035 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 303-312 TI - Emerging role of bone morphogenetic protein 4 in metabolic disorders. JO - Diabetes VL - 70 IS - 2 PB - Amer Diabetes Assoc PY - 2021 SN - 0012-1797 ER - TY - JOUR AB - Type 2 diabetes has become a pandemic and leads to late diabetic complications of organs including kidney and eye. Lowering hyperglycemia is the typical therapeutic goal in clinical medicine. However, hyperglycemia may only be a symptom of diabetes but not the sole cause of late diabetic complications, Instead, other diabetes-related alterations could be causative. Here, we studied the role of CaM Kinase II δ (CaMKIIδ) that is known to be activated through diabetic metabolism. CaMKIIδ is expressed ubiquitously and might therefore affect several different organ systems. We crossed diabetic leptin receptor mutant mice to mice lacking CaMKIIδ globally. Remarkably, CaMKIIδ-deficient diabetic mice did not develop hyperglycemia. As potential underlying mechanisms, we provide evidence for improved insulin sensing with increased glucose transport into skeletal muscle but also reduced hepatic glucose production. Despite normoglycemia, CaMKIIδ-deficient diabetic mice developed the full picture of diabetic nephropathy but diabetic retinopathy was prevented. We also unmasked a retina-specific gene expression signature that might contribute to CaMKII-dependent retinal diabetic complications. These data challenge the clinical concept of normalizing hyperglycemia in diabetes as a causative treatment strategy for late diabetic complications and call for a more detailed analysis of intracellular metabolic signals in different diabetic organs. AU - Chen, J.* AU - Fleming, T.* AU - Katz, S.* AU - Dewenter, M.* AU - Hofmann, K.* AU - Saadatmand, A.* AU - Kronlage, M.* AU - Werner, M.P.* AU - Pokrandt, B.* AU - Schreiter, F.* AU - Lin, J.* AU - Katz, D.* AU - Morgenstern, J.* AU - Elwakiel, A.* AU - Sinn, P.* AU - Gröne, H.J.* AU - Hammes, H.P.* AU - Nawroth, P.P. AU - Isermann, B.* AU - Sticht, C.* AU - Brügger, B.* AU - Katus, H.A.* AU - Hagenmueller, M.* AU - Backs, J.* C1 - 60637 C2 - 49512 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 616-626 TI - CaM kinase II-δ is required for diabetic hyperglycemia and retinopathy but not nephropathy. JO - Diabetes VL - 70 IS - 2 PB - Amer Diabetes Assoc PY - 2021 SN - 0012-1797 ER - TY - JOUR AB - Targeting of the Glucose-dependent Insulinotropic Polypeptide receptor GIPR is an emerging strategy in anti-diabetic drug development. The aim of this study was to develop a Positron Emission Tomography (PET) radioligand for the GIPR, to enable the assessment of target distribution and drug target engagement in vivo.The GIPR selective peptide S02-GIP was radiolabeled with Gallium-68. The resulting PET tracer [68Ga]S02-GIP-T4 was evaluated for affinity and specificity to human GIPR (huGIPR). The in vivo GIPR binding of [68Ga]S02-GIP-T4, as well as the occupancy of a drug candidate with GIPR activity, was assessed in non-human primates (NHP) by PET.[68Ga]S02-GIP-T4 bound with nanomolar affinity and high selectivity to huGIPR in overexpressing cells. In vivo pancreatic binding in NHP could be dose dependently inhibited by co-injection of unlabelled S02-GIP-T4. Finally, subcutaneous pre-treatment with a high dose of a drug candidate with GIPR activity led to a decreased pancreatic binding of [68Ga]S02-GIP-T4, corresponding to a GIPR drug occupancy of almost 90%. [68Ga]S02-GIP-T4 demonstrated a safe dosimetric profile, allowing for repeated studies in humans. In conclusion, [68Ga]S02-GIP-T4 is a novel PET biomarker for safe, non-invasive, and quantitative assessment of GIPR target distribution and drug occupancy. AU - Eriksson, O.* AU - Velikyan, I.* AU - Haack, T.* AU - Bossart, M.* AU - Evers, A.* AU - Lorenz, K.* AU - Laitinen, I.* AU - Larsen, P.J.* AU - Plettenburg, O. AU - Johansson, L.* AU - Pierrou, S.* AU - Wagner, M.* C1 - 61342 C2 - 50171 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 842-853 TI - Drug occupancy assessment at the glucose-dependent insulinotropic polypeptide (GIP) receptor by positron emission tomography. JO - Diabetes VL - 70 IS - 4 PB - Amer Diabetes Assoc PY - 2021 SN - 0012-1797 ER - TY - JOUR AB - Lifestyle intervention (LI) can prevent type 2 diabetes, but response to LI varies depending on risk subphenotypes. We tested if prediabetic individuals with low risk benefit from conventional LI and individuals with high risk benefit from an intensification of LI in a multi-center randomized controlled intervention over 12 months with 2 years follow up. 1105 prediabetic individuals based on ADA glucose criteria were stratified into a high- and low-risk phenotype, based on previously described thresholds of insulin secretion, insulin sensitivity and liver fat content. Low-risk individuals were randomly assigned to conventional LI according to the DPP protocol or control (1:1), high-risk individuals to conventional or intensified LI with doubling of required exercise (1:1). A total of 908 (82%) participants completed the study. In high-risk individuals, the difference between conventional and intensified LI in post-challenge glucose change was -0.29 mmol/l [CI:-0.54;-0.04], p=0.025. Liver fat (-1.34 percentage points [CI:-2.17;-0.50], p=0.002) and cardiovascular risk (-1.82[CI:-3.13-0.50],p=0.007) underwent larger reductions with intensified than with conventional LI. During a follow up of 3 years, intensified compared to conventional LI had a higher probability to normalize glucose tolerance (p=0.008). In conclusion, it is possible in high-risk individuals with prediabetes to improve glycemic and cardiometabolic outcomes by intensification of LI. Individualized, risk-phenotype-based LI may be beneficial for the prevention of diabetes. AU - Fritsche, A. AU - Wagner, R. AU - Heni, M. AU - Kantartzis, K. AU - Machann, J. AU - Schick, F.* AU - Lehmann, R. AU - Peter, A. AU - Dannecker, C. AU - Fritsche, L. AU - Valenta, V. AU - Nawroth, P.P. AU - Kopf, S.* AU - Pfeiffer, A.F.* AU - Kabisch, S.* AU - Dambeck, U.* AU - Stumvoll, M.* AU - Blüher, M.* AU - Birkenfeld, A.L.* AU - Schwarz, P.* AU - Hauner, H.* AU - Clavel, J.* AU - Seißler, J.* AU - Lechner, A.* AU - Müssig, K.* AU - Weber, K.* AU - Laxy, M. AU - Bornstein, S.* AU - Schürmann, A.* AU - Roden, M.* AU - Hrabě de Angelis, M. AU - Stefan, N. AU - Häring, H.-U. C1 - 63045 C2 - 51125 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 2785-2795 TI - Different effects of lifestyle intervention in high- and low-risk prediabetes. JO - Diabetes VL - 70 IS - 12 PB - Amer Diabetes Assoc PY - 2021 SN - 0012-1797 ER - TY - JOUR AB - A novel clustering approach identified five subgroups of diabetes with distinct progression trajectories of complications. We hypothesized that these subgroups differ in multiple biomarkers of inflammation. Serum levels of 74 biomarkers of inflammation were measured in 414 individuals with recent adult-onset diabetes from the German Diabetes Study (GDS) allocated to five subgroups based on data-driven analysis. Pairwise differences between subgroups for biomarkers were assessed with generalized linear mixed models before (model 1) and after adjustment (model 2) for the clustering variables. Participants were assigned to five subgroups: severe autoimmune diabetes (SAID, 21%), severe insulin-deficient diabetes (SIDD, 3%), severe insulin-resistant diabetes (SIRD, 9%), mild obesity-related diabetes (MOD, 32%) and mild age-related diabetes (MARD, 35%). In model 1, 23 biomarkers showed ≥1 pairwise difference between subgroups (Bonferroni-corrected p<0.0007). Biomarker levels were generally highest in SIRD and lowest in SIDD. All 23 biomarkers correlated with ≥1 of the clustering variables. In model 2, three biomarkers (CASP-8, EN-RAGE, IL-6) showed at least one pairwise difference between subgroups (e.g. lower CASP8, EN-RAGE and IL-6 in SIDD vs. all other subgroups, all p<0.0007). Thus, novel diabetes subgroups show multiple differences in biomarkers of inflammation, underlining a prominent role of inflammatory pathways in particular in SIRD. AU - Herder, C.* AU - Maalmi, H.* AU - Strassburger, K.* AU - Zaharia, O.P.* AU - Ratter, J.M.* AU - Karusheva, Y.* AU - Elhadad, M.A. AU - Bódis, K.* AU - Bongaerts, B.W.C.* AU - Rathmann, W.* AU - Trenkamp, S.* AU - Waldenberger, M. AU - Burkart, V.* AU - Szendroedi, J.* AU - Roden, M.* C1 - 61494 C2 - 50316 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 1198-1208 TI - Differences in biomarkers of inflammation between novel subgroups of recent-onset diabetes. JO - Diabetes VL - 70 IS - 5 PB - Amer Diabetes Assoc PY - 2021 SN - 0012-1797 ER - TY - JOUR AB - Children's plasma metabolome, especially lipidome reflects gene regulation and dietary exposures, heralding the development of islet autoantibodies (IA) and type 1 diabetes (T1D). The TEDDY study enrolled 8676 newborns by screening HLA-DR-DQ genotypes at six clinical centers in four countries; profiled metabolome and measured concentrations of ascorbic acid, 25-hydroxyvitamin D (25(OH)D), erythrocyte membrane fatty acids following birth until IA seroconversion under nested case-control design. We grouped children having an initial autoantibody only against insulin (IAA-first) or glutamic acid decarboxylase (GADA-first) by unsupervised clustering of temporal lipidome, identifying a subgroup of children having early onset of each initial autoantibody, i.e., IAA-first by 12 months and GADA-first by 21 months, consistent with population-wide early seroconversion age. Differential analysis showed that infants having reduced plasma ascorbic acid and cholesterol experienced IAA-first earlier, while early onset of GADA-first was preceded by reduced sphingomyelins at infancy. Plasma 25(OH)D prior to either autoantibody was lower in T1D progressors compared to non-progressors, with simultaneous lower diglycerides, lysophosphatidylcholines, triglycerides, alanine before GADA-first. Plasma ascorbic acid and 25(OH)D at infancy were lower in HLA-DR3/DR4 children among IA cases but not in matched controls, implying gene expression dysregulation of circulating vitamins as latent signals for IA or T1D progression. AU - Li, Q.* AU - Liu, X.* AU - Yang, J.* AU - Erlund, I.* AU - Lernmark, A.* AU - Hagopian, W.* AU - Rewers, M.* AU - She, J.X.* AU - Toppari, J.* AU - Ziegler, A.-G. AU - Akolkar, B.* AU - Krischer, J.P.* C1 - 60657 C2 - 49566 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 282-292 TI - Plasma metabolome and circulating vitamins stratified onset age of an initial islet autoantibody and progression to type 1 diabetes: The TEDDY Study. JO - Diabetes VL - 70 IS - 1 PB - Amer Diabetes Assoc PY - 2021 SN - 0012-1797 ER - TY - JOUR AB - Medium-chain fatty acids (MCFAs) have in rodents been shown to have protective effects on glucose homeostasis during high-fat overfeeding. In this study, we investigated whether dietary MCFAs protect against insulin resistance induced by a hypercaloric high-fat diet in humans. Healthy, lean men ingested a eucaloric control diet and a three-day hypercaloric high-fat diet (+75% energy, 81-83E% fat) in randomized order. For one group (n=8), the high-fat diet was enriched with saturated long-chain FAs (LCSFA-HFD), while the other group (n=9) ingested a matched diet, but with ∼30 g (5E%) saturated MCFAs (MCSFA-HFD) in substitution for a corresponding fraction of the saturated LCFAs. A hyperinsulinemic-euglycemic clamp with femoral arteriovenous balance and glucose tracer was applied after the control and hypercaloric diets. In LCSFA-HFD, whole body insulin sensitivity and peripheral insulin-stimulated glucose disposal were reduced. These impairments were prevented in MCSFA-HFD, accompanied by increased basal FA oxidation, maintained glucose metabolic flexibility, increased non-oxidative glucose disposal related to lower starting glycogen content and increased glycogen synthase activity, together with increased muscle lactate production. In conclusion, substitution of a small amount of dietary LCFAs with MCFAs rescues insulin action in conditions of lipid-induced energy excess. AU - Lundsgaard, A.M.* AU - Fritzen, A.M.* AU - Sjøberg, K.A.* AU - Kleinert, M. AU - Richter, E.A.* AU - Kiens, B.* C1 - 60655 C2 - 49563 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 91-98 TI - Small amounts of dietary medium-chain fatty acids protect against insulin resistance during caloric excess in humans. JO - Diabetes VL - 70 IS - 1 PB - Amer Diabetes Assoc PY - 2021 SN - 0012-1797 ER - TY - JOUR AB - Analysis of data from clinical cohorts, and more recently from human pancreatic tissue, indicates that reduced prohormone processing is an early and persistent finding in type 1 diabetes. In this article, we review the current state of knowledge regarding alterations in islet prohormone expression and processing in type 1 diabetes and consider the clinical impact of these findings. Lingering questions, including pathologic etiologies and consequences of altered prohormone expression and secretion in type 1 diabetes, and the natural history of circulating prohormone production in health and disease, are considered. Finally, key next steps required to move forward in this area are outlined, including longitudinal testing of relevant clinical populations, studies that probe the genetics of altered prohormone processing, the need for combined functional and histologic testing of human pancreatic tissues, continued interrogation of the intersection between prohormone processing and autoimmunity, and optimal approaches for analysis. Successful resolution of these questions may offer the potential to use altered prohormone processing as a biomarker to inform therapeutic strategies aimed at personalized intervention during the natural history of type 1 diabetes and as a pathogenic anchor for identification of potential disease-specific endotypes. AU - Rodriguez-Calvo, T. AU - Chen, Y.C.* AU - Verchere, C.B.* AU - Haataja, L.* AU - Arvan, P.* AU - Leete, P.* AU - Richardson, S.J.* AU - Morgan, N.G.* AU - Qian, W.J.* AU - Pugliese, A.* AU - Atkinson, M.* AU - Evans-Molina, C.* AU - Sims, E.K.* C1 - 61944 C2 - 50524 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 1038-1050 TI - Altered β-cell prohormone processing and secretion in type 1 diabetes. JO - Diabetes VL - 70 IS - 5 PB - Amer Diabetes Assoc PY - 2021 SN - 0012-1797 ER - TY - JOUR AB - In type 1 diabetes, a lifelong autoimmune disease, T cells infiltrate the islets and the exocrine pancreas in high numbers. CD8+ T cells are the main cell type found in the insulitic lesion, and CD8+ T cells reactive against beta cell antigens have been detected in the periphery and in the pancreas of subjects with short and long disease duration. The Diabetes Virus Detection (DiViD) study collected pancreatic tissue, by pancreatic tail resection, from living patients with recent-onset type 1 diabetes. These tissues have been extensively studied by the scientific community, but the autoreactive nature of the T cell infiltrate has remained unexplored. Our objective was to determine the number and localization of these cells in pancreas samples obtained through the DiViD study. Here, we demonstrate the presence of high frequencies of CD8+ T cells reactive against a highly relevant epitope derived from the preproinsulin signal peptide in pancreatic tissue samples from these donors. We additionally show the heterogeneity of islet distribution and CD8+ T cell infiltration. Our findings contribute to the current limited existing knowledge on T cell reactivity in the pancreas of recent onset type 1 diabetic donors, and indicate that antigen-specific therapies directed towards preproinsulin could have high clinical impact. AU - Rodriguez-Calvo, T. AU - Krogvold, L.* AU - Amirian, N.* AU - Dahl-Jørgensen, K.* AU - von Herrath, M.* C1 - 60945 C2 - 49998 SP - 752-758 TI - One in ten CD8+ cells in the pancreas of living individuals with recent onset type 1 diabetes recognizes the preproinsulin epitope PPI15-24. JO - Diabetes VL - 70 IS - 3 PY - 2021 SN - 0012-1797 ER - TY - JOUR AB - Differences in glucose metabolism among categories of prediabetes have not been systematically investigated. In this longitudinal study, participants (N=2111) underwent 2h-75g OGTT at baseline and 48 months. HbA1c was also measured. We classified participants as having isolated prediabetes defect (impaired fasting glucose, IFG; impaired glucose tolerance, IGT; HbA1c-prediabetes, IA1c), two defects (IFG+IGT, IFG+IA1c, IGT+IA1c), or all defects (IFG+IGT+IA1c). Beta-cell function (BCF) and insulin sensitivity (IS) were assessed from OGTT. At baseline, when pooling participants with isolated defects, they showed impairment in both BCF and IS compared to healthy controls. Pooled groups with two or three defects showed progressive further deterioration. Among groups with isolated defect, IGT showed lower IS, insulin secretion at reference glucose (ISRr), and insulin secretion potentiation (p<0.002). Conversely, IA1c showed higher IS and ISRr (p<0.0001). Among groups with two defects, we similarly found differences in both BCF and IS. At 48 months, we found higher type 2 diabetes incidence for progressively increasing number of prediabetes defects (odds ratio >2, p<0.008). In conclusion, the prediabetes groups showed differences in type/degree of glucometabolic impairment. Compared to the pooled group with isolated defects, those with double or triple defect showed progressive differences in diabetes incidence. AU - Tura, A.* AU - Grespan, E.* AU - Göbl, C.S.* AU - Koivula, R.W.* AU - Franks, P.W.* AU - Pearson, E.R.* AU - Walker, M.* AU - Forgie, I.M.* AU - Giordano, G.N.* AU - Pavo, I.* AU - Ruetten, H.* AU - Dermitzakis, E.T.* AU - McCarthy, M.I.* AU - Pedersen, O.* AU - Schwenk, J.M.* AU - Adamski, J. AU - De Masi, F.* AU - Tsirigos, K.D.* AU - Brunak, S.* AU - Viñuela, A.* AU - Mahajan, A.* AU - McDonald, T.J.* AU - Kokkola, T.* AU - Vangipurapu, J.* AU - Cederberg, H.* AU - Laakso, M.* AU - Rutters, F.* AU - Elders, P.J.M.* AU - Koopman, A.D.M.* AU - Beulens, J.W.* AU - Ridderstråle, M.* AU - Hansen, T.H.* AU - Allin, K.H.* AU - Hansen, T.* AU - Vestergaard, H.* AU - Mari, A.* AU - IMI DIRECT Consortium (Grallert, H. AU - Sharma, S. AU - Thorand, B.) C1 - 62528 C2 - 50932 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 2092-2106 TI - Profiles of glucose metabolism in different prediabetes phenotypes, classified by fasting glycemia, 2-hour OGTT, glycated hemoglobin, and 1-hour OGTT: An IMI DIRECT study. JO - Diabetes VL - 70 IS - 9 PB - Amer Diabetes Assoc PY - 2021 SN - 0012-1797 ER - TY - JOUR AB - Glucagon-like peptide 1 receptor (GLP-1R) imaging with radiolabeled exendin has proven to be a powerful tool to quantify beta-cell mass (BCM) in vivo. As GLP-1R expression is thought to be influenced by glycemic control, we examined the effect of blood glucose (BG) levels on GLP-1R-mediated exendin uptake in both murine and human islets and its implications for BCM quantification. Periods of hyperglycemia significantly reduced exendin uptake in murine and human islets, which was paralleled by a reduction in GLP-1R expression. Detailed mapping of the tracer uptake and insulin and GLP-1R expression conclusively demonstrated that the observed reduction in tracer uptake directly correlates to GLP-1R expression levels. Importantly, the linear correlation between tracer uptake and beta-cell area was maintained in spite of the reduced GLP-1R expression levels. Subsequent normalization of BG levels restored absolute tracer uptake and GLP-1R expression in beta-cells and the observed loss in islet volume was halted. This manuscript emphasizes the potency of nuclear imaging techniques to monitor receptor regulation noninvasively. Our findings have significant implications for clinical practice, indicating that BG levels should be near-normalized for at least 3 weeks prior to GLP-1R agonist treatment or quantitative radiolabeled exendin imaging for BCM analysis. AU - Buitinga, M.* AU - Cohrs, C.M. AU - Eter, W.A.* AU - Claessens-Joosten, L.* AU - Frielink, C.* AU - Bos, D.* AU - Sandker, G.* AU - Brom, M.* AU - Speier, S. AU - Gotthardt, M.* C1 - 59969 C2 - 49149 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 2246-2252 TI - Non-invasive monitoring of glycemia-induced regulation of GLP-1R expression in murine and human islets of Langerhans. JO - Diabetes VL - 69 IS - 11 PB - Amer Diabetes Assoc PY - 2020 SN - 0012-1797 ER - TY - JOUR AB - With an estimated prevalence of 463 million affected, type 2 diabetes represents a major challenge to health care systems worldwide. Analyzing the plasma proteomes of individuals with type 2 diabetes may illuminate hitherto unknown functional mechanisms underlying disease pathology. We assessed the associations between type 2 diabetes and >1,000 plasma proteins in the Cooperative Health Research in the Region of Augsburg (KORA) F4 cohort (n = 993, 110 cases), with subsequent replication in the third wave of the Nord-Trøndelag Health Study (HUNT3) cohort (n = 940, 149 cases). We computed logistic regression models adjusted for age, sex, BMI, smoking status, and hypertension. Addition-ally, we investigated associations with incident type 2 diabetes and performed two-sample bidirectional Mendelian randomization (MR) analysis to prioritize our results. Association analysis of prevalent type 2 diabetes revealed 24 replicated proteins, of which 8 are novel. Proteins showing association with incident type 2 diabetes were aminoacylase-1, growth hormone receptor, and insulin-like growth factor–binding protein 2. Aminoacylase-1 was associated with both prevalent and incident type 2 diabetes. MR analysis yielded nominally significant causal effects of type 2 diabetes on cathepsin Z and rennin, both known to have roles in the pathophysiological pathways of cardiovascular disease, and of sex hormone–binding globulin on type 2 diabetes. In conclusion, our high-throughput pro-teomics study replicated previously reported type 2 diabetes–protein associations and identified new candidate proteins possibly involved in the pathogenesis of type 2 diabetes. AU - Elhadad, M.A. AU - Jonasson, C.* AU - Huth, C. AU - Wilson, R. AU - Gieger, C. AU - Matias-Garcia, P.R. AU - Grallert, H. AU - Graumann, J.* AU - Gailus-Durner, V. AU - Rathmann, W.* AU - von Toerne, C. AU - Hauck, S.M. AU - Koenig, W.* AU - Sinner, M.F.* AU - Oprea, T.I.* AU - Suhre, K.* AU - Thorand, B. AU - Hveem, K.* AU - Peters, A. AU - Waldenberger, M. C1 - 60285 C2 - 49094 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 2766-2778 TI - Deciphering the plasma proteome of type 2 diabetes. JO - Diabetes VL - 69 IS - 12 PB - Amer Diabetes Assoc PY - 2020 SN - 0012-1797 ER - TY - JOUR AB - Early and precise identification of individuals with pre-diabetes and type 2 diabetes (T2D) at risk for progressing to chronic kidney disease (CKD) is essential to prevent complications of diabetes. Here, we identify and evaluate prospective metabolite biomarkers and the best set of predictors of CKD in the longitudinal, population-based Cooperative Health Research in the Region of Augsburg (KORA) cohort by targeted metabolomics and machine learning approaches. Out of 125 targeted metabolites, sphingomyelin C18:1 and phosphatidylcholine diacyl C38:0 were identified as candidate metabolite biomarkers of incident CKD specifically in hyperglycemic individuals followed during 6.5 years. Sets of predictors for incident CKD developed from 125 metabolites and 14 clinical variables showed highly stable performances in all three machine learning approaches and outperformed the currently established clinical algorithm for CKD. The two metabolites in combination with five clinical variables were identified as the best set of predictors, and their predictive performance yielded a mean area value under the receiver operating characteristic curve of 0.857. The inclusion of metabolite variables in the clinical prediction of future CKD may thus improve the risk prediction in people with prediabetes and T2D. The metabolite link with hyperglycemia-related early kidney dysfunction warrants further investigation. AU - Huang, J. AU - Huth, C. AU - Covic, M. AU - Troll, M. AU - Adam, J. AU - Zukunft, S. AU - Prehn, C. AU - Wang, L. AU - Nano, J. AU - Scheerer, M.F. AU - Neschen, S. AU - Kastenmüller, G. AU - Suhre, K.* AU - Laxy, M. AU - Schliess, F.* AU - Gieger, C. AU - Adamski, J. AU - Hrabě de Angelis, M. AU - Peters, A. AU - Wang-Sattler, R. C1 - 60284 C2 - 49099 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 2756-2765 TI - Machine learning approaches reveal metabolic signatures of incident chronic kidney disease in individuals with prediabetes and type 2 diabetes. JO - Diabetes VL - 69 IS - 12 PB - Amer Diabetes Assoc PY - 2020 SN - 0012-1797 ER - TY - JOUR AB - Clinical studies have suggested that changes in peripheral nerve microcirculation may contribute to nerve damage in diabetic polyneuropathy (DN). High-sensitivity troponin T (hsTNT) assays have been recently shown to provide predictive values for both cardiac and peripheral microangiopathy in type 2 diabetes (T2D). This study investigated the association of sciatic nerve structural damage in 3 Tesla (3T) magnetic resonance neurography (MRN) with hsTNT and N-terminal pro-brain natriuretic peptide serum levels in patients with T2D. MRN at 3T was performed in 51 patients with T2D (23 without DN, 28 with DN) and 10 control subjects without diabetes. The sciatic nerve's fractional anisotropy (FA), a marker of structural nerve integrity, was correlated with clinical, electrophysiological, and serological data. In patients with T2D, hsTNT showed a negative correlation with the sciatic nerve's FA (r = -0.52, P < 0.001), with a closer correlation in DN patients (r = -0.66, P < 0.001). hsTNT further correlated positively with the neuropathy disability score (r = 0.39, P = 0.005). Negative correlations were found with sural nerve conduction velocities (NCVs) (r = -0.65, P < 0.001) and tibial NCVs (r = -0.44, P = 0.002) and amplitudes (r = -0.53, P < 0.001). This study is the first to show that hsTNT is a potential indicator for structural nerve damage in T2D. Our results indirectly support the hypothesis that microangiopathy contributes to structural nerve damage in T2D. AU - Jende, J.M.E.* AU - Groener, J.B.* AU - Kender, Z.* AU - Hahn, A.* AU - Morgenstern, J.* AU - Heiland, S.* AU - Nawroth, P.P. AU - Bendszus, M.* AU - Kopf, S.* AU - Kurz, F.T.* C1 - 58649 C2 - 48205 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 713-723 TI - Troponin T parallels structural nerve damage in type 2 diabetes: A cross-sectional study using magnetic resonance neurography. JO - Diabetes VL - 69 IS - 4 PB - Amer Diabetes Assoc PY - 2020 SN - 0012-1797 ER - TY - JOUR AU - Kleinert, M. AU - Müller, T.D. C1 - 59719 C2 - 49021 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 1605-1607 TI - A new FGF21 analog for the treatment of fatty liver disease. JO - Diabetes VL - 69 IS - 8 PB - Amer Diabetes Assoc PY - 2020 SN - 0012-1797 ER - TY - JOUR AB - Autoimmunity against pancreatic beta -cell autoantigens is a characteristic of childhood type 1 diabetes (T1D). Autoimmunity usually appears in genetically susceptible children with the development of autoantibodies against (pro)insulin in early childhood. The offspring of mothers with T1D are protected from this process. The aim of this study was to determine whether the protection conferred by maternal T1D is associated with improved neonatal tolerance against (pro)insulin. Consistent with improved neonatal tolerance, the offspring of mothers with T1D had reduced cord blood CD4(+) T-cell responses to proinsulin and insulin, a reduction in the inflammatory profile of their proinsulin-responsive CD4(+) T cells, and improved regulation of CD4(+) T cell responses to proinsulin at 9 months of age, as compared with offspring with a father or sibling with T1D. Maternal T1D was also associated with a modest reduction in CpG methylation of the INS gene in cord blood mononuclear cells from offspring with a susceptible INS genotype. Our findings support the concept that a maternal T1D environment improves neonatal immune tolerance against the autoantigen (pro)insulin. AU - Knoop, J. AU - Eugster, A.* AU - Gavrisan, A. AU - Lickert, R. AU - Sedlmeier, E.-M. AU - Dietz, S.* AU - Lindner, A. AU - Warncke, K.* AU - Hummel, N. AU - Ziegler, A.-G. AU - Bonifacio, E. C1 - 57758 C2 - 48111 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 661-669 TI - Maternal type 1 diabetes reduces autoantigen-responsive CD4(+) T cells in Offspring. JO - Diabetes VL - 69 IS - 3 PB - Amer Diabetes Assoc PY - 2020 SN - 0012-1797 ER - TY - JOUR AB - Children at increased genetic risk for type 1 diabetes (T1D) after environmental exposures may develop pancreatic islet autoantibodies (IA) at a very young age. Metabolic profile changes over time may imply responses to exposures and signal development of the first IA. Our present research in The Environmental Determinants of Diabetes in the Young (TEDDY) study aimed to identify metabolome-wide signals preceding the first IA against GAD (GADA-first) or against insulin (IAA-first). We profiled metabolomes by mass spectrometry from children's plasma at 3-month intervals after birth until appearance of the first IA. A trajectory analysis discovered each first IA preceded by reduced amino acid proline and branched-chain amino acids (BCAAs), respectively. With independent time point analysis following birth, we discovered dehydroascorbic acid (DHAA) contributing to the risk of each first IA, and γ-aminobutyric acid (GABAs) associated with the first autoantibody against insulin (IAA-first). Methionine and alanine, compounds produced in BCAA metabolism and fatty acids, also preceded IA at different time points. Unsaturated triglycerides and phosphatidylethanolamines decreased in abundance before appearance of either autoantibody. Our findings suggest that IAA-first and GADA-first are heralded by different patterns of DHAA, GABA, multiple amino acids, and fatty acids, which may be important to primary prevention of T1D. AU - Li, Q.* AU - Parikh, H.* AU - Butterworth, M.D.* AU - Lernmark, Å.* AU - Hagopian, W.* AU - Rewers, M.* AU - She, J.-X.* AU - Toppari, J.* AU - Ziegler, A.-G. AU - Akolkar, B.* AU - Fiehn, O.* AU - Fan, S.* AU - Krischer, J.P.* AU - Teddy Study Group* C1 - 58108 C2 - 48207 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 465-476 TI - Longitudinal metabolome-wide signals prior to the appearance of a first islet autoantibody in children participating in the TEDDY Study. JO - Diabetes VL - 69 IS - 3 PB - Amer Diabetes Assoc PY - 2020 SN - 0012-1797 ER - TY - JOUR AB - Genes of the Notch signaling pathway are expressed in different cell types and organs at different time points during embryonic development and adulthood. The Notch ligand Delta-like 1 (DLL1) controls the decision between endocrine and exocrine fates of multipotent progenitors in the developing pancreas, and loss of Dll1 leads to premature endocrine differentiation. However, the role of Delta-Notch signaling in adult tissue homeostasis is not well understood. Here, we describe the spatial expression pattern of Notch pathway components in adult murine pancreatic islets and show that DLL1 and DLL4 are specifically expressed in beta-cells, whereas JAGGED1 is expressed in alpha-cells. We show that mice lacking both DLL1 and DLL4 in adult beta-cells display improved glucose tolerance, increased glucose-stimulated insulin secretion, and hyperglucagonemia. In contrast, overexpression of the intracellular domain of DLL1 in adult murine pancreatic beta-cells results in impaired glucose tolerance and reduced insulin secretion, both in vitro and in vivo. These results suggest that Notch ligands play specific roles in the adult pancreas and highlight a novel function of the Delta/Notch pathway in beta-cell insulin secretion. AU - Rubey, M. AU - Chhabra, N.F. AU - Gradinger, D. AU - Sanz-Moreno, A. AU - Lickert, H. AU - Przemeck, G.K.H. AU - Hrabě de Angelis, M. C1 - 58109 C2 - 48198 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 915-926 TI - DLL1- and DLL4-mediated Notch signaling is essential for adult pancreatic islet homeostasis. JO - Diabetes VL - 69 IS - 5 PB - Amer Diabetes Assoc PY - 2020 SN - 0012-1797 ER - TY - JOUR AU - Rutter, G.A.* AU - Ninov, N. AU - Salem, V.* AU - Hodson, D.J.* C1 - 59934 C2 - 49958 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - E10-E11 TI - Comment on Satin et al. "Take Me To Your Leader": An electrophysiological appraisal of the role of Hhb cells in pancreatic islets. Diabetes 2020;69:830-836. JO - Diabetes VL - 69 IS - 9 PB - Amer Diabetes Assoc PY - 2020 SN - 0012-1797 ER - TY - JOUR AB - Leptin influences food intake by informing the brain about the status of body fat stores. Rare LEP mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by admin-istering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concen-trations. We identify five novel variants, including four missense variants, in LEP, ZNF800, KLHL31, and ACTL9, and one intergenic variant near KLF14. The missense variant Val94Met (rs17151919) in LEP was common in individuals of African ancestry only, and its association with lower leptin concentrations was specific to this ancestry (P = 2 × 10-16, n = 3,901). Using in vitro analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting that leptin regulates early adiposity. AU - Yaghootkar, H.* AU - Zhang, Y.* AU - Spracklen, C.N.* AU - Karaderi, T.* AU - Huang, L.O.* AU - Bradfield, J.P.* AU - Schurmann, C.* AU - Fine, R.S.* AU - Preuss, M.H.* AU - Kutalik, Z.* AU - Wittemans, L.B.L.* AU - Lu, Y.* AU - Metz, S.* AU - Willems, S.M.* AU - Li-Gao, R.* AU - Grarup, N.* AU - Wang, S.* AU - Molnos, S. AU - Sandoval-Zárate, A.A.* AU - Nalls, M.A.* AU - Lange, L.A.* AU - Haesser, J.* AU - Guo, X.* AU - Lyytikäinen, L.P.* AU - Feitosa, M.F.* AU - Sitlani, C.M.* AU - Venturini, C.* AU - Mahajan, A.* AU - Kacprowski, T.* AU - Wang, C.A.* AU - Chasman, D.I.* AU - Amin, N.* AU - Broer, L.* AU - Robertson, N.* AU - Young, K.L.* AU - Allison, M.* AU - Auer, P.L.* AU - Blüher, M.* AU - Borja, J.B.* AU - Bork-Jensen, J.* AU - Carrasquilla, G.D.* AU - Christofidou, P.* AU - Demirkan, A.* AU - Doege, C.A.* AU - Garcia, M.E.* AU - Graff, M.* AU - Guo, K.* AU - Hakonarson, H.* AU - Hong, J.* AU - Chen, Y.D.I.* AU - Jackson, R.* AU - Jakupović, H.* AU - Jousilahti, P.* AU - Justice, A.E.* AU - Kähönen, M.* AU - Kizer, J.R.* AU - Kriebel, J. AU - LeDuc, C.A.* AU - Li, J.* AU - Lind, L.* AU - Luan, J.* AU - Mackey, D.A.* AU - Mangino, M.* AU - Männistö, S.* AU - Carli, J.F.M.* AU - Medina-Gomez, C.* AU - Mook-Kanamori, D.O.* AU - Morris, A.P.* AU - de Mutsert, R.* AU - Nauck, M.* AU - Prokic, I.* AU - Pennell, C.E.* AU - Pradhan, A.D.* AU - Psaty, B.M.* AU - Raitakari, O.T.* AU - Scott, R.A.* AU - Skaaby, T.* AU - Strauch, K. AU - Taylor, K.D.* AU - Teumer, A.* AU - Uitterlinden, A.G.* AU - Wu, Y.* AU - Yao, J.* AU - Walker, M.* AU - North, K.E.* AU - Kovacs, P.* AU - Ikram, M.A.* AU - van Duijn, C.M.* AU - Ridker, P.M.* AU - Lye, S.J.* AU - Homuth, G.* AU - Ingelsson, E.* AU - Spector, T.D.* AU - McKnight, B.* AU - Province, M.A.* AU - Lehtimäki, T.* AU - Adair, L.S.* AU - Rotter, J.I.* AU - Reiner, A.P.* AU - Wilson, J.G.* AU - Harris, T.B.* AU - Ripatti, S* AU - Grallert, H. AU - Meigs, J.B* AU - Salomaa, V.* AU - Hansen, T.* AU - van Dijk, K.W.* AU - Wareham, N.J.* AU - Grant, S.F.A.* AU - Langenberg, C.* AU - Frayling, T.M.* AU - Lindgren, C.M.* AU - Mohlke, K.L.* AU - Leibel, R.L.* AU - Loos, R.J.F.* AU - Kilpeläinen, T.O.* C1 - 60615 C2 - 49523 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 2806-2818 TI - Genetic studies of leptin concentrations implicate leptin in the regulation of early adiposity. JO - Diabetes VL - 69 IS - 12 PB - Amer Diabetes Assoc PY - 2020 SN - 0012-1797 ER - TY - JOUR AB - The ADAMTS9 rs4607103 C allele is one of the few gene variants proposed to increase the risk of type 2 diabetes through an impairment of insulin sensitivity. We show that the variant is associated with increased expression of the secreted ADAMTS9 and decreased insulin sensitivity and signaling in human skeletal muscle. In line with this, mice lacking Adamts9 selectively in skeletal muscle have improved insulin sensitivity. The molecular link between ADAMTS9 and insulin signaling was characterized further in a model where ADAMTS9 was overexpressed in skeletal muscle. This selective over expression resulted in decreased insulin signaling presumably mediated through alterations of the integrin 131 signaling pathway and disruption of the intracellular cytoskeletal organization. Furthermore, this led to impaired mitochondria! function in mouse muscle-an observation found to be of translational character because humans carrying the ADAMTS9 risk allele have decreased expression of mitochondrial markers. Finally, we found that the link between ADAMTS9 overexpression and impaired insulin signaling could be due to accumulation of harmful lipid intermediates. Our findings contribute to the understanding of the molecular mechanisms underlying insulin resistance and type 2 diabetes and point to inhibition of ADAMTS9 as a potential novel mode of treating insulin resistance. AU - Graae, A.S.* AU - Grarup, N.* AU - Ribel-Madsen, R.* AU - Lystbæk, S.H.* AU - Boesgaard, T.W.* AU - Staiger, H. AU - Fritsche, A. AU - Wellner, N.* AU - Sulek, K.* AU - Kjolby, M.* AU - Backe, M.B.* AU - Chubanava, S.* AU - Prats, C.* AU - Serup, A.K.* AU - Birk, J.B.* AU - Dubail, J.* AU - Gillberg, L.* AU - Vienberg, S.G.* AU - Nykjær, A.* AU - Kiens, B.* AU - Wojtaszewski, J.F.P.* AU - Larsen, S.* AU - Apte, S.S.* AU - Häring, H.-U. AU - Vaag, A.* AU - Zethelius, B.* AU - Pedersen, O.* AU - Treebak, J.T.* AU - Hansen, T.* AU - Holst, B.* C1 - 55586 C2 - 46375 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 502-514 TI - ADAMTS9 regulates skeletal muscle insulin sensitivity through extracellular matrix alterations. JO - Diabetes VL - 68 IS - 3 PB - Amer Diabetes Assoc PY - 2019 SN - 0012-1797 ER - TY - JOUR AB - Studies on magnetic resonance neurography (MRN) in diabetic polyneuropathy (DPN) have found proximal sciatic nerve lesions. The aim of this study was to evaluate the functional relevance of sciatic nerve lesions in DPN, expecting correlations with the impairment of large fiber function. 61 patients with diabetes mellitus type 2 (48 with, 13 without DPN) and 12 controls were enrolled, undergoing MRN, quantitative sensory testing, and electrophysiological examinations. There were differences in mechanical detection (Aβ fibers) and mechanical pain (Aδ fibers), but not in thermal pain and thermal detection clusters (C fibers) between the groups. Lesion load correlated with lower Aα, Aβ, and Aδ fiber, but not C fiber function in all participants. Patients with lower function showed a higher load of nerve lesions than patients with elevated function or no measurable deficit despite apparent DPN. Longer diabetes duration was associated with higher lesion load in patients with DPN, suggesting that nerve lesions in DPN may accumulate over time and become clinically relevant once a critical amount of nerve fascicles is affected. Moreover, MRN is an objective method for determining lower function mainly in medium and large fibers in DPN. AU - Groener, J.B.* AU - Jende, J.M.E.* AU - Kurz, F.T.* AU - Kender, Z.* AU - Treede, R.D.* AU - Schuh-Hofer, S.* AU - Nawroth, P.P. AU - Bendszus, M.* AU - Kopf, S.* C1 - 57630 C2 - 47942 SP - 436-447 TI - Understanding diabetic neuropathy: From subclinical nerve lesions to severe nerve fiber deficits. A cross-sectional study in patients with type 2 diabetes and healthy controls. JO - Diabetes VL - 69 IS - 3 PY - 2019 SN - 0012-1797 ER - TY - JOUR AB - Obesity is taking on worldwide epidemic proportions, yet effective pharmacological agents with long-term efficacy remain unavailable. Previously, we designed the iminosugar N-adamantine-methyloxypentyl-deoxynojirimycin (AMP-DNM), which potently improves glucose homeostasis by lowering excessive glycosphingolipids. Here we show that AMP-DNM promotes satiety and activates brown adipose tissue (BAT) in obese rodents. Moreover, we demonstrate that the mechanism mediating these favorable actions depends on oral, but not central, administration of AMP-DNM, which ultimately stimulates systemic glucagon-like peptide 1 (GLP1) secretion. We evidence an essential role of brain GLP1 receptors (GLP1r), as AMP-DNM fails to promote satiety and activate BAT in mice lacking the brain GLP1r as well as in mice treated intracerebroventricularly with GLP1r antagonist exendin-9. In conclusion, AMP-DNM markedly ameliorates metabolic abnormalities in obese rodents by restoring satiety and activating BAT through central GLP1r, while improving glucose homeostasis by mechanisms independent of central GLP1r. AU - Herrera Moro Chao, D.* AU - Wang, Y.* AU - Foppen, E.* AU - Ottenhoff, R.* AU - van Roomen, C.* AU - Parlevliet, E.T.* AU - van Eijk, M.J.T.* AU - Verhoek, M.* AU - Boot, R.* AU - Marques, A.R.* AU - Scheij, S.* AU - Mirzaian, M.* AU - Kooijman, S.* AU - Jansen, K.* AU - Wang, D.* AU - Mergen, C. AU - Seeley, R.J.* AU - Tschöp, M.H. AU - Overkleeft, H.* AU - Rensen, P.C.N.* AU - Kalsbeek, A.* AU - Aerts, J.M.F.G.* AU - Yi, C.X.* C1 - 57542 C2 - 47835 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 2223-2234 TI - The iminosugar AMP-DNM improves satiety and activates brown adipose tissue through GLP1. JO - Diabetes VL - 68 IS - 12 PB - Amer Diabetes Assoc PY - 2019 SN - 0012-1797 ER - TY - JOUR AB - The risk for autoimmunity and subsequently type 1 diabetes is 10-fold higher in children with a first-degree family history of type 1 diabetes (FDR children) than in children in the general population (GP children). We analyzed children with high-risk HLA genotypes (n = 4,573) in the longitudinal TEDDY birth cohort to determine how much of the divergent risk is attributable to genetic enrichment in affected families. Enrichment for susceptible genotypes of multiple type 1 diabetes-associated genes and a novel risk gene, BTNL2, was identified in FDR children compared with GP children. After correction for genetic enrichment, the risks in the FDR and GP children converged but were not identical for multiple islet autoantibodies (hazard ratio [HR] 2.26 [95% CI 1.6-3.02]) and for diabetes (HR 2.92 [95% CI 2.05-4.16]). Convergence varied depending upon the degree of genetic susceptibility. Risks were similar in the highest genetic susceptibility group for multiple islet autoantibodies (14.3% vs .12.7%) and diabetes (4.8% vs. 4.1%) and were up to 5.8-fold divergent for children in the lowest genetic susceptibility group, decreasing incrementally in GP children but not in FDR children. These findings suggest that additional factors enriched within affected families preferentially increase the risk of autoimmunity and type 1 diabetes in lower genetic susceptibility strata. AU - Hippich, M. AU - Beyerlein, A. AU - Hagopian, W.A.* AU - Krischer, J.P.* AU - Vehik, K.* AU - Knoop, J. AU - Winker, C. AU - Toppari, J.* AU - Lernmark, Å.* AU - Rewers, M.J.* AU - Steck, A.K.* AU - She, J.X.* AU - Akolkar, B.* AU - Robertson, C.C.* AU - Onengut-Gumuscu, S.* AU - Rich, S.S.* AU - Bonifacio, E.* AU - Ziegler, A.-G. AU - The Teddy Study Group* C1 - 55250 C2 - 46302 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 847-857 TI - Genetic contribution to the divergence in type 1 diabetes risk between children from the general population and children from affected families. JO - Diabetes VL - 68 IS - 3 PB - Amer Diabetes Assoc PY - 2019 SN - 0012-1797 ER - TY - JOUR AB - Recent genetic studies have identified alleles associated with opposite effects on adiposity and risk of type 2 diabetes. We aimed to identify more of these variants and test the hypothesis that such favorable adiposity alleles are associated with higher subcutaneous fat and lower ectopic fat. We combined MRI data with genome-wide association studies of body fat percentage (%) and metabolic traits. We report 14 alleles, including 7 newly characterized alleles, associated with higher adiposity but a favorable metabolic profile. Consistent with previous studies, individuals carrying more favorable adiposity alleles had higher body fat % and higher BMI but lower risk of type 2 diabetes, heart disease, and hypertension. These individuals also had higher subcutaneous fat but lower liver fat and a lower visceral-to- subcutaneous adipose tissue ratio. Individual alleles associated with higher body fat % but lower liver fat and lower risk of type 2 diabetes included those in PPARG, GRB14, and IRS1, whereas the allele in ANKRD55 was paradoxically associated with higher visceral fat but lower risk of type 2 diabetes. Most identified favorable adiposity alleles are associated with higher subcutaneous and lower liver fat, a mechanism consistent with the beneficial effects of storing excess triglycerides in metabolically low-risk depots. AU - Ji, Y.* AU - Yiorkas, A.M.* AU - Frau, F.* AU - Mook-Kanamori, D.O.* AU - Staiger, H. AU - Thomas, E.L.* AU - Atabaki-Pasdar, N.* AU - Campbell, A.* AU - Tyrrell, J.* AU - Jones, S.E.* AU - Beaumont, R.N.* AU - Wood, A.R.* AU - Tuke, M.A.* AU - Ruth, K.S.* AU - Mahajan, A.* AU - Murray, A.* AU - Freathy, R.M.* AU - Weedon, M.N.* AU - Hattersley, A.T.* AU - Hayward, C.* AU - Machann, J. AU - Häring, H.-U. AU - Franks, P.* AU - de Mutsert, R.* AU - Pearson, E.* AU - Stefan, N. AU - Frayling, T.M.* AU - Allebrandt, K.V.* AU - Bell, J.D.* AU - Blakemore, A.I.* AU - Yaghootkar, H.* C1 - 55061 C2 - 46030 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 207-219 TI - Genome-wide and abdominal MRI data provide evidence that a genetically determined favorable adiposity phenotype is characterized by lower ectopic liver fat and lower risk of type 2 diabetes, heart disease, and hypertension. JO - Diabetes VL - 68 IS - 1 PB - Amer Diabetes Assoc PY - 2019 SN - 0012-1797 ER - TY - JOUR AB - Nonalcoholic fatty liver disease (NAFLD) is a risk factor for type 2 diabetes (T2D). We aimed to identify the peripheral blood DNA methylation signature of hepatic fat. We conducted epigenome-wide association studies of hepatic fat in 3,400 European ancestry (EA) participants and in 401 Hispanic ancestry and 724 African ancestry participants from four population-based cohort studies. Hepatic fat was measured using computed tomography or ultrasound imaging and DNA methylation was assessed at >400,000 cytosine-guanine dinucleotides (CpGs) in whole blood or CD14+ monocytes using a commercial array. We identified 22 CpGs associated with hepatic fat in EA participants at a false discovery rate <0.05 (corresponding P = 6.9 x 10(-6)) with replication at Bonferroni-corrected P < 8.6 x 10(-4). Mendelian randomization analyses supported the association of hypomethylation of cg08309687 (LINC00649) with NAFLD (P = 2.5 x 10(-4)). Hypomethylation of the same CpG was also associated with risk for new-onset T2D (P = 0.005). Our study demonstrates that a peripheral blood-derived DNA methylation signature is robustly associated with hepatic fat accumulation. The hepatic fat-associated CpGs may represent attractive biomarkers for T2D. Future studies are warranted to explore mechanisms and to examine DNA methylation signatures of NAFLD across racial/ethnic groups. AU - Ma, J.* AU - Nano, J. AU - Ding, J.* AU - Zheng, Y.* AU - Hennein, R.* AU - Liu, C.* AU - Speliotes, E.K.* AU - Huan, T.* AU - Song, C.* AU - Mendelson, M.M.* AU - Joehanes, R.* AU - Long, M.T.* AU - Liang, L.* AU - Smith, J.A.* AU - Reynolds, L.M.* AU - Ghanbari, M.* AU - Muka, T.* AU - van Meurs, J.B.J.* AU - Alferink, L.J.M.* AU - Franco, O.H.* AU - Dehghan, A.* AU - Ratliff, S.* AU - Zhao, W.* AU - Bielak, L.F.* AU - Kardia, S.L.R.* AU - Peyser, P.A.* AU - Ning, H.* AU - VanWagner, L.B.* AU - Lloyd-Jones, D.M.* AU - Carr, J.J.* AU - Greenland, P.* AU - Lichtenstein, A.H.* AU - Hu, F.B.* AU - Liu, Y.* AU - Hou, L.* AU - Darwish Murad, S.* AU - Levy, D.* C1 - 55918 C2 - 46694 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 1073-1083 TI - A peripheral blood DNA methylation signature of hepatic fat reveals a potential causal pathway for non-alcoholic fatty liver disease. JO - Diabetes VL - 68 IS - 5 PB - Amer Diabetes Assoc PY - 2019 SN - 0012-1797 ER - TY - JOUR AB - Neurotensin (NT), a gut hormone and neuropeptide, increases in circulation after bariatric surgery in rodents and humans and inhibits food intake in mice. However, its potential to treat obesity and the subsequent metabolic dysfunctions have been difficult to assess owing to its short half-life in vivo. Here, we demonstrate that a long-acting, pegylated analog of the NT peptide (P-NT) reduces food intake, body weight, and adiposity in diet-induced obese mice when administered once daily for 6 days. Strikingly, when P-NT was combined with the glucagon-like peptide 1 mimetic liraglutide, the two peptides syner-gized to reduce food intake and body weight relative to each monotherapy, without inducing a taste aversion. Further, P-NT and liraglutide coadministration improved glycemia and reduced steatohepatitis. Finally, we show that the melanocortin pathway is central for P-NT–induced anorexia and necessary for the full synergistic effect of P-NT and liraglutide combination therapy. Overall, our data suggest that P-NT and liraglutide combination therapy could be an enhanced treatment for obesity with improved tolerability compared with liraglutide monotherapy. AU - Ratner, C.* AU - He, Z.* AU - Grunddal, K.V.* AU - Skov, L.J.* AU - Hartmann, B.* AU - Zhang, F.* AU - Feuchtinger, A. AU - Bjerregaard, A.* AU - Christoffersen, C.* AU - Tschöp, M.H. AU - Finan, B.* AU - DiMarchi, R.D.* AU - Leinninger, G.M.* AU - Williams, K.W.* AU - Clemmensen, C.* AU - Holst, B.* C1 - 55793 C2 - 46565 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 1329-1340 TI - Long-acting neurotensin synergizes with liraglutide to reverse obesity through a melanocortin-dependent pathway. JO - Diabetes VL - 68 IS - 6 PB - Amer Diabetes Assoc PY - 2019 SN - 0012-1797 ER - TY - JOUR AB - Recent studies suggest that insulin-like growth factor binding protein 2 (IGFBP-2) may protect against type 2 diabetes, but population-based human studies are scarce. We aimed to investigate the prospective association of circulating IGFBP-2 concentrations and of differential methylation in the IGFBP-2 gene with type 2 diabetes risk. AU - Wittenbecher, C.* AU - Ouni, M.* AU - Kuxhaus, O.* AU - Jähnert, M.* AU - Gottmann, P.* AU - Teichmann, A.* AU - Meidtner, K.* AU - Kriebel, J. AU - Grallert, H. AU - Pischon, T.* AU - Boeing, H.* AU - Schulze, M.B.* AU - Schürmann, A.* C1 - 55059 C2 - 46042 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 188-197 TI - Insulin-like growth factor binding protein 2 (IGFBP-2) and the risk of developing type 2 diabetes. JO - Diabetes VL - 68 IS - 1 PB - Amer Diabetes Assoc PY - 2019 SN - 0012-1797 ER - TY - JOUR AB - Progression to clinical type 1 diabetes varies among children who develop beta-cell autoantibodies. Differences in autoantibody patterns could relate to disease progression and etiology. Here we modeled complex longitudinal auto-antibody profiles by using a novel wavelet-based algorithm. We identified clusters of similar profiles associated with various types of progression among 600 children from The Environmental Determinants of Diabetes in the Young (TEDDY) birth cohort study; these children developed persistent insulin autoantibodies (IAA), GAD autoantibodies (GADA), insulinoma-associated antigen 2 autoantibodies (IA-2A), or a combination of these, and they were followed up prospectively at 3- to 6-month intervals (median follow-up 6.5 years). Children who developed multiple autoantibody types (n = 370) were clustered, and progression from seroconversion to clinical diabetes within 5 years ranged between clusters from6%(95% CI 0, 17.4) to 84% (59.2, 93.6). Children who seroconverted early in life (median age <2 years) and developed IAA and IA-2A that were stable-positive on follow-up had the highest risk of diabetes, and this risk was unaffected by GADA status. Clusters of children who lacked stable-positive GADA responses contained more boys and lower frequencies of the HLA-DR3 allele. Our novel algorithm allows refined grouping of beta-cell autoantibody-positive children who distinctly progressed to clinical type 1 diabetes, and it provides new opportunities in searching for etiological factors and elucidating complex disease mechanisms. AU - Endesfelder, D. AU - zu Castell-Rüdenhausen, W. AU - Bonifacio, E.* AU - Rewers, M.* AU - Hagopian, W.A.* AU - She, J.X.* AU - Lernmark, A.* AU - Toppari, J.* AU - Vehik, K.* AU - Williams, A.J.K.* AU - Yu, L.* AU - Akolkar, B.* AU - Krischer, J.P.* AU - Ziegler, A.-G. AU - Achenbach, P. C1 - 54502 C2 - 45637 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 119-130 TI - Time-resolved autoantibody profiling facilitates stratification of preclinical type 1 diabetes in children. JO - Diabetes VL - 68 IS - 1 PB - Amer Diabetes Assoc PY - 2018 SN - 0012-1797 ER - TY - JOUR AB - Prospective analyses of biomarkers of inflammation and distal sensorimotor polyneuropathy (DSPN) are scarce and limited to innate immunity. We therefore aimed to assess associations between biomarkers reflecting multiple aspects of immune activation and DSPN. The study was based on 127 case subjects with incident DSPN and 386 noncase subjects from the population-based Cooperative Health Research in the Region of Augsburg (KORA) F4/FF4 cohort (follow-up 6.5 years). Proximity extension assay technology was used to measure serum levels of biomarkers of inflammation. Of 71 biomarkers assessed, 26 were associated with incident DSPN. After adjustment for multiple testing, higher levels of six biomarkers remained related to incident DSPN. Three of these proteins (MCP-3/CCL7, MIG/CXCL9, IP-10/CXCL10) were chemokines, and the other three (DNER, CD40, TNFRSF9) were soluble forms of transmembrane receptors. The chemokines had neurotoxic effects on neuroblastoma cells in vitro. Addition of all six biomarkers improved the C statistic of a clinical risk model from 0.748 to 0.783 (P = 0.011). Pathway analyses indicated that multiple cell types from innate and adaptive immunity are involved in the development of DSPN. We thus identified novel associations between biomarkers of inflammation and incident DSPN pointing to a complex cross talk between innate and adaptive immunity in the pathogenesis of the disease. AU - Herder, C.* AU - Kannenberg, J.M.* AU - Carstensen-Kirberg, M.* AU - Strom, A.* AU - Bönhof, 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 - 54140 C2 - 45360 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 2434-2442 TI - A systemic inflammatory signature reflecting crosstalk between innate and adaptive immunity is associated with polyneuropathy: KORA F4/FF4 Study. JO - Diabetes VL - 67 IS - 11 PB - Amer Diabetes Assoc PY - 2018 SN - 0012-1797 ER - TY - JOUR AB - Glucagon, an essential regulator of glucose and lipid metabolism, also promotes weight loss, in part through potentiation of fibroblast growth factor 21 (FGF21) secretion. However, FGF21 is only a partial mediator of metabolic actions ensuing from glucagon receptor (GCGR) activation, prompting us to search for additional pathways. Intriguingly, chronic GCGR agonism increases plasma bile acid levels. We hypothesized that GCGR agonism regulates energy metabolism, at least in part, through farnesoid X receptor (FXR). To test this hypothesis, we studied whole-body and liver-specific FXR-knockout (Fxr∆liver) mice. Chronic GCGR agonist (IUB288) administration in diet-induced obese (DIO) Gcgr, Fgf21, and Fxr whole-body or liver-specific knockout (∆liver) mice failed to reduce body weight when compared with wild-type (WT) mice. IUB288 increased energy expenditure and respiration in DIO WT mice, but not Fxr∆liver mice. GCGR agonism increased [14C]palmitate oxidation in hepatocytes isolated from WT mice in a dose-dependent manner, an effect blunted in hepatocytes from Fxr∆liver mice. Our data clearly demonstrate that control of whole-body energy expenditure by GCGR agonism requires intact FXR signaling in the liver. This heretofore-unappreciated aspect of glucagon biology has implications for the use of GCGR agonism in the therapy of metabolic disorders. AU - Kim, T.* AU - Nason, S.* AU - Holleman, C.* AU - Pepin, M.* AU - Wilson, L.C.* AU - Berryhill, T.F.* AU - Wende, A.R.* AU - Steele, C.* AU - Young, M.E.* AU - Barnes, S.* AU - Drucker, D.J.* AU - Finan, B.* AU - DiMarchi, R.* AU - Perez-Tilve, D.* AU - Tschöp, M.H. AU - Habegger, K.M.* C1 - 53686 C2 - 44951 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 1773-1782 TI - Glucagon receptor signaling regulates energy metabolism via hepatic farnesoid X receptor and fibroblast growth factor 21. JO - Diabetes VL - 67 IS - 9 PB - Amer Diabetes Assoc PY - 2018 SN - 0012-1797 ER - TY - JOUR AB - Fetuin-A, a hepatic-origin protein, is strongly positively associated with risk of type 2 diabetes in human observational studies, but it is unknown whether this association is causal. Weaimed to study the potential causal relation of circulating fetuin-A to risk of type 2 diabetes in a Mendelian randomization study with single nucleotide polymorphisms located in the fetuin-A-encoding AHSG gene. We used data from eight European countries of the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study including 10,020 incident cases. Plasma fetuin-A concentration was measured in a subset of 965 subcohort participants and 654 case subjects. A genetic score of the AHSG single nucleotide polymorphisms was strongly associated with fetuin-A (28% explained variation). Using the genetic score as instrumental variable of fetuin-A, we observed no significant association of a 50 mu g/mL higher fetuin-A concentration with diabetes risk (hazard ratio 1.02 [95% CI 0.97, 1.07]). Combining our results with those from the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium (12,171 case subjects) also did not suggest a clear significant relation of fetuin-A with diabetes risk. In conclusion, although there is mechanistic evidence for an effect of fetuin-A on insulin sensitivity and secretion, this study does not support a strong, relevant relationship between circulating fetuin-A and diabetes risk in the general population. AU - Kroeger, J.* AU - Meidtner, K.* AU - Stefan, N. AU - Guevara, M.* AU - Kerrison, N.D.* AU - Ardanaz, E.* AU - Aune, D.* AU - Boeing, H.* AU - Dorronsoro, M.* AU - Dow, C.* AU - Fagherazzi, G.* AU - Franks, P.W.* AU - Freisling, H.* AU - Gunter, M.J.* AU - Maria Huerta, J.* AU - Kaaks, R.* AU - Key, T.J.* AU - Khaw, K.T.* AU - Krogh, V.* AU - Kuehn, T.* AU - Mancini, F.R.* AU - Mattiello, A.* AU - Nilsson, P.M.* AU - Olsen, A.* AU - Overvad, K.* AU - Palli, D.* AU - Ramon Quiros, J.* AU - Rolandsson, O.* AU - Sacerdote, C.* AU - Sala, N.* AU - Salamanca-Fernandez, E.* AU - Sluijs, I.* AU - Spijkerman, A.M.W.* AU - Tjonneland, A.* AU - Tsilidis, K.K.* AU - Tumino, R.* AU - van der Schouw, Y.T.* AU - Forouhi, N.G.* AU - Sharp, S.J.* AU - Langenberg, C.* AU - Riboli, E.* AU - Schulze, M.B.* AU - Wareham, N.J.* C1 - 54066 C2 - 45292 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 1200-1205 TI - Circulating fetuin - A and risk of type 2 diabetes : A mendelian randomization analysis. JO - Diabetes VL - 67 IS - 6 PB - Amer Diabetes Assoc PY - 2018 SN - 0012-1797 ER - TY - JOUR AB - The Takeda-G-protein-receptor-5 (TGR5) mediates physiological actions of bile acids. Since it was shown that TGR5 is expressed in pancreatic tissue, a direct TGR5 activation in -cells is currently postulated and discussed. The current study reveals that oleanolic acid (OLA) affects murine -cell function by TGR5 activation. Both a G(s) inhibitor and an inhibitor of adenylyl cyclase (AC) prevented stimulating effects of OLA. Accordingly, OLA augmented the intracellular cAMP concentration. OLA and two well-established TGR5 agonists, RG239 and tauroursodeoxycholic acid (TUDCA), acutely promoted stimulus-secretion coupling (SSC). OLA reduced K-ATP current and elevated current through Ca2+ channels. Accordingly, in mouse and human -cells, TGR5 ligands increased the cytosolic Ca2+ concentration by stimulating Ca2+ influx. Higher OLA concentrations evoked a dual reaction, probably due to activation of a counterregulating pathway. Protein kinase A (PKA) was identified as a downstream target of TGR5 activation. In contrast, inhibition of phospholipase C and phosphoinositide 3-kinase did not prevent stimulating effects of OLA. Involvement of exchange protein directly activated by cAMP 2 (Epac2) or farnesoid X receptor (FXR2) was ruled out by experiments with knockout mice. The proposed pathway was not influenced by local glucagon-like peptide 1 (GLP-1) secretion from -cells, shown by experiments with MIN6 cells, and a GLP-1 receptor antagonist. In summary, these data clearly demonstrate that activation of TGR5 in -cells stimulates insulin secretion via an AC/cAMP/PKA-dependent pathway, which is supposed to interfere with SSC by affecting K-ATP and Ca2+ currents and thus membrane potential. AU - Maczewsky, J.* AU - Kaiser, J.* AU - Gresch, A.* AU - Gerst, F. AU - Düfer, M.* AU - Krippeit-Drews, P.* AU - Drews, G.* C1 - 54709 C2 - 45800 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 324-336 TI - TGR5 activation promotes stimulus-secretion coupling of pancreatic -cells via a PKA-dependent pathway. JO - Diabetes VL - 67 IS - 11 PB - Amer Diabetes Assoc PY - 2018 SN - 0012-1797 ER - TY - JOUR AU - Mueller, K.M.* AU - Hartmann, K.* AU - Kaltenecker, D.* AU - Vettorazzi, S.* AU - Bauer, M.* AU - Mauser, L.* AU - Amann, S.* AU - Jall, S. AU - Fischer, K. AU - Esterbauer, H.* AU - Müller, T.D. AU - Tschöp, M.H. AU - Magnes, C.* AU - Haybaeck, J.* AU - Scherer, T.* AU - Bordag, N.* AU - Tuckermann, J.P.* AU - Moriggl, R.* C1 - 55500 C2 - 46193 SP - 343-344 TI - Erratum. Adipocyte glucocorticoid Receptor deficiency attenuates aging- and HFD-induced obesity and impairs the feeding-fasting transition. Diabetes 2017;66:272-286. JO - Diabetes VL - 67 IS - 2 PY - 2018 SN - 0012-1797 ER - TY - JOUR AB - We examined the association between plasma 25-hydroxyvitamin D [25(OH)D] concentration and islet autoimmunity (IA) and whether vitamin D gene polymorphisms modify the effect of 25(OH)D on IA risk. We followed 8,676 children at increased genetic risk of type 1 diabetes at six sites in the U.S. and Europe. We defined IA as positivity for at least one autoantibody (GADA, IAA, or IA-2A) on two or more visits. We conducted a risk set sampled nested case-control study of 376 IA case subjects and up to 3 control subjects per case subject. 25(OH)D concentration was measured on all samples prior to, and including, the first IA positive visit. Nine polymorphisms in,andwere analyzed as effect modifiers of 25(OH)D. Adjusting for HLA-DR-DQ and ancestry, higher childhood 25(OH)D was associated with lower IA risk (odds ratio = 0.93 for a 5 nmol/L difference; 95% CI 0.89, 0.97). Moreover, this association was modified byrs7975232 (interaction= 0.0072), where increased childhood 25(OH)D was associated with a decreasing IA risk based upon number of minor alleles: 0 (1.00; 0.93, 1.07), 1 (0.92; 0.89, 0.96), and 2 (0.86; 0.80, 0.92). Vitamin D andmay have a combined role in IA development in children at increased genetic risk for type 1 diabetes. AU - Norris, J.M.* AU - Lee, H.S.* AU - Frederiksen, B.* AU - Erlund, I.* AU - Uusitalo, U.* AU - Yang, J.A.* AU - Lernmark, A.* AU - Simell, O.* AU - Toppari, J.* AU - Rewers, M.* AU - TEDDY Study Group (Ziegler, A.-G.) AU - She, J.X.* AU - Onengut-Gumuscu, S.* AU - Chen, W.M.* AU - Rich, S.S.* AU - Sundvall, J.* AU - Akolkar, B.* AU - Krischer, J.* AU - Virtanen, S.M.* AU - Hagopian, W.* C1 - 53004 C2 - 44253 SP - 146-154 TI - Plasma 25-hydroxyvitamin D concentration and risk of islet autoimmunity. JO - Diabetes VL - 67 IS - 1 PY - 2018 SN - 0012-1797 ER - TY - JOUR AB - Celastrol, a plant-derived constituent of traditional Chinese medicine, has been proposed to offer significant potential as an antiobesity drug. However, the molecular mechanism for this activity is unknown. We show that the weight-lowering effects of celastrol are driven by decreased food consumption. Although young Lep(ob) mice respond with a decrease in food intake and body weight, adult Lep(db) and Lep(ob) mice are unresponsive to celastrol, suggesting that functional leptin signaling in adult mice is required to elicit celastrol's catabolic actions. Protein tyrosine phosphatase 1 (PTP1B), a leptin negative-feedback regulator, has been previously reported to be one of celastrol's targets. However, we found that global PTP1B knockout (KO) and wild-type (WT) mice have comparable weight loss and hypophagia when treated with celastrol. Increased levels of uncoupling protein 1 (UCP1) in subcutaneous white and brown adipose tissue suggest celastrol-induced thermogenesis as a further mechanism. However, diet-induced obese UCP1 WT and KO mice have comparable weight loss upon celastrol treatment, and celastrol treatment has no effect on energy expenditure under ambient housing or thermoneutral conditions. Overall, our results suggest that celastrol-induced weight loss is hypophagia driven and age-dependently mediated by functional leptin signaling. Our data encourage reconsideration of therapeutic antiobesity strategies built on leptin sensitization. AU - Pfuhlmann, K. AU - Schriever, S.C. AU - Baumann, P. AU - Kabra, D.G.* AU - Harrison, L. AU - Mazibuko-Mbeje, S. AU - Contreras, R.E.* AU - Kyriakou, E. AU - Simonds, S.E.* AU - Tiganis, T.* AU - Cowley, M.A.* AU - Woods, S.C.* AU - Jastroch, M. AU - Clemmensen, C. AU - de Angelis, M. AU - Schramm, K.-W. AU - Sattler, M. AU - Messias, A.C. AU - Tschöp, M.H. AU - Pfluger, P.T. C1 - 54211 C2 - 45439 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 2456-2465 TI - Celastrol-induced weight loss is driven by hypophagia and independent from UCP1. JO - Diabetes VL - 67 IS - 9 PB - Amer Diabetes Assoc PY - 2018 SN - 0012-1797 ER - TY - JOUR AB - Islet autoantibodies (IAs) precede the clinical onset of type 1 diabetes (T1D); however, the knowledge is limited about whether the prodrome affects complete blood counts (CBCs) in 4- to 12-year-old children with increased genetic risk for T1D. This study tested whether CBCs were altered in 4- to 12-year-old children without (n = 376) or with one or several IAs against insulin, GAD65, or IA-2 (n = 72). CBC was analyzed during longitudinal follow-up in 448 Swedish children enrolled in The Environmental Determinants of Diabetes in the Young (TEDDY) study. A linear mixed-effects model was used to assess potential association between IA and CBC measurements over time. The white blood cell and neutrophil counts were reduced in children with IAs, primarily in boys. In contrast, girls had lower levels of hemoglobin and hematocrit. Positivity for multiple IAs showed the lowest counts in white blood cells and neutrophils in boys and red blood cells, hemoglobin, and hematocrit in girls. These associations were primarily observed in children with the HLA-DR3-DQ2/DR4-DQ8 genotype. We conclude that the reduction in neutrophils and red blood cells in children with multiple IAs and HLA-DR3-DQ2/DR4-DQ8 genotype may signal a sex-dependent islet autoimmunity detected in longitudinal CBCs. AU - Salami, F.* AU - Lee, H.* AU - Freyhult, E.* AU - Larsson, H.E.* AU - Lernmark, A.* AU - Törn, C.* AU - TEDDY Study Group (Ziegler, A.-G. AU - Beyerlein, A. AU - Gavrisan, A. AU - Gezginci, C. AU - Hummel, M. AU - Hummel, S. AU - Knopff, A. AU - Koletzko, S. AU - Stock, J. AU - Scholz, M. AU - Roth, R. AU - Warncke, K. AU - Wendel, L. AU - Winkler, C.) C1 - 54743 C2 - 45797 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 2329-2336 TI - Reduction in white blood cell, neutrophil, and red blood cell counts related to sex, HLA, and islet autoantibodies in Swedish TEDDY children at increased risk for type 1 diabetes. JO - Diabetes VL - 67 IS - 11 PB - Amer Diabetes Assoc PY - 2018 SN - 0012-1797 ER - TY - JOUR AB - Identification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near (rs9942471, = 4.5 × 10) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at and , both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD. AU - van Zuydam, N.R.* AU - Ahlqvist, E.* AU - Sandholm, N.* AU - Deshmukh, H.* AU - Rayner, N.W.* AU - Ladenvall, C.* AU - Ziemek, D.* AU - Fauman, E.* AU - Robertson, N.R.* AU - McKeigue, P.M.* AU - Valo, E.* AU - Forsblom, C.* AU - Harjutsalo, V.* AU - Perna, A.* AU - Rurali, E.* AU - Marcovecchio, M.L.* AU - Igo, R.P.* AU - Salem, R.M.* AU - Perico, N.* AU - Lajer, M.* AU - Käräjämäki, A.* AU - Imamura, M.* AU - Kubo, M.* AU - Takahashi, A.* AU - Sim, X.* AU - Liu, J.* AU - van Dam, R.M.* AU - Jiang, G.* AU - Tam, C.H.T.* AU - Luk, A.O.Y.* AU - Lee, H.M.* AU - Lim, C.K.P.* AU - Szeto, C.C.* AU - So, W.Y.* AU - Chan, J.C.N.* AU - Ang, S.F.* AU - Dorajoo, R.* AU - Wang, L.* AU - Clara, T.S.H.* AU - McKnight, A.J.* AU - Duffy, S.* AU - Pezzolesi, M.G.* AU - Marre, M.* AU - Gyorgy, B.* AU - Hadjadj, S.* AU - Hiraki, L.T.* AU - Ahluwalia, T.S.* AU - Almgren, P.* AU - Schulz, C.A.* AU - Orho-Melander, M.* AU - Linneberg, A.* AU - Christensen, C.* AU - Witte, D.R.* AU - Grarup, N.* AU - Brandslund, I.* AU - Melander, O.* AU - Paterson, A.D.* AU - Tregouet, D.* AU - Maxwell, A.P.* AU - Lim, S.C.* AU - Ma, R.C.W.* AU - Tai, E.S.* AU - Maeda, S.* AU - Lyssenko, V.* AU - Tuomi, T.* AU - Krolewski, A.S.* AU - Rich, S.S.* AU - Hirschhorn, J.N.* AU - Florez, J.C* AU - Dunger, D.B.* AU - Pedersen, O.* AU - Hansen, T.* AU - Rossing, P.* AU - Remuzzi, G.* AU - SUMMIT Investigators (Thorand, B. AU - Gieger, C. AU - Grallert, H. AU - Ludwig, T. AU - Nitz, B. AU - Wang-Sattler, R. AU - Zierer, A.) C1 - 54030 C2 - 45206 SP - 1414-1427 TI - A genome-wide association study of diabetic kidney disease in subjects with type 2 diabetes. JO - Diabetes VL - 67 IS - 7 PY - 2018 SN - 0012-1797 ER - TY - JOUR AU - Adam, J. AU - Brandmaier, S. AU - Troll, M. AU - Rotter, M. AU - Mohney, R.P.* AU - Heier, M. AU - Adamski, J. AU - Li, Y.* AU - Neschen, S. AU - Kastenmüller, G. AU - Suhre, K.* AU - Ankerst, D.P.* AU - Meitinger, T. AU - Wang-Sattler, R. C1 - 51024 C2 - 42746 CY - Alexandria SP - e3-e4 TI - Response to comment on Adam et al. Metformin effect on nontargeted metabolite profiles in patients with type 2 diabetes and in multiple murine tissues. Diabetes 2016;65:3776-3785. JO - Diabetes VL - 66 IS - 5 PB - Amer Diabetes Assoc PY - 2017 SN - 0012-1797 ER - TY - JOUR AB - Detailed pathophysiological manifestations of early disease in the context of prediabetes are poorly understood. This study aimed to evaluate the extent of early signs of metabolic and cardio-cerebrovascular complications affecting multiple organs in individuals with prediabetes. Subjects without a history of stroke, coronary artery disease, or peripheral artery disease were enrolled in a case-control study nested within the Cooperative Health Research in the Region of Augsburg (KORA) FF4 cohort and underwent comprehensive MRI assessment to characterize cerebral parameters (white matter lesions, microbleeds), cardiovascular parameters (carotid plaque, left ventricular function, and myocardial late gadolinium enhancement [LGE]), and metabolic parameters (hepatic proton-density fat fraction [PDFF] and subcutaneous and visceral abdominal fat). Among 400 subjects who underwent MRI, 103 subjects had prediabetes and 54 had established diabetes. Subjects with prediabetes had an increased risk for carotid plaque and adverse functional cardiac parameters, including reduced early diastolic filling rates as well as a higher prevalence of LGE compared with healthy control subjects. In addition, people with prediabetes had significantly elevated levels of PDFF and total and visceral fat. Thus, subjects with prediabetes show early signs of subclinical disease that include vascular, cardiac, and metabolic changes, as measured by whole-body MRI after adjusting for cardiometabolic risk factors. AU - Bamberg, F.* AU - Hetterich, H.* AU - Rospleszcz, S. AU - Lorbeer, R.* AU - Auweter, S.D.* AU - Schlett, C.L.* AU - Schafnitzel, A.* AU - Bayerl, C.* AU - Schindler, A.* AU - Saam, T.* AU - Müller-Peltzer, K.* AU - Sommer, W.* AU - Zitzelsberger, T.* AU - Machann, J.* AU - Ingrisch, M.* AU - Selder, S.* AU - Rathmann, W.* AU - Heier, M. AU - Linkohr, B. AU - Meisinger, C. AU - Weber, C.* AU - Ertl-Wagner, B.* AU - Massberg, S.* AU - Reiser, M.F.* AU - Peters, A. C1 - 50256 C2 - 42154 CY - Alexandria SP - 158-169 TI - Subclinical disease burden as assessed by whole-body MRI in subjects with prediabetes, subjects with diabetes, and normal control subjects from the general population: The KORA-MRI study. JO - Diabetes VL - 66 IS - 1 PB - Amer Diabetes Assoc PY - 2017 SN - 0012-1797 ER - TY - JOUR AB - Neuronal circuits in the brain help to control feeding behavior and systemic metabolism in response to afferent nutrient and hormonal signals. Although astrocytes have historically been assumed to be less relevant for such neuroendocrine control, we asked whether lipid uptake via lipoprotein lipase (LPL) in astrocytes is required for the central regulation of energy homeostasis. Ex vivo studies with hypothalamic-derived astrocytes showed that LPL expression is up-regulated by oleic acid; whereas it is decreased in response to palmitic acid or triglyceride. Likewise, astrocytic LPL deletion reduced the accumulation of lipid drops in those glial cells. Consecutive in vivo studies showed that the postnatal ablation of LPL in glial fibrillary acidic protein (GFAP)-expressing astrocytes induced exaggerated body weight gain and glucose intolerance in mice exposed to a high-fat diet (HFD). Intriguingly, astrocytic LPL deficiency also triggered increased ceramide content in the hypothalamus, which may contribute to hypothalamic insulin resistance. We conclude that hypothalamic LPL functions in astrocytes to ensure appropriately balanced nutrient sensing, ceramide distribution, body weight regulation and glucose metabolism. AU - Gao, Y. AU - Layritz, C. AU - Legutko, B. AU - Eichmann, T.O.* AU - Laperrousaz, E.* AU - Moullé, V.S.* AU - Cruciani-Guglielmacci, C.* AU - Magnan, C.* AU - Luquet, S.* AU - Woods, S.C.* AU - Eckel, R.H.* AU - Yi, C.-X. AU - Garcia-Caceres, C. AU - Tschöp, M.H. C1 - 51529 C2 - 43280 CY - Alexandria SP - 2555-2563 TI - Disruption of lipid uptake in astroglia exacerbates diet induced obesity. JO - Diabetes VL - 66 IS - 10 PB - Amer Diabetes Assoc PY - 2017 SN - 0012-1797 ER - TY - JOUR AB - Intranasal spray application facilitates insulin delivery to the human brain. Although brain insulin modulates peripheral metabolism, the mechanisms involved remain elusive. Twenty-one men underwent two hyperinsulinemic-euglycemic clamps with D-[6,6-H-2(2)] glucose infusion to measure endogenous glucose production and glucose disappearance. On two separate days, participants received intranasal insulin or placebo. Insulin spillover into circulation after intranasal insulin application was mimicked by an intravenous insulin bolus on placebo day. On a different day, brain insulin sensitivity was assessed by functional MRI. Glucose infusion rates (GIRs) had to be increased more after nasal insulin than after placebo to maintain euglycemia in lean but not in overweight people. The increase in GIRs was associated with regional brain insulin action in hypothalamus and striatum. Suppression of endogenous glucose production by circulating insulin was more pronounced after administration of nasal insulin than after placebo. Furthermore, glucose uptake into tissue tended to be higher after nasal insulin application. No such effects were detected in overweight participants. By increasing insulin-mediated suppression of endogenous glucose production and stimulating peripheral glucose uptake, brain insulin may improve glucose metabolism during systemic hyperinsulinemia. Obese people appear to lack these mechanisms. Therefore, brain insulin resistance in obesity may have unfavorable consequences for whole-body glucose homeostasis. AU - Heni, M. AU - Wagner, R. AU - Kullmann, S. AU - Gancheva, S. AU - Roden, M. AU - Peter, A. AU - Stefan, N. AU - Preissl, H. AU - Häring, H.-U. AU - Fritsche, A. C1 - 51471 C2 - 43145 CY - Alexandria SP - 1797-1806 TI - Hypothalamic and striatal insulin action suppresses endogenous glucose production and may stimulate glucose uptake during hyperinsulinemia in lean but not in overweight men. JO - Diabetes VL - 66 IS - 7 PB - Amer Diabetes Assoc PY - 2017 SN - 0012-1797 ER - TY - JOUR AB - In pancreatic beta cells, mitochondrial bioenergetics control glucose-stimulated insulin secretion (GSIS). Mitochondrial dynamics are generally associated with quality control, maintaining the functionality of bioenergetics. By acute pharmacological inhibition of mitochondrial fission protein Drp1, we here demonstrate that mitochondrial fission is necessary for GSIS in mouse and human islets. We confirm that genetic silencing of Drp1 increases mitochondrial proton leak in MIN6 cells. However, our comprehensive analysis of pancreatic islet bioenergetics reveals that Drp1 does not control insulin secretion via its effect on proton leak but instead via modulation of glucose-fuelled respiration. Notably, pyruvate fully rescues the impaired insulin secretion of fission-deficient beta cells, demonstrating that defective mitochondrial dynamics solely impact substrate supply upstream of oxidative phosphorylation. The present findings provide novel insights in how mitochondrial dysfunction may cause pancreatic beta cell failure. In addition, the results will stimulate new thinking in the intersecting fields of mitochondrial dynamics and bioenergetics, as treatment of defective dynamics in mitochondrial diseases appears to be possible by improving metabolism upstream of mitochondria. AU - Kabra, U.D. AU - Pfuhlmann, K. AU - Migliorini, A. AU - Keipert, S. AU - Lamp, D. AU - Korsgren, O.* AU - Gegg, M. AU - Woods, S.C.* AU - Pfluger, P.T. AU - Lickert, H. AU - Affourtit, C.* AU - Tschöp, M.H. AU - Jastroch, M. C1 - 50653 C2 - 42768 CY - Alexandria SP - 1247-1257 TI - Direct substrate delivery into mitochondrial-fission deficient pancreatic islets rescues insulin secretion. JO - Diabetes VL - 66 IS - 5 PB - Amer Diabetes Assoc PY - 2017 SN - 0012-1797 ER - TY - JOUR AU - Kahn, C.R.* AU - Ussar, S. C1 - 51023 C2 - 42747 CY - Alexandria SP - e6-e6 TI - Response to comment on Ussar et al. Regulation of glucose uptake and enteroendocrine function by the intestinal epithelial insulin receptor. Diabetes 2017;66:886-896. JO - Diabetes VL - 66 IS - 5 PB - Amer Diabetes Assoc PY - 2017 SN - 0012-1797 ER - TY - JOUR AB - In addition to its pivotal role in psychosocial behavior, the hypothalamic neuropeptide oxytocin contributes to metabolic control by suppressing eating behavior. Its involvement in glucose homeostasis is less clear, although pilot experiments suggest that oxytocin improves glucose homeostasis. We assessed the effect of intranasal oxytocin (24 IU) administered to 29 healthy, fasted male subjects on glucose homeostasis measured by means of an oral glucose tolerance test. Parameters of glucose metabolism were analyzed according to the oral minimal model. Oxytocin attenuated the peak excursion of plasma glucose and augmented the early increases in insulin and C-peptide concentrations in response to the glucose challenge, while slightly blunting insulin and C-peptide peaks. Oral minimal model analyses revealed that oxytocin compared to placebo induced a pronounced increase in beta-cell responsivity (PHItotal) that was largely due to an enhanced dynamic response (PHId), and a more than two-fold improvement in glucose tolerance (disposition index). ACTH, cortisol, glucagon and non-esterified fatty acid concentrations were not or only marginally affected. These results indicate that oxytocin plays a significant role in the acute regulation of glucose metabolism in healthy humans and render the oxytocin system a potential target of antidiabetic treatment. AU - Klement, J.* AU - Ott, V.* AU - Rapp, K.* AU - Brede, S.* AU - Piccinini, F.* AU - Cobelli, C.* AU - Lehnert, H.* AU - Hallschmid, M. C1 - 49322 C2 - 41734 CY - Alexandria SP - 264-271 TI - Oxytocin improves beta-cell responsivity and glucose tolerance in healthy men. JO - Diabetes VL - 66 IS - 2 PB - Amer Diabetes Assoc PY - 2017 SN - 0012-1797 ER - TY - JOUR AB - This paper seeks to determine whether factors related to autoimmunity risk remain significant after the initiation of two or more diabetes-related autoantibodies and continue to contribute to T1D risk among autoantibody positive children in The Environmental Determinants of Diabetes in the Young (TEDDY) study. Characteristics included are age at multiple autoantibody positivity, sex, selected high-risk HLA-DR-DQ genotypes, relationship to a family member with T1D, autoantibody at seroconversion, INS gene (rs1004446_A), and non-HLA gene polymorphisms identified by the Type 1 Diabetes Genetics Consortium. The risk of progression to T1D was not different among those with or without a family history of T1D (p=0.39) nor HLA-DR-DQ genotypes (p=0.74). Age at developing multiple autoantibodies (HR=0.96 per 1 month increase in age, 95% CI=0.95, 0.97, p<0.001) and the type of first autoantibody (when more than a single autoantibody was the first appearing indication of seroconversion [p=0.006]) were statistically significant. Female sex was also a significant risk factor (p=0.03). Three SNPs were associated with increased diabetes risk (rs10517086_A, [p=0.03], rs1534422_G, [p=0.006], and rs2327832_G in TNFAIP3 [p=0.03]), and one with decreased risk (rs1004446_A in INS, [p=0.006]). The TEDDY data suggest that non-HLA gene polymorphisms may play a different role in the initiation of autoimmunity than they do in progression to T1D once autoimmunity has appeared. The strength of these associations may be related to the age of the population and the high-risk HLA-DR-DQ subtypes studied. AU - Krischer, J.P.* AU - Liu, X.* AU - Lernmark, A.* AU - Hagopian, W.A.* AU - Rewers, M.J.* AU - She, J.X.* AU - Toppari, J.* AU - Ziegler, A.-G. AU - Akolkar, B.* 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 - Warncke, K. AU - Wendel, L. AU - Winkler, C.) C1 - 51895 C2 - 43555 CY - Alexandria SP - 3122-3129 TI - The influence of type 1 diabetes genetic susceptibility regions, age, sex, and family history to the progression from multiple autoantibodies to type 1 diabetes: A TEDDY Study Report. JO - Diabetes VL - 66 IS - 12 PB - Amer Diabetes Assoc PY - 2017 SN - 0012-1797 ER - TY - JOUR AB - Tbx15 is a member of the T-box gene family of mesodermal developmental genes. We have recently shown that Tbx15 plays a critical role in the formation and metabolic programming of glycolytic myofibers in skeletal muscle. Tbx15 is also differentially expressed among white adipose tissue (WAT) in different body depots. In the current study, using three independent methods, we show that even within a single WAT depot, high Tbx15 expression is restricted to a subset of preadipocytes and mature white adipocytes. Gene expression and metabolic profiling demonstrate that the Tbx15(Hi) preadipocyte and adipocyte subpopulations of cells are highly glycolytic, whereas Tbx15(Low) preadipocytes and adipocytes in the same depot are more oxidative and less glycolytic. Likewise, in humans, expression of TBX15 in subcutaneous and visceral WAT is positively correlated with markers of glycolytic metabolism and inversely correlated with obesity. Furthermore, overexpression of Tbx15 is sufficient to reduce oxidative and increase glycolytic metabolism in cultured adipocytes. Thus, Tbx15 differentially regulates oxidative and glycolytic metabolism within subpopulations of white adipocytes and preadipocytes. This leads to a functional heterogeneity of cellular metabolism within WAT that has potential impact in the understanding of human metabolic diseases. AU - Lee, K.Y.* AU - Sharma, R.* AU - Gase, G.* AU - Ussar, S. AU - Li, Y.* AU - Welch, L.* AU - Berryman, D.E.* AU - Kispert, A.* AU - Blüher, M.* AU - Kahn, C.R.* C1 - 52287 C2 - 43844 CY - Alexandria SP - 2822-2829 TI - Tbx15 defines a glycolytic subpopulation and white adipocyte heterogeneity. JO - Diabetes VL - 66 IS - 11 PB - Amer Diabetes Assoc PY - 2017 SN - 0012-1797 ER - TY - JOUR AB - To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) in AKT2 and fasting insulin, a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders. The low-frequency allele is associated with a 12% increase in fasting plasma insulin (FI) levels. This variant is present at 1.1% frequency in Finns but virtually absent in individuals from other ancestries. Carriers of the FI-increasing allele had increased 2-hour insulin values, decreased insulin sensitivity, and increased risk of type 2 diabetes (odds ratio=1.05). In cellular studies, the AKT2-Thr50 protein exhibited a partial loss of function. We extend the allelic spectrum for coding variants in AKT2 associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of AKT2. AU - Manning, A.* AU - Highland, H.M.* AU - Gasser, J.* AU - Sim, X.* AU - Tukiainen, T.* AU - Fontanillas, P.* AU - Grarup, N.* AU - Rivas, M.A.* AU - Mahajan, A.* AU - Locke, A.E.* AU - Cingolani, P.* AU - Pers, T.H.* AU - Viñuela, A.* AU - Brown, A.A.* AU - Wu, Y.* AU - Flannick, J.* AU - Fuchsberger, C.* AU - Gamazon, E.R.* AU - Gaulton, K.J.* AU - Im, H.K.* AU - Teslovich, T.M.* AU - Blackwell, T.W.* AU - Bork-Jensen, J.* AU - Burtt, N.P.* AU - Chen, Y.* AU - Green, T.* AU - Hartl, C.* AU - Kang, H.M.* AU - Kumar, A.* AU - Ladenvall, C.* AU - Ma, C.* AU - Moutsianas, L.* AU - Pearson, R.D.* AU - Perry, J.R.* AU - Rayner, N.W.* AU - Robertson, N.R.* AU - Scott, L.J.* AU - van de Bunt, M.* AU - Eriksson, J.G.* AU - Jula, A.* AU - Koskinen, S.* AU - Lehtimäki, T.* AU - Palotie, A.* AU - Raitakari, O.T.* AU - Jacobs, S.B.* AU - Wessel, J.* AU - Chu, A.Y.* AU - Scott, R.A.* AU - Goodarzi, M.O.* AU - Blancher, C.* AU - Buck, G.* AU - Buck, D.* AU - Chines, P.S.* AU - Gabriel, S.* AU - Gjesing, A.P.* AU - Groves, C.J.* AU - Hollensted, M.* AU - Huyghe, J.R.* AU - Jackson, A.U.* AU - Jun, G.* AU - Justesen, J.M.* AU - Mangino, M.* AU - Murphy, J.* AU - Neville, M.* AU - Onofrio, R.* AU - Small, K.S.* AU - Stringham, H.M.* AU - Trakalo, J.* AU - Banks, E.* AU - Carey, J.* AU - Carneiro, M.O.* AU - DePristo, M.* AU - Farjoun, Y.* AU - Fennell, T.* AU - Goldstein, J.I.* AU - Grant, G.B.* AU - Hrabě de Angelis, M. AU - Maguire, J.* AU - Neale, B.M.* AU - Poplin, R.* AU - Purcell, S.* AU - Schwarzmayr, T. AU - Shakir, K.* AU - Smith, J.D.* AU - Strom, T.M. AU - Wieland, T. AU - Lindstrom, J.* AU - Brandslund, I.* AU - Christensen, C.* AU - Surdulescu, G.L.* AU - Lakka, T.A.* AU - Doney, A.S.* AU - Nilsson, P.* AU - Wareham, N.J.* AU - Langenberg, C.* AU - Varga, T.V.* AU - Franks, P.W.* AU - Rolandsson, O.* AU - Rosengren, A.H.* AU - Farook, V.S.* AU - Thameem, F.* AU - Puppala, S.* AU - Kumar, S.* AU - Lehman, D.M.* AU - Jenkinson, C.P.* AU - Curran, J.E.* AU - Hale, D.E.* AU - Fowler, S.P.* AU - Arya, R.* AU - DeFronzo, R.A.* AU - Abboud, H.E.* AU - Syvänen, A.C.* AU - Hicks, P.J.* AU - Palmer, N.D.* AU - Ng, M.C.* AU - Bowden, D.W.* AU - Freedman, B.I.* AU - Esko, T.* AU - Mägi, R.* AU - Milani, L.* AU - Mihailov, E.* AU - Metspalu, A.* AU - Narisu, N.* AU - Kinnunen, L.* AU - Bonnycastle, L.L.* AU - Swift, A.* AU - Pasko, D.* AU - Wood, A.R.* AU - Fadista, J.* AU - Pollin, T.I.* AU - Barzilai, N.* AU - Atzmon, G.* AU - Glaser, B.* AU - Thorand, B. AU - Strauch, K. AU - Peters, A. AU - Roden, M.* AU - Müller-Nurasyid, M. AU - Liang, L.* AU - Kriebel, J. AU - Illig, T. AU - Grallert, H. AU - Gieger, C. AU - Meisinger, C. AU - Lannfelt, L.* AU - Musani, S.K.* AU - Griswold, M.E.* AU - Taylor, H.A.* AU - Wilson, G.* AU - Correa, A.* AU - Oksa, H.* AU - Scott, W.R.* AU - Afzal, U.* AU - Tan, S.T.* AU - Loh, M.* AU - Chambers, J.C.* AU - Sehmi, J.* AU - Kooner, J.S.* AU - Lehne, B.* AU - Cho, Y.S.* AU - Lee, J.Y.* AU - Han, B.G.* AU - Käräjämäki, A.* AU - Qi, Q.* AU - Qi, L.* AU - Huang, J.* AU - Hu, F.B.* AU - Melander, O.* AU - Orho-Melander, M.* AU - Below, J.E.* AU - Aguilar, D.* AU - Wong, T.Y.* AU - Liu, J.* AU - Khor, C.C.* AU - Chia, K.S.* AU - Lim, W.Y.* AU - Cheng, C.Y.* AU - Chan, E.* AU - Tai, E.S.* AU - Aung, T.* AU - Linneberg, A.* AU - Isomaa, B.* AU - Meitinger, T. AU - Tuomi, T.* AU - Hakaste, L.* AU - Kravic, J.* AU - Jørgensen, M.E.* AU - Lauritzen, T.* AU - Deloukas, P.* AU - Stirrups, K.E.* AU - Owen, K.R.* AU - Farmer, A.J.* AU - Frayling, T.M.* AU - O'Rahilly, S.P.* AU - Walker, M.* AU - Levy, J.C.* AU - Hodgkiss, D.* AU - Hattersley, A.T.* AU - Kuulasmaa, T.* AU - Stancáková, A.* AU - Barroso, I.* AU - Bharadwaj, D.* AU - Chan, J.* AU - Chandak, G.R.* AU - Daly, M.J.* AU - Donnelly, P.J.* AU - Ebrahim, S.B.* AU - Elliott, P.* AU - Fingerlin, T.E.* AU - Froguel, P.* AU - Hu, C.* AU - Jia, W.* AU - Ma, R.C.* AU - McVean, G.* AU - Park, T.* AU - Prabhakaran, D.* AU - Sandhu, M.* AU - Scott, J.* AU - Sladek, R.* AU - Tandon, N.* AU - Teo, Y.Y.* AU - Zeggini, E.* AU - Watanabe, R.M.* AU - Koistinen, H.A.* AU - Kesaniemi, Y.A.* AU - Uusitupa, M.* AU - Spector, T.D.* AU - Salomaa, V.* AU - Rauramaa, R.* AU - Palmer, C.N.* AU - Prokopenko, I.* AU - Morris, A.D.* AU - Bergman, R.N.* AU - Collins, F.S.* AU - Lind, L.* AU - Ingelsson, E.* AU - Tuomilehto, J.* AU - Karpe, F.* AU - Groop, L.* AU - Jørgensen, T.* AU - Hansen, T.* AU - Pedersen, O.* AU - Kuusisto, J.* AU - Abecasis, G.* AU - Bell, G.I.* AU - Blangero, J.* AU - Cox, N.J.* AU - Duggirala, R.* AU - Seielstad, M.* AU - Wilson, J.G.* AU - Dupuis, J.* AU - Ripatti, S.* AU - Hanis, C.L.* AU - Florez, J.C* AU - Mohlke, K.L.* AU - Meigs, J.B.* AU - Laakso, M.* AU - Morris, A.P.* AU - Boehnke, M.* AU - Altshuler, D.* AU - McCarthy, M.I.* AU - Gloyn, A.L.* AU - Lindgren, C.M.* C1 - 50801 C2 - 42817 CY - Alexandria SP - 2019-2032 TI - A low-frequency inactivating Akt2 variant enriched in the Finnish population is associated with fasting insulin levels and type 2 diabetes risk. JO - Diabetes VL - 66 IS - 7 PB - Amer Diabetes Assoc PY - 2017 SN - 0012-1797 ER - TY - JOUR AU - Rodriguez-Calvo, T. AU - Atkinson, M.* AU - Von Herrath, M.G.* C1 - 51774 C2 - 43488 CY - Alexandria SP - e10-e11 TI - Response to comment on Rodriguez-Calvo et al. Increase in pancreatic proinsulin and preservation of β-cell mass in autoantibody-positive donors prior to type 1 diabetes onset. diabetes 2017;66:1334-1345. JO - Diabetes VL - 66 IS - 9 PB - Amer Diabetes Assoc PY - 2017 SN - 0012-1797 ER - TY - JOUR AU - Rodriguez-Calvo, T. AU - Atkinson, M.* AU - Von Herrath, M.G.* C1 - 53049 C2 - 44284 SP - e10-e11 TI - Response to comment on Rodriguez-Calvo et al. Increase in pancreatic proinsulin and preservation of β-cell mass in autoantibody-positive donors prior to type 1 diabetes onset. Diabetes 2017;66:1334–1345. JO - Diabetes VL - 66 IS - 9 PY - 2017 SN - 0012-1797 ER - TY - JOUR AU - Scerbo, M.J. AU - Gerdes, J.M. C1 - 50497 C2 - 42382 CY - Alexandria SP - 256-257 TI - Bonding with beta-cells-a role for oxytocin in glucose handling. JO - Diabetes VL - 66 IS - 2 PB - Amer Diabetes Assoc PY - 2017 SN - 0012-1797 ER - TY - JOUR AB - To characterise type 2 diabetes (T2D) associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D cases and 132,532 controls of European ancestry after imputation using the 1000 Genomes multi-ethnic reference panel. Promising association signals were followed-up in additional data sets (of 14,545 or 7,397 T2D cases and 38,994 or 71,604 controls). We identified 13 novel T2D-associated loci (p<5×10(-8)), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common SNVs. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion, and in adipocytes, monocytes and hepatocytes for insulin action-associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology. AU - Scott, R.A.* AU - Scott, L.J.* AU - Mägi, R.* AU - Marullo, L.* AU - Gaulton, K.J.* AU - Kaakinen, M.* AU - Pervjakova, N.* AU - Pers, T.H.* AU - Johnson, A.D.* AU - Eicher, J.D.* AU - Jackson, A.U.* AU - Ferreira, T.* AU - Lee, Y.* AU - Ma, C.* AU - Steinthorsdottir, V.* AU - Thorleifsson, G.* AU - Qi, L.* AU - van Zuydam, N.R.* AU - Mahajan, A.* AU - Chen, H.* AU - Almgren, P.* AU - Voight, B.F.* AU - Grallert, H. AU - Müller-Nurasyid, M. AU - Ried, J.S. AU - Rayner, W.N.* AU - Robertson, N.* AU - Karssen, L.C.* AU - van Leeuwen, E.M.* AU - Willems, S.M.* AU - Fuchsberger, C.* AU - Kwan, P.* AU - Teslovich, T.M.* AU - Chanda, P.* AU - Li, M.* AU - Lu, Y.* AU - Dina, C.* AU - Thuillier, D.* AU - Yengo, L.* AU - Jiang, L.* AU - Sparso, T.* AU - Kestler, H.A.* AU - Chheda, H.* AU - Eisele, L.* AU - Gustafsson, S.* AU - Frånberg, M.* AU - Strawbridge, R.J.* AU - Benediktsson, R.* AU - Hreidarsson, A.B.* AU - Kong, A.* AU - Sigurðsson, G.* AU - Kerrison, N.D.* AU - Luan, J.* AU - Liang, L.* AU - Meitinger, T. AU - Roden, M.* AU - Thorand, B. AU - Esko, T.* AU - Mihailov, E.* AU - Fox, C.* AU - Liu, C.-T.* AU - Rybin, D.* AU - Isomaa, B.* AU - Lyssenko, V.* AU - Tuomi, T.* AU - Couper, D.J.* AU - Pankow, J.S.* AU - Grarup, N.* AU - Have, C.T.* AU - Jørgensen, M.E.* AU - Jørgensen, T.* AU - Linneberg, A.* AU - Cornelis, M.C.* AU - van Dam, R.M.* AU - Hunter, D.J.* AU - Kraft, P.* AU - Sun, Q.* AU - Edkins, S.* AU - Owen, K.R.* AU - Perry, J.R.* AU - Wood, A.R.* AU - Zeggini, E.* AU - Tajes-Fernandes, J.* AU - Abecasis, G.R.* AU - Bonnycastle, L.L.* AU - Chines, P.S.* AU - Stringham, H.M.* AU - Koistinen, H.A.* AU - Kinnunen, L.* AU - Sennblad, B.* AU - Mühleisen, T.W.* AU - Nöthen, M.M.* AU - Pechlivanis, S.* AU - Baldassarre, D.* AU - Gertow, K.* AU - Humphries, S.E.* AU - Tremoli, E.* AU - Klopp, N. AU - Meyer, J. AU - Steinbach, G.* AU - Wennauer, R.* AU - Eriksson, J.G.* AU - Mӓnnistö, S.* AU - Peltonen, L.* AU - Tikkanen, E.* AU - Charpentier, G.* AU - Eury, E.* AU - Lobbens, S.* AU - Gigante, B.* AU - Leander, K.* AU - McLeod, O.* AU - Bottinger, E.P.* AU - Gottesman, O.* AU - Ruderfer, D.* AU - Blüher, M.* AU - Kovacs, P.* AU - Tönjes, A.* AU - Maruthur, N.M.* AU - Scapoli, C.* AU - Erbel, R.* AU - Jöckel, K.H.* AU - Moebus, S.* AU - de Faire, U.* AU - Hamsten, A.* AU - Stumvoll, M.* AU - Deloukas, P.* AU - Donnelly, P.J.* AU - Frayling, T.M.* AU - Hattersley, A.T.* AU - Ripatti, S.* AU - Salomaa, V.* AU - Pedersen, N.L.* AU - Boehm, B.O.* AU - Bergman, R.N.* AU - Collins, F.S.* AU - Mohlke, K.L.* AU - Tuomilehto, J.* AU - Hansen, T.* AU - Pedersen, O.* AU - Barroso, I.* AU - Lannfelt, L.* AU - Ingelsson, E.* AU - Lind, L.* AU - Lindgren, C.M.* AU - Cauchi, S.* AU - Froguel, P.* AU - Loos, R.J.* AU - Balkau, B.* AU - Boeing, H.* AU - Franks, P.W.* AU - Gurrea, A.B.* AU - Palli, D.* AU - van der Schouw, Y.T.* AU - Altshuler, D.* AU - Groop, L.C.* AU - Langenberg, C.* AU - Wareham, N.J.* AU - Sijbrands, E.* AU - van Duijn, C.M.* AU - Florez, J.C* AU - Meigs, J.B.* AU - Boerwinkle, E.* AU - Gieger, C. AU - Strauch, K. AU - Metspalu, A.* AU - Morris, A.D.* AU - Palmer, C.N.* AU - Hu, F.B.* AU - Thorsteinsdottir, U.* AU - Stefansson, K.* AU - Dupuis, J.* AU - Morris, A.P.* AU - Boehnke, M.* AU - McCarthy, M.I.* AU - Prokopenko, I.* C1 - 51233 C2 - 43098 CY - Alexandria SP - 2888-2902 TI - An expanded genome-wide association study of type 2 diabetes in Europeans. JO - Diabetes VL - 66 IS - 11 PB - Amer Diabetes Assoc PY - 2017 SN - 0012-1797 ER - TY - BOOK AU - Tschöp, M.H. AU - DiMarchi, R.* C1 - 51295 C2 - 43146 CY - Alexandria SP - 1766-1769 TI - Single-molecule combinatorial therapeutics for treating obesity and diabetes. JO - Diabetes VL - 66 IS - 7 PB - Amer Diabetes Assoc PY - 2017 SN - 0012-1797 ER - TY - JOUR AB - Insulin receptors (IRs) and IGF-I receptors (IGF-IR) are major regulators of metabolism and cell growth throughout the body; however, their roles in the intestine remain controversial. Here we show that genetic ablation of the IR or IGF-IR in intestinal epithelial cells of mice does not impair intestinal growth or development or the composition of the gut microbiome. However, the loss of IRs alters intestinal epithelial gene expression, especially in pathways related to glucose uptake and metabolism. More importantly, the loss of IRs reduces intestinal glucose uptake. As a result, mice lacking the IR in intestinal epithelium retain normal glucose tolerance during aging compared with controls, which show an age-dependent decline in glucose tolerance. Loss of the IR also results in a reduction of glucose-dependent insulinotropic polypeptide (GIP) expression from enteroendocrine K-cells and decreased GIP release in vivo after glucose ingestion but has no effect on glucagon-like peptide 1 expression or secretion. Thus, the IR in the intestinal epithelium plays important roles in intestinal gene expression, glucose uptake, and GIP production, which may contribute to pathophysiological changes in individuals with diabetes, metabolic syndrome, and other insulin-resistant states. AU - Ussar, S. AU - Haering, M.-F.* AU - Fujisaka, S.* AU - Lutter, D. AU - Lee, K.Y.* AU - Li, N.* AU - Gerber, G.K.* AU - Bry, L.* AU - Kahn, C.R.* C1 - 50806 C2 - 42891 CY - Alexandria SP - 886-896 TI - Regulation of glucose uptake and enteroendocrine function by the intestinal epithelial insulin receptor. JO - Diabetes VL - 66 IS - 4 PB - Amer Diabetes Assoc PY - 2017 SN - 0012-1797 ER - TY - JOUR AB - Glucose is the primary driver of hypothalamic POMC neurons. Here, we show that endothelial HIF-1α controls glucose uptake in the hypothalamus, and, that it is up-regulated in conditions of under-nourishment during which POMC neuronal activity is decreased. Endothelium-specific knockdown of HIF-1α impairs the ability of POMC neurons to adapt to the changing metabolic environment in vivo resulting in overeating of mice after food deprivation. The impaired functioning of POMC neurons was reversed ex vivo or by parenchymal glucose administration. These observations indicate an active role for endothelial cells in the central control of metabolism and suggest that central vascular impairments may cause metabolic disorders. AU - Varela, L.* AU - Suyama, S.* AU - Huang, Y.* AU - Shanabrough, M.* AU - Tschöp, M.H. AU - Gao, X.B.* AU - Giodano, F.J.* AU - Horvath, T.L. C1 - 50717 C2 - 42863 CY - Alexandria SP - 1511-1520 TI - Endothelial HIF-1α enables hypothalamic glucose uptake to drive POMC neurons. JO - Diabetes VL - 66 IS - 6 PB - Amer Diabetes Assoc PY - 2017 SN - 0012-1797 ER - TY - JOUR AB - Glucagon levels are classically suppressed after glucose challenge. It is still not clear as to whether a lack of suppression contributes to hyperglycemia and thus to the development of diabetes. We investigated the association of postchallenge change in glucagon during oral glucose tolerance tests (OGTTs), hypothesizing that higher postchallenge glucagon levels are observed in subjects with impaired glucose tolerance (IGT). Glucagon levels were measured during OGTT in a total of 4,194 individuals without diabetes in three large European cohorts. Longitudinal changes in glucagon suppression were investigated in 50 participants undergoing a lifestyle intervention. Only 66-79% of participants showed suppression of glucagon at 120 min (fold change glucagon(120/0) <1) during OGTT, whereas 21-34% presented with increasing glucagon levels (fold change glucagon(120/0) 1). Participants with nonsuppressed glucagon(120) had a lower risk of IGT in all cohorts (odds ratio 0.44-0.53, P < 0.01). They were also leaner and more insulin sensitive and had lower liver fat contents. In the longitudinal study, an increase of fold change glucagon(120/0) was associated with an improvement in insulin sensitivity (P = 0.003). We characterize nonsuppressed glucagon(120) during the OGTT. Lower glucagon suppression after oral glucose administration is associated with a metabolically healthier phenotype, suggesting that it is not an adverse phenomenon. AU - Wagner, R. AU - Hakaste, L.H.* AU - Ahlqvist, E.* AU - Heni, M. AU - Machann, J. AU - Schick, F.* AU - Van Obberghen, E.* AU - Stefan, N. AU - Gallwitz, B. AU - Tuomi, T.* AU - Häring, H.-U. AU - Groop, L.* AU - Fritsche, A. C1 - 51022 C2 - 42697 CY - Alexandria SP - 1373-1379 TI - Nonsuppressed glucagon after glucose challenge as a potential predictor for glucose tolerance. JO - Diabetes VL - 66 IS - 5 PB - Amer Diabetes Assoc PY - 2017 SN - 0012-1797 ER - TY - JOUR AB - In the article listed above, the last sentence of the abstract was erroneously stated as “Our results suggested an association between long-term exposure to air pollution and IR in the general population was attributable mainly to individuals with diabetes.” The sentence should have read: “Our results suggested an association between long-term exposure to air pollution and IR in the general population that was attributable mainly to individuals with prediabetes.” The editors apologize for this error. The online version has been updated to correct this error. AU - Wolf, K. AU - Popp, A.* AU - Schneider, A.E. AU - Breitner-Busch, S. AU - Hampel, R. AU - Rathmann, W.* AU - Herder, C.* AU - Roden, M.* AU - Koenig, W.* AU - Meisinger, C. AU - Peters, A. C1 - 52038 C2 - 43660 CY - Alexandria SP - 2725-2725 TI - Erratum. Association between long-term exposure to air pollution and biomarkers related to insulin resistance, subclinical inflammation, and adipokines (vol 65, pg 3314, 2016). JO - Diabetes VL - 66 IS - 10 PB - Amer Diabetes Assoc PY - 2017 SN - 0012-1797 ER - TY - JOUR AB - Understanding the physiological mechanisms by which common variants predispose to type 2 diabetes requires large studies with detailed measures of insulin secretion and sensitivity. Here we performed the largest genome-wide association study of first-phase insulin secretion, as measured by intravenous glucose tolerance tests, using up to 5,567 individuals without diabetes from 10 studies. We aimed to refine the mechanisms of 178 known associations between common variants and glycemic traits and identify new loci. Thirty type 2 diabetes or fasting glucose-raising alleles were associated with a measure of first-phase insulin secretion at P < 0.05 and provided new evidence, or the strongest evidence yet, that insulin secretion, intrinsic to the islet cells, is a key mechanism underlying the associations at the HNF1A, IGF2BP2, KCNQ1, HNF1B, VPS13C/C2CD4A, FAF1, PTPRD, AP3S2, KCNK16, MAEA, LPP, WFS1, and TMPRSS6 loci. The fasting glucose-raising allele near PDX1, a known key insulin transcription factor, was strongly associated with lower first-phase insulin secretion but has no evidence for an effect on type 2 diabetes risk. The diabetes risk allele at TCF7L2 was associated with a stronger effect on peak insulin response than on C-peptide-based insulin secretion rate, suggesting a possible additional role in hepatic insulin clearance or insulin processing. In summary, our study provides further insight into the mechanisms by which common genetic variation influences type 2 diabetes risk and glycemic traits. AU - Wood, A.R.* AU - Jonsson, A.* AU - Jackson, A.U.* AU - Wang, N.* AU - van Leewen, N.* AU - Palmer, N.D.* AU - Kobes, S.* AU - Deelen, J.* AU - Boquete-Vilarino, L.* AU - Paananen, J.* AU - Stancáková, A.* AU - Boomsma, D.I.* AU - de Geus, E.J.C.* AU - Eekhoff, E.M.W.* AU - Fritsche, A. AU - Kramer, M.* AU - Nijpels, G.* AU - Simonis-Bik, A.* AU - van Haeften, T.W.* AU - Mahajan, A.* AU - Boehnke, M.* AU - Bergman, R.N.* AU - Tuomilehto, J.* AU - Collins, F.S.* AU - Mohlke, K.L.* AU - Banasik, K.* AU - Groves, C.J.* AU - McCarthy, M.I.* AU - Pearson, E.R.* AU - Natali, A.* AU - Mari, A.* AU - Buchanan, T.A.* AU - Taylor, K.D.* AU - Xiang, A.H.* AU - Gjesing, A.P.* AU - Grarup, N.* AU - Eiberg, H.* AU - Pedersen, O.* AU - Chen, Y.* AU - Laakso, M.* AU - Norris, J.M.* AU - Smith, U.* AU - Wagenknecht, L.E.* AU - Baier, L.J.* AU - Bowden, D.W.* AU - Hansen, T.* AU - Walker, M.* AU - Watanabe, R.M.* AU - 't Hart, L.M.* AU - Hanson, R.L.* AU - Frayling, T.M.* C1 - 51657 C2 - 43371 CY - Alexandria SP - 2296-2309 TI - A genome-wide association study of IVGTT-based measures of first-phase insulin secretion refines the underlying physiology of type 2 diabetes variants. JO - Diabetes VL - 66 IS - 8 PB - Amer Diabetes Assoc PY - 2017 SN - 0012-1797 ER - TY - JOUR AB - Metformin is the first-line oral medication to increase insulin sensitivity in patients with type 2 diabetes (T2D). Our aim is to investigate metformin's pleiotropic effect using a non-targeted metabolomics approach. We analyzed 353 metabolites in fasting serum samples of the population-based human KORA F4 cohort. To compare T2D patients treated with metformin (mt-T2D, n=74) and those without antidiabetic medication (ndt-T2D, n=115), we used multivariable linear regression models in a cross-sectional study. We applied generalized estimating equation to confirm the initial findings in longitudinal samples of 683 KORA participants. In a translational approach, we used murine plasma, liver, skeletal muscle, and epididymal adipose tissue samples from metformin treated-db/db mice to further corroborate our findings from the human study. We identified two metabolites significantly (P<1.42E-04) associated with metformin treatment. Citrulline showed lower values and an unknown metabolite X-21365 showed higher relative concentrations in human serum when comparing mt-T2D with ndt-T2D. Citrulline was confirmed to be significantly (P<2.96E-04) decreased at seven years' follow up in patients who started metformin treatment. In mice, we validated significantly (P<4.52E-07) lower citrulline values in plasma, skeletal muscle, and adipose tissue of metformin treated animals, but not in their liver. The lowered values of citrulline we observed by using a non-targeted approach, most likely result from metformin's pleiotropic effect on the interlocked urea and nitric oxide cycle. The translational data derived from of multiple murine tissues corroborated and complemented the findings from the human cohort. AU - Adam, J. AU - Brandmaier, S. AU - Leonhardt, J. AU - Scheerer, M.F. AU - Mohney, R.P.* AU - Xu, T. AU - Bi, J.* AU - Rotter, M. AU - Troll, M. AU - Chi, S. AU - Heier, M. AU - Herder, C.* AU - Rathmann, W.G.* AU - Giani, G.* AU - Adamski, J. AU - Illig, T.* AU - Strauch, K. AU - Li, Y.* AU - Gieger, C. AU - Peters, A. AU - Suhre, K. AU - Ankerst, D.P.* AU - Meitinger, T. AU - Hrabě de Angelis, M. AU - Roden, M.* AU - Neschen, S. AU - Kastenmüller, G. AU - Wang-Sattler, R. C1 - 49478 C2 - 30100 CY - Alexandria SP - 3776-3785 TI - Metformin effect on non-targeted metabolite profiles in patients with type 2 diabetes and multiple murine tissues. JO - Diabetes VL - 65 IS - 12 PB - Amer Diabetes Assoc PY - 2016 SN - 0012-1797 ER - TY - JOUR AB - A substantial number of people at risk to develop type 2 diabetes could not improve insulin sensitivity by physical training intervention. We studied the mechanisms of this impaired exercise response in 20 middle-aged individuals at high risk to develop type 2 diabetes who performed a controlled eight weeks cycling and walking training at 80 % individual VO2peak. Participants identified as non-responders in insulin sensitivity (based on Matsuda index) did not differ in pre-intervention parameters compared to high responders. The failure to increase insulin sensitivity after training correlates with impaired up-regulation of mitochondrial fuel oxidation genes in skeletal muscle, and with the suppression of the upstream regulators PGC1α and AMPKα2. The muscle transcriptome of the non-responders is further characterized by an activation of TGFβ and TGFβ target genes, which is associated with increases in inflammatory and macrophage markers. TGFβ1 as inhibitor of mitochondrial regulators and insulin signaling is validated in human skeletal muscle cells. Activated TGFβ1 signaling down-regulates the abundance of PGC1α, AMPKα2, mitochondrial transcription factor TFAM, and of mitochondrial enzymes. Thus, the data suggest that increased TGFβ activity in skeletal muscle can attenuate the improvement of mitochondrial fuel oxidation after training and contribute to the failure to increase insulin sensitivity. AU - Böhm, A. AU - Hoffmann, C.* AU - Irmler, M. AU - Schneeweiss, P.* AU - Schnauder, G.* AU - Sailer, C. AU - Schmid, V.* AU - Hudemann, J.* AU - Machann, J.* AU - Schick, F.* AU - Beckers, J. AU - Hrabě de Angelis, M. AU - Staiger, H. AU - Fritsche, A. AU - Stefan, N. AU - Nieß, A.M.* AU - Häring, H.-U. AU - Weigert, C. C1 - 48975 C2 - 41507 CY - Alexandria SP - 2849-2861 TI - TGFβ contributes to impaired exercise response by suppression of mitochondrial key regulators in skeletal muscle. JO - Diabetes VL - 65 IS - 10 PB - Amer Diabetes Assoc PY - 2016 SN - 0012-1797 ER - TY - JOUR AB - Emerging insulin resistance is normally compensated by increased insulin production of pancreatic β-cells, thereby maintaining normoglycemia. However, it is unclear whether this is achieved by adaption of β-cell function, mass, or both. Most importantly it is still unknown which of these adaptive mechanisms fail when type 2 diabetes develops. We performed longitudinal in vivo imaging of β-cell calcium dynamics and islet mass of transplanted islets of Langerhans throughout diet-induced progression from normal glucose homeostasis, over compensation of insulin resistance to pre-diabetes. The results show that compensation of insulin resistance is predominated by alterations of β-cell function, while islet mass only gradually expands. Hereby, functional adaptation is mediated by increased calcium efficacy, which involves Epac signaling. Prior to prediabetes, β-cell function displays decreased stimulated calcium dynamics, whereas islet mass continues to increase through prediabetes onset. Thus, our data reveal a predominant role of islet function with distinct contributions of triggering and amplifying pathway in the in vivo processes preceding diabetes onset. These findings support protection and recovery of β-cell function as primary goal for prevention and treatment of diabetes and provide insight into potential therapeutic targets. AU - Chen, C. AU - Chmelova, H. AU - Cohrs, C.M. AU - Chouinard, J.A. AU - Jahn, S. AU - Stertmann, J. AU - Uphues, I.* AU - Speier, S. C1 - 48641 C2 - 41227 CY - Alexandria SP - 2676-2685 TI - Alterations in β-cell calcium dynamics and efficacy outweigh islet mass adaptation in compensation of insulin resistance and prediabetes onset. JO - Diabetes VL - 65 IS - 9 PB - Amer Diabetes Assoc PY - 2016 SN - 0012-1797 ER - TY - JOUR AB - Central fat accumulation is a strong risk factor for type 2 diabetes. Genome-wide association studies have identified numerous loci associated with body fat distribution. The objectives of the current study are to examine whether genes in genetic loci linked to fat distribution can be linked to fat cell size and number (morphology) and/or adipose tissue function. We show, in a cohort of 114 women, that almost half of the 96 genes in these loci are indeed associated with abdominal subcutaneous adipose tissue parameters. Thus, adipose mRNA expression of the genes is strongly related to adipose morphology, catecholamine-induced lipid mobilization (lipolysis), or insulin-stimulated lipid synthesis in adipocytes (lipogenesis). In conclusion, the genetic influence on body fat distribution could be mediated via several specific alterations in adipose tissue morphology and function, which in turn may influence the development of type 2 diabetes. AU - Dahlman, I.* AU - Rydén, M.* AU - Brodin, D.* AU - Grallert, H. AU - Strawbridge, R.J.* AU - Arner, P.* C1 - 47731 C2 - 39546 CY - Alexandria SP - 433-437 TI - Numerous genes in loci associated with body fat distribution are linked to adipose function. JO - Diabetes VL - 65 IS - 2 PB - Amer Diabetes Assoc PY - 2016 SN - 0012-1797 ER - TY - JOUR AB - Bezafibrate (BEZ), a pan activator of peroxisome proliferator-activated receptors (PPARs), has been generally used to treat hyperlipidemia for decades. Clinical trials with type 2 diabetes patients indicated that BEZ also has beneficial effects on glucose metabolism, although the underlying mechanisms of these effects remain elusive. Even less is known about a potential role for BEZ in treating type 1 diabetes. Here we show that BEZ markedly improves hyperglycemia and glucose and insulin tolerance in streptozotocin (STZ)-treated mice, an insulin-deficient mouse model of type 1 diabetes. BEZ treatment of STZ mice significantly suppressed the hepatic expression of genes that are annotated in inflammatory processes, whereas the expression of PPAR and insulin target gene transcripts was increased. Furthermore, BEZ-treated mice also exhibited improved metabolic flexibility as well as an enhanced mitochondrial mass and function in the liver. Finally, we show that the number of pancreatic islets and the area of insulin positive cells tended to be higher in BEZ-treated mice. Our data suggest that BEZ may improve impaired glucose metabolism by augmenting hepatic mitochondrial performance, suppressing hepatic inflammatory pathways, and improving insulin sensitivity and metabolic flexibility. Thus, BEZ treatment might also be useful for patients with impaired glucose tolerance or diabetes. AU - Frankó, A. AU - Huypens, P. AU - Neschen, S. AU - Irmler, M. AU - Rozman, J. AU - Rathkolb, B. AU - Neff, F. AU - Prehn, C. AU - Dubois, G. AU - Baumann, M. AU - Massinger, R. AU - Gradinger, D. AU - Przemeck, G.K.H. AU - Repp, B. AU - Aichler, M. AU - Feuchtinger, A. AU - Schommers, P.* AU - Stöhr, O.* AU - Sanchez-Lasheras, C.* AU - Adamski, J. AU - Peter, A. AU - Prokisch, H. AU - Beckers, J. AU - Walch, A.K. AU - Fuchs, H. AU - Wolf, E.* AU - Schubert, M.* AU - Wiesner, R.J.* AU - Hrabě de Angelis, M. C1 - 48789 C2 - 41338 CY - Alexandria SP - 2540-2552 TI - Bezafibrate improves insulin sensitivity and metabolic flexibility in STZ-treated diabetic mice. JO - Diabetes VL - 65 IS - 9 PB - Amer Diabetes Assoc PY - 2016 SN - 0012-1797 ER - TY - JOUR AU - García-Cáceres, C. AU - Tschöp, M.H. C1 - 47972 C2 - 39809 CY - Alexandria SP - 551-553 TI - Hypothalamic injury: Fish oil to the rescue! JO - Diabetes VL - 65 IS - 3 PB - Amer Diabetes Assoc PY - 2016 SN - 0012-1797 ER - TY - JOUR AB - In obese individuals the visceral adipose tissue (VAT) becomes seat of chronic low grade inflammation (metaflammation). But the mechanistic link between increased adiposity and metaflammation remains largely unclear. We report here that in obese individuals deregulation of a specific adipokine, chemerin, contributes to innate initiation of metaflammation, by recruiting circulating plasmacytoid dendritic cells (pDCs) into visceral adipose tissue via chemokine-like receptor 1 (CMKLR1). Adipose tissue-derived high mobility group B1 (HMGB1) protein, activates toll-like receptor 9 (TLR9) in the adipose-recruited pDCs by transporting extracellular DNA via receptor for advanced glycation endproducts (RAGE) and induces production of type I interferons. Type I interferons in turn help in proinflammatory polarization of adipose-resident macrophages. Interferon signature gene expression in VAT correlates with both adipose tissue and systemic insulin resistance in obese individuals, represented by ADIPO-IR and HOMA2-IR respectively, and defines two subgroups with different susceptibility to insulin resistance. Thus our study reveals a hitherto unknown pathway that drives adipose tissue inflammation and consequent insulin resistance in obesity. AU - Ghosh, A.R.* AU - Bhattacharya, R.* AU - Bhattacharya, S.* AU - Nargis, T.* AU - Rahaman, O.* AU - Duttagupta, P.* AU - Raychaudhuri, D.* AU - Chen Liu, C.S.* AU - Roy, S.* AU - Ghosh, P.* AU - Khanna, S.* AU - Chaudhuri, T.* AU - Tantia, O.* AU - Haak, S. AU - Bandyopadhyay, S.* AU - Mukhopadhyay, S.* AU - Chakrabarti, P.* AU - Ganguly, D.* C1 - 49330 C2 - 41754 CY - Alexandria SP - 3440-3452 TI - Adipose recruitment and activation of plasmacytoid dendritic cells fuel metaflammation. JO - Diabetes VL - 65 IS - 11 PB - Amer Diabetes Assoc PY - 2016 SN - 0012-1797 ER - TY - JOUR AB - Maternal obesity is a worldwide problem associated with increased risk of metabolic diseases in the offspring. Genetic deletion of the Gastric Inhibitory Polypeptide Receptor (GIPR) prevents high fat diet induced obesity in mice due to specific changes in energy and fat cell metabolism. We investigated whether GIP-associated pathways may be targeted by fetal programming and mimicked the situation by exposing pregnant mice to control or high fat diet (HFD) during pregnancy (IU) and lactation (L). Male wild type (WT) and Gipr(-/-) offspring received control chow until 25 weeks of age followed by 20 weeks of HFD. Gipr(-/-) offspring of mice exposed to HFD during IU/L became insulin resistant, obese, exhibited increased adipose tissue inflammation and decreased peripheral tissue substrate utilization after being re-introduced to HFD similar to WT mice on regular chow during IU/L. They showed decreased hypothalamic insulin sensitivity compared to Gipr(-/-) mice on control diet during IU/L. DNA-methylation analysis revealed increased methylation of CpG-dinucleotides and differential transcription factor binding of promoter regions of genes involved in lipid oxidation in muscle of Gipr(-/-) offspring on HFD during IU/L which were inversely correlated with gene expression levels. Our data identify GIP-regulated metabolic pathways that are targeted by fetal programming. AU - Kruse, M.* AU - Keyhani-Nejad, F.* AU - Isken, F.* AU - Nitz, B. AU - Kretschmer, A. AU - Reischl, E. AU - de Las Heras Gala, T. AU - Osterhoff, M.A.* AU - Grallert, H. AU - Pfeiffer, A.F.* C1 - 47497 C2 - 40604 CY - Alexandria SP - 574-584 TI - A high fat diet during mouse pregnancy and lactation targets GIP-regulated metabolic pathways in adult male offspring. JO - Diabetes VL - 65 IS - 3 PB - Amer Diabetes Assoc PY - 2016 SN - 0012-1797 ER - TY - JOUR AB - Increased growth in early childhood has been suggested to increase the risk of type 1 diabetes. This study explored the relationship between weight, height and development of persistent islet autoimmunity and progression to type 1 diabetes during the first 4 years of life in 7,468 children at genetic risk of type 1 diabetes, followed in Finland, Germany, Sweden and US. Growth data collected every third month were used to estimate individual growth curves using mixed models. Cox proportional hazards models were used to evaluate the body size and risk of islet autoimmunity and T1D. In the overall cohort, development of islet autoimmunity (n=575) was related to weight z-scores at 12 months, (HR 1.16 per 1.14 kg in males or per 1.02 kg in females; 95%CI 1.06-1.27, p<0.001, FDR=0.008), but not at 24 or 36 months. A similar relationship was seen between weight z-scores and development of multiple islet autoantibodies (1 year, HR 1.21 95%CI 1.08-1.35, p=0.001, FDR=0.008; 2 years, HR 1.18 95% CI 1.06-1.32, p=0.004, FDR=0.02). No association was found between weight or height and type 1 diabetes (n=169). In conclusion, greater weight in the first years of life was associated with an increased risk of development of islet autoimmunity. AU - Larsson, H.E.* AU - Vehik, K.* AU - Haller, M.J.* AU - Liu, X.* AU - Akolkar, B.* AU - Hagopian, W.* AU - Krischer, J.* AU - Lernmark, A.* AU - She, J.X.* AU - Simell, O.* AU - Toppari, J.* AU - Ziegler, A.-G. AU - Rewers, M.* 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 - 48161 C2 - 39946 CY - Alexandria SP - 1988-1995 TI - Growth and risk for islet autoimmunity and progression to type 1 diabetes in early childhood: The Environmental Determinants of Diabetes in the Young Study. JO - Diabetes VL - 65 IS - 7 PB - Amer Diabetes Assoc PY - 2016 SN - 0012-1797 ER - TY - JOUR AB - Glucocorticoids (GCs) are important regulators of systemic energy metabolism, while aberrant GC action is linked to metabolic dysfunctions. Yet, the extent to which normal and pathophysiologic energy metabolism depend on the glucocorticoid receptor (GR) in adipocytes remains unclear. Here, we demonstrate that adipocyte GR-deficiency in mice significantly impacts systemic metabolism in different energetic states. Plasma metabolomics and biochemical analyses revealed a marked global effect of GR-deficiency on systemic metabolite abundance and thus, substrate partitioning in fed and fasted states. This correlated with a decreased lipolytic capacity of GR-deficient adipocytes under post-absorptive and fasting conditions, resulting from impaired signal transduction from β-adrenergic receptors to adenylate cyclase. Upon prolonged fasting, the impaired lipolytic response resulted in abnormal substrate utilization and lean mass wasting. Conversely, GR-deficiency attenuated aging-/diet-associated obesity, adipocyte hypertrophy and liver steatosis. Systemic glucose tolerance was improved in obese GR-deficient mice, which was associated with increased insulin signaling in muscle and adipose tissue.We conclude that the GR in adipocytes exerts central, but diverging roles in the regulation of metabolic homeostasis depending on the energetic state: The adipocyte GR is indispensable for the feeding-fasting transition, but also promotes adiposity and associated metabolic disorders in fat-fed and aged mice. AU - Mueller, K.M.* AU - Hartmann, K.* AU - Kaltenecker, D.* AU - Vettorazzi, S.* AU - Bauer, M.* AU - Mauser, L.* AU - Amann, S.* AU - Jall, S. AU - Fischer, K. AU - Esterbauer, H.* AU - Müller, T.D. AU - Tschöp, M.H. AU - Magnes, C.* AU - Haybaeck, J.* AU - Scherer, T.* AU - Bordag, N.* AU - Tuckermann, J.P.* AU - Moriggl, R.* C1 - 49536 C2 - 40769 CY - Alexandria SP - 272-286 TI - Adipocyte glucocorticoid receptor deficiency attenuates aging and HFDinduced obesity, and impairs the feedingfasting transition. JO - Diabetes VL - 66 IS - 2 PB - Amer Diabetes Assoc PY - 2016 SN - 0012-1797 ER - TY - JOUR AB - Elevated concentrations of albumin in the urine, albuminuria, are a hallmark of diabetic kidney disease and associate with increased risk for end-stage renal disease and cardiovascular events. To gain insight into the pathophysiological mechanisms underlying albuminuria, we conducted meta-analyses of genome-wide association studies and independent replication in up to 5,825 individuals of European ancestry with diabetes mellitus and up to 46,061 without diabetes, followed by functional studies. Known associations of variants in CUBN, encoding cubilin, with the urinary albumin-to-creatinine ratio (UACR) were confirmed in the overall sample (p=2.4*10(-10)). Gene-by-diabetes interactions were detected and confirmed for variants in HS6ST1 and near RAB38/CTSC. SNPs at these loci demonstrated a genetic effect on UACR in individuals with but not without diabetes. The change in average UACR per minor allele was 21% for HS6ST1 and 13% for RAB38/CTSC (p=6.3*10(-7) and 5.8*10(-7), respectively). Experiments using streptozotocin-treated diabetic Rab38 knockout and control rats showed higher urinary albumin concentrations and reduced amounts of megalin and cubilin at the proximal tubule cell surface in Rab38 knockout vs. control rats. Relative expression of RAB38 was higher in tubuli of patients with diabetic kidney disease compared to controls. The loci identified here confirm known and highlight novel pathways influencing albuminuria. AU - Teumer, A.* AU - Tin, A.* AU - Sorice, R.* AU - Gorski, M.* AU - Yeo, N.C.* AU - Chu, A.Y.* AU - Li, M.* AU - Li, Y.* AU - Mijatovic, V.* AU - Ko, Y.A.* AU - Taliun, D.* AU - Luciani, A.* AU - Chen, M.H.* AU - Yang, Q.* AU - Foster, M.C.* AU - Olden, M.* AU - Hiraki, L.T.* AU - Tayo, B.O.* AU - Fuchsberger, C.* AU - Dieffenbach, A.K.* AU - Shuldiner, A.R.* AU - Smith, A.V.* AU - Zappa, A.M.* AU - Lupo, A.* AU - Kollerits, B.* AU - Ponte, B.* AU - Stengel, B.* AU - Krämer, B.K.* AU - Paulweber, B.* AU - Mitchell, B.D.* AU - Hayward, C.* AU - Helmer, C.* AU - Meisinger, C. AU - Gieger, C. AU - Shaffer, C.M.* AU - Müller, C.* AU - Langenberg, C.* AU - Ackermann, D.* AU - Siscovick, D.* AU - Boerwinkle, E.E.* AU - Kronenberg, F.* AU - Ehret, G.B.* AU - Homuth, G.* AU - Waeber, G.* AU - Navis, G.* AU - Gambaro, G.* AU - Malerba, G.* AU - Eiriksdottir, G.* AU - Li, G.* AU - Wichmann, H.-E. AU - Grallert, H. AU - Wallaschofski, H.* AU - Völzke, H.* AU - Brenner, H.* AU - Kramer, H.* AU - Leach, I.M.* AU - Rudan, I.* AU - Hillege, J.L.* AU - Beckmann, J.S.* AU - Lambert, J.C.* AU - Luan, J.* AU - Zhao, J.H.* AU - Chalmers, J.* AU - Coresh, J.* AU - Denny, J.C.* AU - Butterbach, K.* AU - Launer, L.J.* AU - Ferrucci, L.* AU - Kedenko, L.* AU - Haun, M.* AU - Metzger, M.* AU - Woodward, M.* AU - Hoffman, M.J.* AU - Nauck, M.* AU - Waldenberger, M. AU - Pruijm, M.* AU - Bochud, M.* AU - Rheinberger, M.* AU - Verweij, N.* AU - Wareham, N.J.* AU - Endlich, N.* AU - Soranzo, N.* AU - Polasek, O.* AU - van der Harst, P.* AU - Pramstaller, P.P.* AU - Vollenweider, P.* AU - Wild, P.S.* AU - Gansevoort, R.T.* AU - Rettig, R.* AU - Biffar, R.* AU - Carroll, R.J.* AU - Katz, R.* AU - Loos, R.J.* AU - Hwang, S.J.* AU - Coassin, S.* AU - Bergmann, S.* AU - Rosas, S.E.* AU - Stracke, S.* AU - Harris, T.B.* AU - Corre, T.* AU - Zeller, T.* AU - Illig, T. AU - Aspelund, T.* AU - Tanaka, T.* AU - Lendeckel, U.* AU - Völker, U.* AU - Gudnason, V.* AU - Chouraki, V.* AU - Koenig, W.* AU - Kutalik, Z.* AU - O'Connell, J.R.* AU - Parsa, A.* AU - Heid, I.M. AU - Paterson, A.D.* AU - de Boer, I.H.* AU - Devuyst, O.* AU - Lazar, J.* AU - Endlich, K.* AU - Susztak, K.* AU - Tremblay, J.* AU - Hamet, P.* AU - Jacob, H.J.* AU - Böger, C.A.* AU - Fox, C.S.* AU - Pattaro, C.* AU - Köttgen, A.* C1 - 47498 C2 - 40608 CY - Alexandria SP - 803-817 TI - Genome-wide association studies identify genetic loci associated with albuminuria in diabetes. JO - Diabetes VL - 65 IS - 3 PB - Amer Diabetes Assoc PY - 2016 SN - 0012-1797 ER - TY - JOUR AB - Genome-wide association studies (GWAS) have found few common variants that influence fasting measures of insulin sensitivity. We hypothesized that a GWAS of an integrated assessment of fasting and dynamic measures of insulin sensitivity would detect novel common variants. We performed GWAS of the modified Stumvoll Insulin Sensitivity Index (ISI) within the Meta-Analyses of Glucose and Insulin-related traits Consortium. Discovery was performed in 16,753 individuals, and replication was attempted for the 23 most significant novel loci in 13,354 independent individuals. Association with ISI was tested in models adjusted for age, sex, body mass index (BMI) and in a model ("Model 3") analyzing the combined influence of the genotype effect adjusted for BMI and the interaction effect between the genotype and BMI on ISI. In Model 3, three variants reached genome-wide significance: rs13422522 (NYAP2, P=8.87 ×10(-11)), rs12454712 (BCL2, P=2.7×10(-8)) and rs10506418 (FAM19A2, P=1.9×10(-8)). The association at NYAP2 was eliminated by conditioning on the known IRS1 insulin sensitivity locus; the BCL2 and FAM19A2 associations were independent of known cardio-metabolic loci. In conclusion, we identified two novel loci and replicated known variants associated with insulin sensitivity. Further studies are needed to clarify the causal variant and function at the BCL2 and FAM19A2 loci. AU - Walford, G.A.* AU - Gustafsson, S.* AU - Rybin, D.* AU - Stancáková, A.* AU - Chen, H.* AU - Liu, C.-T.* AU - Hong, J.* AU - Jensen, R.A.* AU - Rice, K.* AU - Morris, A.P.* AU - Mägi, R.* AU - Tönjes, A.* AU - Prokopenko, I.* AU - Kleber, M.E.* AU - Delgado, G.* AU - Silbernagel, G.* AU - Jackson, A.U.* AU - Appel, E.V.* AU - Grarup, N.* AU - Lewis, J.P.* AU - Montasser, M.E.* AU - Landenvall, C.* AU - Staiger, H. AU - Luan, J.* AU - Frayling, T.M.* AU - Weedon, M.N.* AU - Xie, W.* AU - Morcillo, S.* AU - Martinez-Larrad, M.T.* AU - Biggs, M.L.* AU - Chen, Y.D.I.* AU - Corbatón-Anchuelo, A.* AU - Færch, K.* AU - Zumaquero, J.M.* AU - Goodarzi, M.O.* AU - Kizer, J.R.* AU - Koistinen, H.A.* AU - Leong, A.* AU - Lind, L.* AU - Lindgren, C.* AU - Machicao, F. AU - Manning, A.K.* AU - Martín-Núñez, G.M.* AU - Rojo-Martínez, G.* AU - Rotter, J.I.* AU - Siscovick, D.S.* AU - Zmuda, J.M.* AU - Zhang, Z.* AU - Serrano-Rios, M.* AU - Smith, U.* AU - Soriguer, F.* AU - Hansen, T.* AU - Jørgensen, T.J.* AU - Linnenberg, A.* AU - Pedersen, O.* AU - Walker, M.* AU - Langenberg, C.* AU - Scott, R.A.* AU - Wareham, N.J.* AU - Fritsche, A. AU - Häring, H.-U. AU - Stefan, N. AU - Groop, L.* AU - O'Connell, J.R.* AU - Boehnke, M.* AU - Bergman, R.N.* AU - Collins, F.S.* AU - Mohlke, K.L.* AU - Tuomilehto, J.* AU - Marz, W.* AU - Kovacs, P.* AU - Stumvoll, M.* AU - Psaty, B.M.* AU - Kuusisto, J.* AU - Laakso, M.* AU - Meigs, J.B.* AU - Dupuis, J.* AU - Ingelsson, E.* AU - Florez, J.C* C1 - 49096 C2 - 41640 CY - Alexandria SP - 3200-3211 TI - Genome-wide association study of the modified Stumvoll Insulin Sensitivity Index identifies BCL2 and FAM19A2 as novel insulin sensitivity loci. JO - Diabetes VL - 65 IS - 10 PB - Amer Diabetes Assoc PY - 2016 SN - 0012-1797 ER - TY - JOUR AB - Insulin resistance (IR) is present long before the onset of type 2 diabetes and results not only from inherited and lifestyle factors but likely also from environmental conditions. We investigated the association between modelled long-term exposure to air pollution at residence and biomarkers related to IR, subclinical inflammation and adipokines.Data was based on 2,944 participants of the KORA (Cooperative Health Research in the Region Augsburg) F4 study conducted in southern Germany (2006-2008). We analysed associations between individual air pollution concentration estimated by land use regression and HOMA-IR, glucose, insulin, HbA1c, leptin, and hs-CRP from fasting samples using multivariable linear regression models. Effect estimates were calculated for the whole study population and subgroups of non-diabetic, pre-diabetic and diabetic individuals.Among all participants, a 7.9μg/m(3) increment in particulate matter <10μm was associated with higher HOMA-IR (15.6% [95%-CI: 4.0;28.6]) and insulin (14.5% [3.6;26.5]).Nitrogen dioxide was associated with HOMA-IR, glucose, insulin, and leptin. Effect estimates for pre-diabetic individuals were much larger and highly statistically significant, while non-diabetic and diabetic individuals showed rather weak associations. No association was seen for HbA1cOur results suggested an association between long-term exposure to air pollution and IR in the general population mainly attributable to pre-diabetic individuals. AU - Wolf, K. AU - Popp, A.* AU - Schneider, A.E. AU - Breitner-Busch, S. AU - Hampel, R. AU - Rathmann, W.G.* AU - Herder, C.* AU - Roden, M.* AU - Koenig, W.* AU - Meisinger, C. AU - Peters, A. AU - KORA Study Group (Heinrich, J. AU - Holle, R. AU - Leidl, R. AU - Meisinger, C. AU - Strauch, K.) C1 - 49452 C2 - 30429 CY - Alexandria SP - 3314-3326 TI - Association between long-term exposure to air pollution and biomarkers related to insulin resistance, subclinical inflammation and adipokines. JO - Diabetes VL - 65 IS - 11 PB - Amer Diabetes Assoc PY - 2016 SN - 0012-1797 ER - TY - JOUR AB - Type 1 diabetes, a disease defined by absolute insulin deficiency, is considered a chronic autoimmune disorder resulting from the destruction of insulin-producing pancreatic b-cells. The incidence of childhood-onset type 1 diabetes has been increasing at a rate of 3%-5% per year globally. Despite the introduction of an impressive array of therapies aimed at improving disease management, no means for a practical cure exist. This said, hope remains high that any of a number of emerging technologies (e.g., continuous glucose monitoring, insulin pumps, smart algorithms), alongside advances in stem cell biology, cell encapsulation methodologies, and immunotherapy, will eventually impact the lives of those with recently diagnosed or established type 1 diabetes. However, efforts aimed at reversing insulin dependence do not address the obvious benefits of disease prevention. Hence, key stretch goals for type 1 diabetes research include identifying improved and increasingly practical means for diagnosing the disease at earlier stages in its natural history (i.e., early, presymptomatic diagnosis), undertaking such efforts in the population at large to optimally identify those with presymptomatic type 1 diabetes, and introducing safe and effective therapeutic options for prevention. AU - Ziegler, A.-G. AU - Bonifacio, E.* AU - Powers, A.C.* AU - Todd, J.A.* AU - Harrison, L.C.* AU - Atkinson, M.A.* C1 - 49946 C2 - 41923 CY - Alexandria SP - 3233-3239 TI - Type 1 diabetes prevention: A goal dependent on accepting a diagnosis of an asymptomatic disease. JO - Diabetes VL - 65 IS - 11 PB - Amer Diabetes Assoc PY - 2016 SN - 0012-1797 ER - TY - JOUR AB - Cure of type 1 diabetes (T1D) by immune intervention at disease onset depends on the restoration of insulin secretion by endogenous beta cells. However, little is known about the potential of beta cell mass and function to recover after autoimmune attack ablation. Utilizing a longitudinal in vivo imaging approach we here show how functional status and mass of beta cells adapt in response to onset and remission of T1D. We demonstrate that infiltration reduces beta cell mass prior to diabetes and, together with emerging hyperglycemia, affects beta cell function. After immune intervention persisting hyperglycemia prevents functional recovery, but promotes beta cell mass increase in mouse islets. When blood glucose levels return to normoglycemia beta cell mass expansion stops and subsequently glucose tolerance recovers in combination with beta cell function. Similar to mouse, human islets exhibit cell exhaustion and recovery in response to transient hyperglycemia. However, the effect of hyperglycemia on human islet mass increase is minor and transient. Our data demonstrate a major role of functional exhaustion and recovery of beta cells during diabetes onset and remission. Therefore, these findings support early intervention therapy of diabetes. AU - Chmelova, H. AU - Cohrs, C.M. AU - Chouinard, J.A. AU - Petzold, C.* AU - Kuhn, M.* AU - Chen, C. AU - Roeder, I.* AU - Kretschmer, K. AU - Speier, S. C1 - 44063 C2 - 39303 CY - Alexandria SP - 2148-2160 TI - Distinct roles of β-cell mass and function during type 1 diabetes onset and remission. JO - Diabetes VL - 64 IS - 6 PB - Amer Diabetes Assoc PY - 2015 SN - 0012-1797 ER - TY - JOUR AB - Observational studies have reported different effects of adiposity on cardiovascular risk factors across age and sex. Since cardiovascular risk factors are enriched in obese individuals, it has not been easy to dissect the effects of adiposity from those of other risk factors. We used a Mendelian randomization approach, applying a set of 32 genetic markers to estimate the causal effect of adiposity on blood pressure, glycemic indices, circulating lipid levels, and markers of inflammation and liver disease in up to 67,553 individuals. All analyses were stratified by age (cutoff 55 years of age) and sex. The genetic score was associated with BMI in both nonstratified analysis (P = 2.8 × 10(-107)) and stratified analyses (all P < 3.3 × 10(-30)). We found evidence of a causal effect of adiposity on blood pressure, and fasting levels of insulin, C-reactive protein, interleukin-6, HDL cholesterol, and triglycerides in a nonstratified analysis and in the <55-year stratum. Further, we found evidence of a smaller causal effect on total cholesterol (P for difference = 0.015) in the ≥55-year stratum than in the <55-year stratum, a finding that could be explained by biology, survival bias, or differential medication. In conclusion, this study extends previous knowledge of the effects of adiposity by providing sex- and age-specific causal estimates on cardiovascular risk factors. AU - Fall, T.* AU - Hägg, S.* AU - Ploner, A.* AU - Mägi, R.* AU - Fischer, K.* AU - Draisma, H.H.* AU - Sarin, A.P.* AU - Benyamin, B.* AU - Ladenvall, C.* AU - Åkerlund, M.* AU - Kals, M.* AU - Esko, T.* AU - Nelson, C.P.* AU - Kaakinen, M.* AU - Huikari, V.* AU - Mangino, M.* AU - Meirhaeghe, A.* AU - Kristiansson, K.* AU - Nuotio, M.L.* AU - Kobl, M. AU - Grallert, H. AU - Dehghan, A.* AU - Kuningas, M.* AU - de Vries, P.S.* AU - de Bruijn, R.F.* AU - Willems, S.M.* AU - Heikkilä, K.* AU - Silventoinen, K.* AU - Pietiläinen, K.H.* AU - Legry, V.* AU - Giedraitis, V.* AU - Goumidi, L.* AU - Syvanen, A.C.* AU - Strauch, K. AU - Koenig, W.* AU - Lichtner, P. AU - Herder, C.* AU - Palotie, A.* AU - Menni, C.* AU - Uitterlinden, A.G.* AU - Kuulasmaa, K.* AU - Havulinna, A.S.* AU - Moreno, L.A.* AU - Gonzalez-Gross, M.* AU - Evans, A.* AU - Tregouet, D.A.* AU - Yarnell, J.W.* AU - Virtamo, J.* AU - Ferrieres, J.* AU - Veronesi, G.* AU - Perola, M.* AU - Arveiler, D.* AU - Brambilla, P.* AU - Lind, L.* AU - Kaprio, J.* AU - Hofman, A.* AU - Stricker, B.H.* AU - van Duijn, C.M.* AU - Ikram, M.A.* AU - Franco, O.H.* AU - Cottel, D.* AU - Dallongeville, J.* AU - Hall, A.S.* AU - Jula, A.* AU - Tobin, M.D.* AU - Penninx, B.W.* AU - Peters, A. AU - Gieger, C. AU - Samani, N.J.* AU - Montgomery, G.W.* AU - Whitfield, J.B.* AU - Martin, N.G.* AU - Groop, L.* AU - Spector, T.D.* AU - Magnusson, P.K.* AU - Amouyel, P.* AU - Boomsma, D.I.* AU - Nilsson, P.M.* AU - Jarvelin, M.R.* AU - Lyssenko, V.* AU - Metspalu, A.* AU - Strachan, D.P.* AU - Salomaa, V.* AU - Ripatti, S.* AU - Pedersen, N.L.* AU - Prokopenko, I.* AU - McCarthy, M.I.* AU - Ingelsson, E.* C1 - 43512 C2 - 36656 CY - Alexandria SP - 1841-1852 TI - Age- and sex-specific causal effects of adiposity on cardiovascular risk factors. JO - Diabetes VL - 64 IS - 5 PB - Amer Diabetes Assoc PY - 2015 SN - 0012-1797 ER - TY - JOUR AB - Studies in rodents suggest that insulin controls hepatic glucose metabolism through brain-liver crosstalk, but human studies using intranasal insulin to mimic central insulin delivery provided conflicting results. In this randomized controlled cross-over trial we investigated effects of intranasal insulin on hepatic insulin sensitivity and energy metabolism in 10 patients with type 2 diabetes and 10 lean healthy participants (CON). Endogenous glucose production (EGP) was monitored with [6,6-(2)H2]glucose, hepatocellular lipids (HCL), adenosine triphosphate (ATP) and inorganic phosphate concentrations with (31)P/(1)H magnetic resonance spectroscopy. Intranasal insulin transiently increased serum insulin, followed by gradual lowering of blood glucose in CON only. Fasting hepatic insulin sensitivity index (HIS) was not affected by intranasal insulin in CON and patients. Only in CON, HCL decreased by 35%, whereas absolute hepatic ATP concentrations increased by 18% after three hours. A subgroup of CON received intravenous insulin to mimic the changes in serum insulin and blood glucose levels observed after intranasal insulin. This resulted in a 34% increase in HCL, without altering hepatic ATP concentrations. In conclusion, intranasal insulin does not affect HIS but rapidly improves hepatic energy metabolism in healthy humans, which is independent of peripheral insulinemia. These effects are blunted in patients with type 2 diabetes. AU - Gancheva, S.* AU - Koliaki, C.* AU - Bierwagen, A.* AU - Nowotny, P.* AU - Heni, M. AU - Fritsche, A. AU - Häring, H.-U. AU - Szendrödi, J.* AU - Roden, M.* C1 - 43088 C2 - 36067 CY - Alexandria SP - 1966-1975 TI - Effects of intranasal insulin on hepatic fat accumulation and energy metabolism in humans. JO - Diabetes VL - 64 IS - 6 PB - Amer Diabetes Assoc PY - 2015 SN - 0012-1797 ER - TY - JOUR AU - Heni, M. AU - Wagner, R.* AU - Kullmann, S. AU - Preissl, H. AU - Fritsche, A. C1 - 44912 C2 - 37139 SP - e8-e9 TI - Response to comment on Heni et al. Central insulin administration improves whole-body insulin sensitivity via hypothalamus and parasympathetic outputs in men. JO - Diabetes VL - 64 IS - 6 PY - 2015 SN - 0012-1797 ER - TY - JOUR AB - Combined use of metformin and a sodium glucose cotransporter 2 inhibitor (SGLT2I) is a promising treatment strategy for type 2 diabetes. The mechanism by which combination treatment provides better glycemic control than metformin or SGLT2I monotherapy remains elusive. Therefore, we investigated the physiological mechanism, by which both compounds lower blood glucose concentrations in diabetic mice. We compared the potential of metformin and the SGLT2I AVE2268 alone or in combination to mitigate hyperglycemia and modulate glucose fluxes in diabetic db/db and Tallyho/JngJ mice. SGLT2I treatment alone elicited a rapid decline in circulating blood glucose levels, which appeared to induce endogenous glucose production. Supplementation of metformin dampened this counter-response and, therefore, combination therapy more efficiently maintained glycemic control. Finally, combination treatment blunted postprandial glucose excursions and improved HbA1c levels within two weeks. Taken together, we conclude that co-application of metformin enhances the glucose-lowering actions of SGLT2I by restraining endogenous glucose production what may provide long-term improvement of glycemic control in type 2 diabetic patients. AU - Neschen, S. AU - Scheerer, M. AU - Seelig, A. AU - Huypens, P. AU - Schultheiss, J. AU - Wu, M. AU - Wurst, W. AU - Rathkolb, B. AU - Suhre, K. AU - Wolf, E.* AU - Beckers, J. AU - Hrabě de Angelis, M. C1 - 31831 C2 - 34790 SP - 284-290 TI - Metformin supports the antidiabetic effect of a sodium glucose cotransporter 2 inhibitor by suppressing endogenous glucose production in diabetic mice. JO - Diabetes VL - 64 IS - 1 PY - 2015 SN - 0012-1797 ER - TY - JOUR AB - Experiments in rodents suggest that hypothalamic insulin signaling essentially contributes to the acute control of peripheral glucose homeostasis. Against this background, we investigated in healthy humans whether intranasal (IN) insulin, which is known to effectively reach the brain compartment, impacts systemic glucose metabolism. Twenty overnight-fasted healthy, normal-weight men were IN administered 210 and 420 IU (10 and 20 IU every 15 min) of the insulin analogue aspart (ins-asp) and placebo, respectively, during experimental sessions lasting 6 h. The use of ins-asp rather than human insulin enabled us to disentangle exogenous and endogenous insulin kinetics. IN insulin dose-dependently decreased plasma glucose concentrations while reducing C-peptide and attenuating endogenous insulin levels. However, we also observed a slight dose-dependent permeation of ins-asp into the circulation. In control experiments mimicking the systemic but not the central nervous uptake of the IN 210 IU dose via IV infusion of ins-asp at a dose of 0.12 mIU/kg/24h (n=10), we obtained essentially identical effects on fasting plasma glucose concentrations. This pattern indicates that sustained IN insulin administration to the human brain to enhance central nervous insulin signaling does not acutely alter systemic glucose homeostasis beyond effects accounted for by concurrent mild hyperinsulinemia. AU - Ott, V.* AU - Lehnert, H.* AU - Staub, J.* AU - Wönne, K.* AU - Born, J. AU - Hallschmid, M. C1 - 32434 C2 - 35068 CY - Alexandria SP - 760-765 TI - Central nervous insulin administration does not potentiate the acute glucoregulatory impact of concurrent mild hyperinsulinemia. JO - Diabetes VL - 64 IS - 3 PB - Amer Diabetes Assoc PY - 2015 SN - 0012-1797 ER - TY - JOUR AB - We investigated the genetic overlap between Alzheimer’s disease (AD) and Parkinson’s disease (PD). Using summary statistics (P-values) from large recent genome-wide association studies (GWAS) (total n=89 904 individuals), we sought to identify single nucleotide polymorphisms (SNPs) associating with both AD and PD. We found and replicated association of both AD and PD with the A allele of rs393152 within the extended MAPT region on chromosome 17 (meta analysis P-value across five independent AD cohorts=1.65 × 10−7). In independent datasets, we found a dose-dependent effect of the A allele of rs393152 on intra-cerebral MAPT transcript levels and volume loss within the entorhinal cortex and hippocampus. Our findings identify the tau-associated MAPT locus as a site of genetic overlap between AD and PD, and extending prior work, we show that the MAPT region increases risk of Alzheimer’s neurodegeneration. AU - Papandonatos, G.D.* AU - Pan, Q.* AU - Pajewski, N.M.* AU - Delahanty, L.M.* AU - Peter, I.* AU - Erar, B.* AU - Ahmad, S.* AU - Harden, M.* AU - Chen, L.* AU - Fontanillas, P.* AU - GIANT Consortium (Albrecht, E. AU - Gieger, C. AU - Grallert, H. AU - Heid, I.M. AU - Illig, T. AU - Müller-Nurasyid, M. AU - Peters, A. AU - Thorand, B. AU - Wichmann, H.-E.) AU - Wagenknecht, L.E.* AU - Kahn, S.E.* AU - Wing, R.R.* AU - Jablonski, K.A.* AU - Huggins, G.S.* AU - Knowler, W.C.* AU - Florez, J.C* AU - McCaffery, J.M.* AU - Franks, P.W.* AU - Diabetes Prevention Program (*) AU - Look AHEAD Research Group (*) C1 - 47581 C2 - 39382 SP - 4312-4321 TI - Genetic predisposition to weight loss and regain with lifestyle intervention: Analyses from the Diabetes Prevention Program and the Look AHEAD randomized controlled trials. JO - Diabetes VL - 64 IS - 12 PY - 2015 SN - 0012-1797 ER - TY - JOUR AB - The FTO gene harbors variation with the strongest effect on adiposity and obesity risk. Previous data support a role for FTO variation in influencing food intake. We conducted a combined analysis of 16,094 boys and girls aged 1-18 years from 14 studies to examine: 1) the association between the FTO rs9939609 variant (or a proxy) and total energy and macronutrient intake; and 2) the interaction between the FTO variant and dietary intake on BMI. We found that the BMI-increasing allele (minor allele) of FTO variant was associated with increased total energy intake (effect per allele=14.3[5.9, 22.7] kcal/day, P=6.5×10(-4)) but not with protein, carbohydrate or fat intake. We also found that protein intake modified the association between the FTO variant and BMI (interactive effect per allele=0.08[0.03, 0.12]SDs, P for interaction=7.2×10(-4)): the association between FTO genotype and BMI was much stronger in individuals with high protein intake (effect per allele=0.10[0.07, 0.13]SDs, P=8.2×10(-10)) than in those with low intake (effect per allele=0.04[0.01, 0.07]SDs, P=0.02). Our results suggest that the FTO variant that confers a predisposition to higher BMI is associated with higher total energy intake and that lower dietary protein intake attenuates the association between FTO genotype and adiposity in children and adolescents. AU - Qi, Q.* AU - Downer, M.K.* AU - Kilpeläinen, T.O.* AU - Taal, H.R.* AU - Barton, S.J.* AU - Ntalla, I.* AU - Standl, M. AU - Boraska, V.* AU - Huikari, V.* AU - Kiefte-de Jong, J.C.* AU - Körner, A.* AU - Lakka, T.A.* AU - Liu, G.* AU - Magnusson, J.* AU - Okuda, M.* AU - Raitakari, O.* AU - Richmond, R.* AU - Scott, R.A.* AU - Bailey, M.E.* AU - Scheuermann, K.* AU - Holloway, J.W.* AU - Inskip, H.M.* AU - Isasi, C.R.* AU - Mossavar-Rahmani, Y.* AU - Jaddoe, V.W.* AU - Laitinen, J.* AU - Lindi, V.* AU - Melén, E.* AU - Pitsiladis, Y.* AU - Pitkänen, N.* AU - Snieder, H.* AU - Heinrich, J. AU - Timpson, N.J.* AU - Wang, T.* AU - Yuji, H.* AU - Zeggini, E.* AU - Dedoussis, G.V.* AU - Kaplan, R.C.* AU - Wylie-Rosett, J.* AU - Loos, R.J.* AU - Hu, F.B.* AU - Qi, L.* C1 - 43520 C2 - 36652 CY - Alexandria SP - 2467-2476 TI - Dietary intake, FTO genetic variants and adiposity: A combined analysis of over 16,000 children and adolescents. JO - Diabetes VL - 64 IS - 7 PB - Amer Diabetes Assoc PY - 2015 SN - 0012-1797 ER - TY - JOUR AB - Genome-wide association studies (GWAS) have uncovered >65 common variants associated with type 2 diabetes (T2D); however, their relevance for drug development is not yet clear. Of note, the first two T2D-associated loci (PPARG and KCNJ11/ABCC8) encode known targets of antidiabetes medications. We therefore tested whether other genes/pathways targeted by antidiabetes drugs are associated with T2D. We compiled a list of 102 genes in pathways targeted by marketed antidiabetic medications and applied Gene Set Enrichment Analysis (MAGENTA [Meta-Analysis Gene-set Enrichment of variaNT Associations]) to this gene set, using available GWAS meta-analyses for T2D and seven quantitative glycemic traits. We detected a strong enrichment of drug target genes associated with T2D (P = 2 × 10(-5); 14 potential new associations), primarily driven by insulin and thiazolidinedione (TZD) targets, which was replicated in an independent meta-analysis (Metabochip). The glycemic traits yielded no enrichment. The T2D enrichment signal was largely due to multiple genes of modest effects (P = 4 × 10(-4), after removing known loci), highlighting new associations for follow-up (ACSL1, NFKB1, SLC2A2, incretin targets). Furthermore, we found that TZD targets were enriched for LDL cholesterol associations, illustrating the utility of this approach in identifying potential side effects. These results highlight the potential biomedical relevance of genes revealed by GWAS and may provide new avenues for tailored therapy and T2D treatment design. AU - Segrè, A.V.* AU - Wei, N.* AU - DIAGRAM Consortium (Florez, J.C* AU - Klopp, N. AU - Illig, T. AU - Müller-Nurasyid, M. AU - Peters, A.) C1 - 44376 C2 - 36805 CY - Alexandria SP - 1470-1483 TI - Pathways targeted by antidiabetes drugs are enriched for multiple genes associated with type 2 diabetes risk. JO - Diabetes VL - 64 IS - 4 PB - Amer Diabetes Assoc PY - 2015 SN - 0012-1797 ER - TY - JOUR AB - Notch pathway activation in podocytes has been shown to play an important role in diabetic kidney disease (DKD) development, however, the receptors and ligands involved in the process have not been identified. Here we report that conditional deletion of Notch1 in podocytes using NPHS2(cre)Notch1(flox/flox) animals resulted in marked amelioration of diabetic kidney disease. On the contrary, podocyte-specific genetic deletion of Notch2 had no effect on albuminuria and mesangial expansion. Notch1-null podocytes were protected from apoptosis and dedifferentiation in vitro, likely explaining the protective phenotype in vivo. Deletion of Notch1 in podocytes also resulted in an increase in Notch2 expression, indicating an interaction between the receptors. At the same time, transgenic overexpression of Notch2 in podocytes did not induce phenotypic changes, while constitutive expression of Notch1 caused rapid development of albuminuria and glomerulosclerosis. In summary, our studies indicate that Notch1 plays a distinct (non-redundant) role in podocytes during diabetic kidney disease development. AU - Sweetwyne, M.T.* AU - Gruenwald, A.* AU - Niranjan, T.* AU - Nishinakamura, R.* AU - Strobl, L.J. AU - Susztak, K.* C1 - 46613 C2 - 37661 SP - 4099-4111 TI - Notch1 and Notch2 in podocytes play differential roles during diabetic nephropathy development. JO - Diabetes VL - 64 IS - 12 PY - 2015 SN - 0012-1797 ER - TY - JOUR AB - The Environmental Determinants of Diabetes in the Young (TEDDY) study prospectively follows 8,677 children enrolled from birth, who carry HLA-susceptibility genotypes for development of islet autoantibodies (IA) and type 1 diabetes (T1D). During the median follow-up time of 57 months, 350 children developed at least one persistent IA (GADA, IA-2A or mIAA) and 84 of them progressed to T1D. We genotyped 5,164 Caucasian children for 41 non-HLA SNPs that achieved genome-wide significance for association with T1D in the GWAS meta-analysis conducted by the Type 1 Diabetes Genetics Consortium. In TEDDY-participants carrying high-risk HLA-genotypes, eight SNPs achieved significant association to development of IA using time-to-event analysis (p<0.05), whereof four were significant after adjustment for multiple testing (p<0.0012): rs2476601 in PTPN22 (hazard ratio [HR] 1.54 [95% CI 1.27-1.88]), rs2292239 in ERBB3 (HR 1.33 [95% CI 1.14-1.55]), rs3184504 in SH2B3 (HR 1.38 [95% CI 1.19-1.61]) and rs1004446 in INS (HR 0.77 [0.66-0.90]). These SNPs were also significantly associated with T1D in particular: rs2476601 (HR 2.42 [95% CI 1.70-3.44]). Although genes in the HLA-region remain the most important genetic risk factors for T1D, other non-HLA genetic factors contribute to IA, a first step in the pathogenesis of T1D, and the progression of the disease. AU - Törn, C.* AU - Hadley, D.* AU - Lee, H.S.* AU - Hagopian, W.* AU - Lernmark, A.* AU - Simell, O.* AU - Rewers, M.* AU - Ziegler, A.-G. AU - Schatz, D.* AU - Akolkar, B.* AU - Onengut-Gumuscu, S.* AU - Chen, W.M.* AU - Toppari, J.* AU - Mykkänen, J.* AU - Ilonen, J.* AU - Rich, S.S.* AU - She, J.X.* AU - Steck, A.K.* AU - Krischer, J.* AU - TEDDY Study Group (Beyerlein, A. AU - Bonifacio, E. AU - Hummel, M. AU - Hummel, S. AU - Foterek, K. AU - Kersting, M. AU - Knopff, A. AU - Koletzko, S. AU - Peplow, C. AU - Roth, R. AU - Stock, J. AU - Strauss, E. AU - Warncke, K. AU - Winkler, C.) C1 - 43131 C2 - 36012 CY - Alexandria SP - 1818-1829 TI - Role of Type 1 diabetes associated SNPs on risk of autoantibody positivity in the TEDDY study. JO - Diabetes VL - 64 IS - 5 PB - Amer Diabetes Assoc PY - 2015 SN - 0012-1797 ER - TY - JOUR AB - Ghrelin, the natural ligand of the growth hormone secretagogue receptor (GHS-R1a), is mainly secreted from the stomach and regulates food intake and energy homeostasis. p27 regulates cell cycle progression in many cell types. Here, we report that rats affected by the multiple endocrine neoplasia syndrome MENX, caused by a p27 mutation, develop pancreatic islet hyperplasia containing elevated numbers of ghrelin-producing epsilon cells. The metabolic phenotype of MENX-affected rats featured high endogenous acylated and unacylated plasma ghrelin levels. Supporting increased ghrelin action, MENX rats show increased food intake, enhanced body fat mass, and elevated plasma levels of triglycerides and cholesterol. Ghrelin effect on food intake was confirmed by treating MENX rats with a GHS-R1a antagonist. At 7,5 months, MENX-affected rats show decreased mRNA levels of hypothalamic GHS-R1a, neuropeptide Y (NPY), and agouti-related protein (AgRP), suggesting that prolonged hyperghrelinemia may lead to decreased ghrelin efficacy. In line with ghrelin's proposed role in glucose metabolism, we find decreased glucose-stimulated insulin secretion (GSIS) in MENX rats while insulin sensitivity is improved. In summary, we provide a novel, non-transgenic rat model with high endogenous ghrelin plasma levels and interestingly, improved glucose tolerance. This model might aid in identifying new therapeutic approaches for obesity and obesity-related diseases including type-2 diabetes. AU - Wiedemann, T. AU - Bielohuby, M.* AU - Müller, T.D. AU - Bidlingmaier, M.* AU - Pellegata, N.S. C1 - 47172 C2 - 39130 CY - Alexandria SP - 406-420 TI - Obesity in MENX rats is accompanied by high circulating levels of ghrelin and improved insulin sensitivity. JO - Diabetes VL - 65 IS - 2 PB - Amer Diabetes Assoc PY - 2015 SN - 0012-1797 ER - TY - JOUR AB - Autoantibodies to glutamate decarboxylase (GADA) are sensitive markers of islet autoimmunity and type 1 diabetes. They form the basis of robust prediction models and are widely used for recruitment of subjects at high risk of type 1 diabetes to prevention trials. However GADA are also found in many individuals at low risk of diabetes progression. To identify the sources of diabetes irrelevant GADA reactivity therefore, we analyzed data from the 2009 and 2010 Diabetes Autoantibody Standardization Program GADA workshop and found that binding of healthy control sera varied according to assay type. Characterization of control sera found positive by radiobinding assay, but negative by ELISA showed that many of these sera reacted to epitopes in the N-terminal region of the molecule. This finding prompted development of an N-terminally truncated GAD65 radiolabel, (35)S-GAD65(96-585), which improved the performance of most GADA radiobinding assays (RBAs) participating in an Islet Autoantibody Standardization Program GADA substudy. These detailed workshop comparisons have identified a source of disease-irrelevant signals in GADA RBAs and suggest that N-terminally truncated GAD labels will enable more specific measurement of GADA in type 1 diabetes. AU - Williams, A.J.* AU - Lampasona, V.* AU - Schlosser, M.* AU - Mueller, P.W.* AU - Pittman, D.L.* AU - Winter, W.E.* AU - Akolkar, B.* AU - Wyatt, R.* AU - Brigatti, C.* AU - Krause, S. AU - Achenbach, P. C1 - 44864 C2 - 37183 CY - Alexandria SP - 3239-3246 TI - Detection of antibodies directed to the N-terminal region of GAD is dependent on assay format and contributes to differences in the specificity of GAD autoantibody assays for type 1 diabetes. JO - Diabetes VL - 64 IS - 9 PB - Amer Diabetes Assoc PY - 2015 SN - 0012-1797 ER - TY - JOUR AB - Autoantibodies to glutamate decarboxylase (GADA) identify individuals at increased risk of type 1 diabetes, but many people currently found GADA positive are unlikely to develop clinical disease. More specific GADA assays are therefore needed. Recent international workshops have shown that reactivity of sera from healthy donors varies according to assay type, and indicated that use of N-terminally truncated GAD65 radiolabels in GADA radiobinding assays is associated with higher specificity. To determine whether a radiobinding assay using radiolabeled GAD65(96-585) identified individuals at higher diabetes risk, samples from recent-onset patients and GADA positive first-degree relatives participating in the Bart's-Oxford type 1 diabetes family study were re-assayed with full-length or N-terminally truncated GAD using the NIDDK harmonized protocol. The sensitivity in patients was the same with both labels, but fewer relatives re-tested positive with truncated GAD. Among relatives who progressed to diabetes, similar proportions were GADA positive when tested with either label, but because of their higher specificity the cumulative risk of diabetes was higher in those with autoantibodies to GAD65(96-585). Autoantibodies to GAD65(96-585) in relatives are more closely associated with diabetes risk than those to full-length GAD, suggesting assays using N-terminally truncated GAD should be used to select participants for intervention trials. AU - Williams, A.J.* AU - Lampasona, V.* AU - Wyatt, R.* AU - Brigatti, C.* AU - Gillespie, K.M.* AU - Bingley, P.J.* AU - Achenbach, P. C1 - 44923 C2 - 37112 CY - Alexandria SP - 3247-3252 TI - Reactivity to N-terminally truncated GAD65(96-585) identifies GAD autoantibodies that are more closely associated with diabetes progression in relatives of patients with type 1 diabetes. JO - Diabetes VL - 64 IS - 9 PB - Amer Diabetes Assoc PY - 2015 SN - 0012-1797 ER - TY - JOUR AB - We recently reported restoration of leptin responsiveness in diet-induced obese (DIO) mice using a pharmacologically-optimized, PEGylated (PEG) leptin analog in combination with exendin-4 or FGF21. However, return of leptin action required discontinuation of high-fat diet (HFD) exposure. Here we assess whether a single peptide possessing balanced co-agonism at the GLP-1 and glucagon receptors can restore leptin responsiveness in DIO mice maintained on HFD. DIO mice were treated with PEG-GLP-1/glucagon (30 nmol/kg every fourth day) to induce a ∼15% body weight loss, once upon they were randomized to continue PEG-GLP-1/glucagon therapy or reassigned to receive supplemental daily PEG-leptin (185 nmol/kg/day). The addition of PEG-leptin to PEG-GLP-1/glucagon resulted in an ∼18% greater weight loss as compared to PEG-GLP-1/glucagon alone, and was accompanied by further decreases in food intake and improved glucose and lipid metabolism. The beneficial effect of PEG-leptin supplementation occurred after an initial body weight loss similar to what we previously reported following reduced dietary fat along with PEG-leptin and exendin-4 or FGF21 co-treatment. In summary, we report that GLP-1/glucagon co-agonism restores leptin responsiveness in mice maintained on a HFD, thus emphasizing the translational value this polypharmacotherapy for the treatment of obesity and diabetes. AU - Clemmensen, C. AU - Chabenne, J.* AU - Finan, B. AU - Sullivan, L.* AU - Fischer, K. AU - Küchler, D. AU - Sehrer, L. AU - Ograjsek, T. AU - Hofmann, S. AU - Schriever, S.C. AU - Pfluger, P.T. AU - Pinkstaff, J.K.* AU - Tschöp, M.H. AU - DiMarchi, R.* AU - Müller, T.D. C1 - 28851 C2 - 33658 SP - 1422-1427 TI - GLP-1/glucagon co-agonism restores leptin responsiveness in obese mice chronically maintained on an obesogenic diet. JO - Diabetes VL - 63 IS - 4 PB - Amer. Diabetes Assoc. PY - 2014 SN - 0012-1797 ER - TY - JOUR AB - The gut microbiome is suggested to play a role in the pathogenesis of autoimmune disorders such as type 1 diabetes. Evidence of anti-islet cell autoimmunity in type 1 diabetes appears in the first years of life, however little is known regarding establishment of the gut microbiome in early infancy. Here, we sought to determine whether differences were present in early composition of the gut microbiome in children who developed anti-islet cell autoimmunity. We investigated the microbiome of 298 stool samples prospectively taken up to age 3 years from 22 case children who developed anti-islet cell autoantibodies, and 22 matched control children who remained islet autoantibody negative in follow-up. The microbiome changed markedly during the first year of life, and was further affected by breast-feeding, food introduction, and birth delivery mode. No differences between anti-islet cell autoantibody positive and negative children were found in bacterial diversity, microbial composition, or single genus abundances. However, substantial alterations in microbial interaction networks were observed at age 0.5 and 2 years in the children who developed anti-islet cell autoantibodies. The findings underscore a role of the microbiome in the pathogenesis of anti-islet cell autoimmunity and type 1 diabetes. AU - Endesfelder, D. AU - zu Castell, W. AU - Ardissone, A.* AU - Davis-Richardson, A.G.* AU - Achenbach, P. AU - Hagen, M. AU - Pflueger, M. AU - Gano, K.A.* AU - Fagen, J.R.* AU - Drew, J.C.* AU - Brown, C.T.* AU - Kolaczkowski, B.* AU - Atkinson, M.J. AU - Schatz, D.* AU - Bonifacio, E. AU - Triplett, E.W.* AU - Ziegler, A.-G. C1 - 30766 C2 - 33845 CY - Alexandria SP - 2006-2014 TI - Compromised gut microbiota networks in children with anti-islet cell autoimmunity. JO - Diabetes VL - 63 IS - 6 PB - Amer Diabetes Assoc PY - 2014 SN - 0012-1797 ER - TY - JOUR AB - Diagnosis of the autoimmune disease type 1 diabetes (T1D) is preceded by the appearance of circulating autoantibodies to pancreatic islets. However, almost nothing is known about events leading to this islet autoimmunity. Previous epidemiological and genetic data have associated viral infections and anti-viral type I interferon (IFN) immune response genes with T1D. Here, we first used DNA microarray analysis to identify IFN-β inducible genes in vitro and then used this set of genes to define an IFN-inducible transcriptional signature in peripheral blood mononuclear cells from a group of active systemic lupus erythematosus patients (N=25). Using this predefined set of 225 IFN signature genes, we investigated expression of the signature in cohorts of healthy controls (N=87), T1D patients (N=64) and a large longitudinal birth cohort of children genetically predisposed to T1D (N=109; 454 microarrayed samples). Expression of the IFN signature was increased in genetically-predisposed children prior to the development of autoantibodies (P=0.0012), but not in established T1D patients. Upregulation of IFN-inducible genes was transient, temporally associated with a recent history of upper respiratory tract infections (P=0.0064) and marked by increased expression of SIGLEC-1 (CD169), a lectin-like receptor expressed on CD14(+) monocytes. DNA variation in IFN-inducible genes altered T1D risk (P=0.007), as exemplified by IFIH1, one of the genes in our IFN signature and for which increased expression is a known disease risk factor. These findings identify transient increased expression of type I IFN genes in pre-clinical diabetes as a risk factor for autoimmunity in children with a genetic predisposition to T1D. AU - Ferreira, R.C.* AU - Guo, H.* AU - Coulson, R.M.* AU - Smyth, D.J.* AU - Pekalski, M.L.* AU - Burren, O.S.* AU - Cutler, A.J.* AU - Doecke, J.D.* AU - Flint, S.* AU - McKinney, E.F.* AU - Lyons, P.A.* AU - Smith, K.G.* AU - Achenbach, P. AU - Beyerlein, A. AU - Dunger, D.B.* AU - Wicker, L.S.* AU - Todd, J.A.* AU - Bonifacio, E.* AU - Wallace, C.* AU - Ziegler, A.-G. C1 - 30713 C2 - 33792 CY - Alexandria SP - 2538-2550 TI - A type I interferon transcriptional signature precedes autoimmunity in children genetically at risk of type 1 diabetes. JO - Diabetes VL - 63 IS - 7 PB - Amer Diabetes Assoc PY - 2014 SN - 0012-1797 ER - TY - JOUR AB - Several bariatric operations are currently used to treat obesity and obesity-related comorbidities. These vary in efficacy, but most are more effective than current pharmaceutical treatments. Roux-en-Y Gastric Bypass (RYGB) produces substantial body weight (BW) loss, enhanced glucose tolerance, and is associated with increased secretion of the gut hormone GLP-1. Given the success of GLP-1-based agents in lowering blood glucose and BW, we hypothesized that an individual sensitivity to GLP-1 receptor agonism could predict metabolic benefits of surgeries associated with increased GLP-1 secretion. One hundred ninety-seven high-fat-diet-induced obese male Long-Evans rats were monitored for BW loss during Exendin-4 (Ex4) administration. Stable populations of responders and non-responders were identified based on Ex4-induced BW loss and GLP-1-induced improvements in glucose tolerance. Sub-populations of Ex4 extreme responders and non-responders received RYGB. Following RYGB, responders and non-responders showed similar BW loss compared to sham, but non-responders retained impaired glucose tolerance. These data indicate that the GLP-1 response tests may predict some but not all of the improvements observed after RYGB. These findings present an opportunity to optimize the use of bariatric surgery based on an improved understanding of GLP-1 biology and suggest an opportunity for a more personalized therapeutic approach to the metabolic syndrome. AU - Habegger, K.M.* AU - Heppner, K.M.* AU - Amburgy, S.E.* AU - Ottaway, N.* AU - Holland, J.* AU - Raver, C.* AU - Bartley, E.* AU - Müller, T.D. AU - Pfluger, P.T. AU - Berger, J.* AU - Toure, M.* AU - Benoit, S.C.* AU - DiMarchi, R.D.* AU - Perez-Tilve, D.* AU - D'Alessio, D.A.* AU - Seeley, R.J.* AU - Tschöp, M.H. C1 - 28145 C2 - 32961 CY - Alexandria SP - 505-513 TI - GLP-1R responsiveness predicts individual gastric bypass efficacy on glucose tolerance in rats. JO - Diabetes VL - 63 IS - 2 PB - Amer. Diabetes Assoc. PY - 2014 SN - 0012-1797 ER - TY - JOUR AB - Animal studies suggest that insulin action in the brain is involved in the regulation of peripheral insulin sensitivity. Whether this holds true in humans is unknown. Using intranasal application of insulin to the human brain, we studied impacts of brain insulin action on whole-body insulin sensitivity and mechanisms involved in this process.Insulin sensitivity was assessed by hyperinsulinemic euglycemic glucose clamp, before and after intranasal application of insulin and placebo in randomized order in lean and obese men. After insulin spray application in lean, higher glucose infusion rate was necessary to maintain euglycemia compared to placebo. Accordingly, clamp-derived insulin sensitivity index improved after insulin spray. In obese subjects, this insulin sensitizing effect could not be detected.Change in the high frequency band of heart rate variability, an estimate of parasympathetic output, correlated positively with change in whole-body insulin sensitivity after intranasal insulin. Improvement in whole-body insulin sensitivity correlated with the change in hypothalamic activity as assessed by functional magnetic resonance imaging.In summary, intranasal insulin improves peripheral insulin sensitivity in lean but not in obese men. Furthermore, brain-derived peripheral insulin sensitization is associated with hypothalamic activity and parasympathetic outputs. Thus, our findings provide novel insights into the regulation of insulin sensitivity and the pathogenesis of insulin resistance in humans. AU - Heni, M. AU - Wagner, R.* AU - Kullmann, S. AU - Veit, R.* AU - Mat-Husin, H.* AU - Linder, K. AU - Benkendorff, C.* AU - Peter, A. AU - Stefan, N. AU - Häring, H.-U. AU - Preissl, H. AU - Fritsche, A. C1 - 31778 C2 - 34770 SP - 4083-4088 TI - Central insulin administration improves whole-body insulin sensitivity via hypothalamus and parasympathetic outputs in men. JO - Diabetes VL - 63 IS - 12 PY - 2014 SN - 0012-1797 ER - TY - JOUR AB - Ghrelin receptors (GHSRs) in the central nervous system (CNS) mediate hyperphagia and adiposity induced by acyl ghrelin (AG). Evidence suggests that des-acyl ghrelin (dAG) has biological activity through GHSR independent mechanisms. We combined in vitro and in vivo approaches to test possible GHSR-mediated biological activity of dAG. Both AG (100nM) and dAG (100nM) significantly increased IP3 formation in HEK-293 cells transfected with human GHSR. As expected, intracerebroventricular (icv) infusion of AG in mice increased fat mass (FM), in comparison with the saline-infused controls. Icv-dAG also increased FM at the highest dose tested (5 nmol/day). Chronic icv infusion of AG or dAG increased glucose-stimulated insulin secretion (GSIS). Subcutaneously infused AG regulated FM and GSIS in comparison to saline-infused control mice, whereas dAG failed to regulate these parameters even with doses that were efficacious when delivered icv. Furthermore, icv-dAG failed to regulate FM and induce hyperinsulinemia in GHSR deficient (Ghsr-/-) mice. In addition, a hyperinsulinemic-euglycemic clamp suggests that icv-dAG impairs glucose clearance without affecting endogenous glucose production. Taken together, these data demonstrate that dAG is an agonist of GHSR and regulates body adiposity and peripheral glucose metabolism through a CNS GHSR-dependent mechanism. AU - Heppner, K.M.* AU - Piechowski, C.L.* AU - Müller, A.* AU - Ottaway, N.* AU - Sisley, S.* AU - Smiley, D.L.* AU - Habegger, K.M.* AU - Pfluger, P.T. AU - DiMarchi, R.* AU - Biebermann, H.* AU - Tschöp, M.H. AU - Sandoval, D.A.* AU - Perez-Tilve, D.* C1 - 28193 C2 - 33005 SP - 122-131 TI - Both acyl and des-acyl ghrelin regulate adiposity and glucose metabolism via CNS ghrelin receptors. JO - Diabetes VL - 63 IS - 1 PB - Amer. Diabetes Assoc. PY - 2014 SN - 0012-1797 ER - TY - JOUR AB - The pro-inflammatory cytokine interleukin (IL)-1β is implicated in the development of insulin resistance and beta-cell dysfunction, whereas higher circulating IL-1 receptor antagonist (IL-1RA - an endogenous inhibitor of IL-1β - has been suggested to improve glycemia and beta-cell function in patients with type 2 diabetes. In order to elucidate the protective role of IL-1RA, this study aimed to identify genetic determinants of circulating IL-1RA concentration and to investigate their associations with immunological and metabolic variables related to cardiometabolic risk. In the analysis of 7 discovery and 4 replication cohort studies, two single nucleotide polymorphisms (SNPs) were independently associated with circulating IL-1RA concentration (rs4251961 at the IL-1RN locus, n=13,955, P=2.76x10(-21); and rs6759676, closest gene locus IL1F10, n=13,994, P=1.73x10(-17)). The proportion of the variance in IL-1RA explained by both SNPs combined was 2.0%. IL-1RA-raising alleles of both SNPs were associated with lower circulating C-reactive protein concentration. The IL-1RA-raising allele of rs6759676 was also associated with lower fasting insulin and lower homeostasis model assessment insulin resistance (HOMA-IR). In conclusion, we show that circulating IL-1RA levels are predicted by two independent SNPs at the IL-1RN and IL-1F10 loci and that genetically raised IL-1RA may be protective against the development of insulin resistance. AU - Herder, C.* AU - Nuotio, M.L.* AU - Shah, S.* AU - Blankenberg, S.* AU - Brunner, E.J.* AU - Carstensen, M.* AU - Gieger, C. AU - Grallert, H. AU - Jula, A.* AU - Kähönen, M.* AU - Kettunen, J.* AU - Kivimaki, M.* AU - Koenig, W.* AU - Kristiansson, K.* AU - Langenberg, C.* AU - Lehtimäki, T.* AU - Luotola, K.* AU - Marzi, C. AU - Müller, C.* AU - Peters, A. AU - Prokisch, H. AU - Raitakari, O.* AU - Rathmann, W.* AU - Roden, M.* AU - Salmi, M.* AU - Schramm, K. AU - Swerdlow, D.I.* AU - Tabak, A.G.* AU - Thorand, B. AU - Wareham, N.J.* AU - Wild, P.S.* AU - Zeller, T.* AU - Hingorani, A.D.* AU - Witte, D.R.* AU - Kumari, M.* AU - Perola, M.* AU - Salomaa, V.* C1 - 31696 C2 - 34663 SP - 4343-4359 TI - Genetic determinants of circulating interleukin-1 receptor antagonist levels and their association with glycemic traits. JO - Diabetes VL - 63 IS - 12 PY - 2014 SN - 0012-1797 ER - TY - JOUR AB - Using an integrative approach where genetic variation, gene expression and clinical phenotypes are assessed in relevant tissues may help functionally characterize the genetic contribution to disease susceptibility. We sought to identify genetic variation influencing skeletal muscle gene expression (eQTL), as well as expression associated with measures of insulin sensitivity. We investigated associations of 3799401 genetic variants with gene expression from >7000 genes from three cohorts (n=104). We identified 287 genes with cis-acting eQTLs (FDR<5%; P<1.96x10(-5)) and 49 expression-insulin sensitivity phenotype associations (i.e. fasting insulin, HOMA-IR and BMI) (FDR<5%; P=1.34x10(-4)). One of these associations, fasting insulin/phosphofructokinase (PFKM), overlaps with an eQTL. Further, the expression of PFKM, a rate-limiting enzyme in glycolysis, was nominally associated with glucose uptake in skeletal muscle (P=0.026, n=42) and over-expressed (PBF-corrected=0.03) in skeletal muscle in T2D patients (n=102) compared with normoglycemic controls (n=87). The PFKM eQTL (rs4547172; PeQTL=7.69x10(-6)) was nominally associated with glucose uptake, glucose oxidation rate, intramuscular triglyceride content, and metabolic flexibility (P=0.016-0.048, n=178). We explored eQTL results using published GWAS data (from DIAGRAM and MAGIC) and a proxy for the PFKM eQTL (rs11168327, r2=0.75), was nominally associated with T2D (PDIAGRAM=2.7x10(-3)). Taken together, our analysis highlights PFKM as a potential regulator of skeletal muscle insulin sensitivity. AU - Keildson, S.* AU - Fadista, J.* AU - Ladenvall, C.* AU - Hedman, A.K.* AU - Elgzyri, T.* AU - Small, K.S.* AU - Grundberg, E.* AU - Nica, A.C.* AU - Glass, D.* AU - Richards, J.B.* AU - Barrett, A.* AU - Nisbet, J.* AU - Zheng, H.F.* AU - Rönn, T.* AU - Ström, K.* AU - Eriksson, K.F.* AU - Prokopenko, I.* AU - MAGIC Consortium (Grallert, H. AU - Gieger, C. AU - Thorand, B. AU - Meisinger, C. AU - Illig, T. AU - Wichmann, H.-E.) AU - DIAGRAM Consortium (Huth, C. AU - Grallert, H. AU - Klopp, N. AU - Meitinger, T. AU - Petersen, A.-K. AU - Thorand, B. AU - Wichmann, H.-E. AU - Illig, T. AU - Gieger, C.) AU - MuTHER Consortium (*) AU - Spector, T.D.* AU - Dermitzakis, E.T.* AU - Deloukas, P.* AU - McCarthy, M.I.* AU - Rung, J.* AU - Groop, L.* AU - Franks, P.W.* AU - Lindgren, C.M.* AU - Hansson, O.* C1 - 28609 C2 - 33481 SP - 1154-1165 TI - Expression of phosphofructokinase in skeletal muscle is influenced by genetic variation and associated with insulin sensitivity. JO - Diabetes VL - 63 IS - 3 PB - Amer. Diabetes Assoc. PY - 2014 SN - 0012-1797 ER - TY - JOUR AB - Unacylated ghrelin (UAG) is the predominant ghrelin isoform in the circulation. Despite its inability to activate the classical ghrelin receptor, preclinical studies suggest that UAG may promote β-cell function. We hypothesized that UAG would oppose the effects of acylated ghrelin (AG) on insulin secretion and glucose tolerance. AG (1 µg/kg/h), UAG (4 µg/kg/h), combined AG+UAG, or saline were infused to 17 healthy subjects (9 M/8 F) on 4 occasions in randomized order. Ghrelin was infused for 30 min to achieve steady-state levels and continued through a 3-h IV glucose tolerance test. The acute insulin response to glucose (AIRg), insulin sensitivity index (SI), disposition index (DI), and IV glucose tolerance (kg) were compared for each subject during the 4 infusions. AG infusion raised fasting glucose levels but had no effect on fasting plasma insulin. Compared to the saline control both AG and AG+UAG decreased AIRg, but UAG alone had no effect. SI did not differ among the treatments. AG, but not UAG, reduced DI and kg and increased plasma growth hormone. UAG did not alter growth hormone, cortisol, glucagon or free fatty acid levels. UAG selectively decreased glucose and fructose consumption compared to the other treatments. In contrast to previous reports, acute administration of UAG does not have independent effects on glucose tolerance or β-cell function, and neither augments nor antagonizes the effects of AG. AU - Tong, J.* AU - Davis, H.W.* AU - Summer, S.* AU - Benoit, S.C.* AU - Haque, A.* AU - Bidlingmaier, M.* AU - Tschöp, M.H. AU - D'Alessio, D.* C1 - 30802 C2 - 33882 CY - Alexandria SP - 2309-2319 TI - Acute administration of unacylated ghrelin has no effect on basal or stimulated insulin secretion in healthy humans. JO - Diabetes VL - 63 IS - 7 PB - Amer Diabetes Assoc PY - 2014 SN - 0012-1797 ER - TY - JOUR AB - Patients with established type 2 diabetes display both beta-cell dysfunction and insulin resistance. To define fundamental processes leading to the diabetic state, we examined the relationship between type 2 diabetes risk variants at 37 established susceptibility loci and indices of proinsulin processing, insulin secretion and insulin sensitivity. We included data from up to 58,614 non-diabetic subjects with basal measures, and 17,327 with dynamic measures. We employed additive genetic models with adjustment for sex, age and BMI, followed by fixed-effects inverse variance meta-analyses. Cluster analyses grouped risk loci into five major categories based on their relationship to these continuous glycemic phenotypes. The first cluster (PPARG, KLF14, IRS1, GCKR) was characterized by primary effects on insulin sensitivity. The second (MTNR1B, GCK) featured risk alleles associated with reduced insulin secretion and fasting hyperglycemia. ARAP1 constituted a third cluster characterized by defects in insulin processing. A fourth cluster (including TCF7L2, SLC30A8, HHEX/IDE, CDKAL1, CDKN2A/2B) was defined by loci influencing insulin processing and secretion without detectable change in fasting glucose. The final group contained twenty risk loci with no clear-cut associations to continuous glycemic traits. By assembling extensive data on continuous glycemic traits, we have exposed the diverse mechanisms whereby type 2 diabetes risk variants impact disease predisposition. AU - Dimas, A.S.* AU - Lagou, V.* AU - Barker, A.* AU - Knowles, J.W.* AU - Mägi, R.* AU - Hivert, M.F.* AU - Benazzo, A.* AU - Rybin, D.* AU - Jackson, A.U.* AU - Stringham, H.M.* AU - Song, C.* AU - Fischer-Rosinsky, A.* AU - Boesgaard, T.W.* AU - Grarup, N.* AU - Abbasi, F.A.* AU - Assimes, T.L.* AU - Hao, K.* AU - Yang, X.* AU - Lecoeur, C.* AU - Barroso, I.* AU - Bonnycastle, L.L.* AU - Böttcher, Y.* AU - Bumpstead, S.* AU - Chines, P.S.* AU - Erdos, M.R.* AU - Graessler, J.* AU - Kovacs, P.* AU - Morken, M.A.* AU - Narisu, N.* AU - Payne, F.* AU - Stancáková, A.* AU - Swift, A.J.* AU - Tönjes, A.* AU - Bornstein, S.R.* AU - Cauchi, S.* AU - Froguel, P.* AU - Meyre, D.* AU - Schwarz, P.E.* AU - Häring, H.-U. AU - Smith, U.* AU - Boehnke, M.* AU - Bergman, R.N.* AU - Collins, F.S.* AU - Mohlke, K.L.* AU - Tuomilehto, J.* AU - Quertemous, T.* AU - Lind, L.* AU - Hansen, T.* AU - Pedersen, O.* AU - Walker, M.* AU - Pfeiffer, A.F.* AU - Spranger, J.* AU - Stumvoll, M.* AU - Meigs, J.B.* AU - Wareham, N.J.* AU - Kuusisto, J.* AU - Laakso, M.* AU - Langenberg, C.* AU - Dupuis, J.* AU - Watanabe, R.M.* AU - Florez, J.C* AU - Ingelsson, E.* AU - McCarthy, M.I.* AU - Prokopenko, I.* AU - MAGIC Investigators (Grallert, H. AU - Gieger, C. AU - Meisinger, C. AU - Thorand, B. AU - Wichmann, H.-E. AU - Illig, T.) C1 - 28575 C2 - 33465 CY - Alexandria SP - 2158-2171 TI - Impact of type 2 diabetes susceptibility variants on quantitative glycemic traits reveals mechanistic heterogeneity. JO - Diabetes VL - 63 IS - 6 PB - Amer. Diabetes Assoc. PY - 2013 SN - 0012-1797 ER - TY - JOUR AB - Metabolomic screening of fasting plasma from nondiabetic subjects identified α-hydroxybutyrate (α-HB) and linoleoyl-glycerophosphocholine (L-GPC) as joint markers of insulin resistance (IR) and glucose intolerance. To test the predictivity of α-HB and L-GPC for incident dysglycemia, α-HB and L-GPC measurements were obtained in two observational cohorts, comprising 1,261 nondiabetic participants from the Relationship between Insulin Sensitivity and Cardiovascular Disease (RISC) study and 2,580 from the Botnia Prospective Study, with 3-year and 9.5-year follow-up data, respectively. In both cohorts, α-HB was a positive correlate and L-GPC a negative correlate of insulin sensitivity, with α-HB reciprocally related to indices of β-cell function derived from the oral glucose tolerance test (OGTT). In follow-up, α-HB was a positive predictor (adjusted odds ratios 1.25 [95% CI 1.00–1.60] and 1.26 [1.07–1.48], respectively, for each standard deviation of predictor), and L-GPC was a negative predictor (0.64 [0.48–0.85] and 0.67 [0.54–0.84]) of dysglycemia (RISC) or type 2 diabetes (Botnia), independent of familial diabetes, sex, age, BMI, and fasting glucose. Corresponding area under the receiver operating characteristic curves were 0.791 (RISC) and 0.783 (Botnia), similar in accuracy when substituting α-HB and L-GPC with 2-h OGTT glucose concentrations. When their activity was examined, α-HB inhibited and L-GPC stimulated glucose-induced insulin release in INS-1e cells. α-HB and L-GPC are independent predictors of worsening glucose tolerance, physiologically consistent with a joint signature of IR and β-cell dysfunction. AU - Ferrannini, E.* AU - Natalai, A.* AU - Camastra, S.* AU - Nannipieri, M.* AU - Mari, A.* AU - Adam, K.-P.* AU - Milburn, M.V.* AU - Kastenmüller, G. AU - Adamski, J. AU - Tuomi, T.* AU - Lyssenko, V.* AU - Groop, L.* AU - Gall, W.E.* C1 - 10900 C2 - 30419 SP - 1730-1737 TI - Early metabolic markers of the development of dysglycemia and type 2 diabetes and their physiological significance. JO - Diabetes VL - 62 IS - 5 PB - American Diabetes Assoc. PY - 2013 SN - 0012-1797 ER - TY - JOUR AB - Metabolomic discovery of biomarkers of type 2 diabetes (T2D) risk may reveal etiological pathways and help to identify individuals at risk for disease. We prospectively investigated the association between serum metabolites measured by targeted metabolomics and risk of T2D in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam (27,548 adults) among all incident cases of T2D (n = 800, mean follow-up 7 years) and a randomly drawn subcohort (n = 2,282). Flow injection analysis tandem mass spectrometry was used to quantify 163 metabolites, including acylcarnitines, amino acids, hexose, and phospholipids, in baseline serum samples. Serum hexose; phenylalanine; and diacyl-phosphatidylcholines C32:1, C36:1, C38:3, and C40:5 were independently associated with increased risk of T2D and serum glycine; sphingomyelin C16:1; acyl-alkyl-phosphatidylcholines C34:3, C40:6, C42:5, C44:4, and C44:5; and lysophosphatidylcholine C18:2 with decreased risk. Variance of the metabolites was largely explained by two metabolite factors with opposing risk associations (factor 1 relative risk in extreme quintiles 0.31 [95% CI 0.21-0.44], factor 2 3.82 [2.64-5.52]). The metabolites significantly improved T2D prediction compared with established risk factors. They were further linked to insulin sensitivity and secretion in the Tübingen Family study and were partly replicated in the independent KORA (Cooperative Health Research in the Region of Augsburg) cohort. The data indicate that metabolic alterations, including sugar metabolites, amino acids, and choline-containing phospholipids, are associated early on with a higher risk of T2D. AU - Floegel, A.* AU - Stefan, N.* AU - Yu, Z. AU - Mühlenbruch, K.* AU - Drogan, D.* AU - Joost, H.-G.* AU - Fritsch, A.* AU - Häring, H.-U.* AU - Hrabě de Angelis, M. AU - Peters, A. AU - Roden, M.* AU - Prehn, C. AU - Wang-Sattler, R. AU - Illig, T. AU - Schulze, M.B.* AU - Adamski, J. AU - Boing, H.* AU - Pischon, T.* C1 - 10418 C2 - 30235 SP - 639-648 TI - Identification of serum metabolites associated with risk of type 2 diabetes using a targeted metabolomic approach. JO - Diabetes VL - 62 IS - 2 PB - American Diabetes Assoc. PY - 2013 SN - 0012-1797 ER - TY - JOUR AB - Glucagon, an essential regulator of glucose homeostasis, also modulates lipid metabolism and promotes weight loss, as reflected by the wasting observed in glucagonoma patients. Recently, coagonist peptides that include glucagon agonism have emerged as promising therapeutic candidates for the treatment of obesity and diabetes. We developed a novel stable and soluble glucagon receptor (GcgR) agonist, which allowed for in vivo dissection of glucagon action. As expected, chronic GcgR agonism in mice resulted in hyperglycemia and lower body fat and plasma cholesterol. Notably, GcgR activation also raised hepatic expression and circulating levels of fibroblast growth factor 21 (FGF21). This effect was retained in isolated primary hepatocytes from wild-type (WT) mice, but not GcgR knockout mice. We confirmed this link in healthy human volunteers, where injection of natural glucagon increased plasma FGF21 within hours. Functional relevance was evidenced in mice with genetic deletion of FGF21, where GcgR activation failed to induce the body weight loss and lipid metabolism changes observed in WT mice. Taken together, these data reveal for the first time that glucagon controls glucose, energy, and lipid metabolism at least in part via FGF21-dependent pathways. AU - Habegger, K.M.* AU - Stemmer, K. AU - Cheng, C.* AU - Müller, T.D. AU - Heppner, K.M.* AU - Ottaway, N.* AU - Holland, J.* AU - Hembree, J.L.* AU - Smiley, D.* AU - Gelfanov, V.* AU - Krishna, R.* AU - Arafat, A.M.* AU - Konkar, A.* AU - Belli, S.* AU - Kapps, M.* AU - Woods, S.C.* AU - Hofmann, S.M. AU - D'Alessio, D.* AU - Pfluger, P.T. AU - Perez-Tilve, D.* AU - Seeley, R.J.* AU - Konishi, M.* AU - Itoh, N.* AU - Kharitonenkov, A.* AU - Spranger, J.* AU - DiMarchi, R.D.* AU - Tschöp, M.H. C1 - 11894 C2 - 30842 SP - 1453-1463 TI - Fibroblast growth factor 21 mediates specific glucagon actions. JO - Diabetes VL - 62 IS - 5 PB - American Diabetes Assoc. PY - 2013 SN - 0012-1797 ER - TY - JOUR AB - Bariatric procedures vary in efficacy, but overall are more effective than behavioral and pharmaceutical treatment. Roux-en-Y Gastric Bypass causes increased secretion of Glucagon-like peptide 1 (GLP-1), and reduces body weight more than adjustable gastric banding (AGB), which does not trigger increased GLP-1 secretion. Since GLP-1-based drugs consistently reduce body weight, we hypothesized that GLP-1 receptor (GLP-1R) agonists would augment the effects of AGB. Male Long Evans rats with diet-induced obesity received AGB implantation or sham surgery. GLP-1R agonism, cannabinoid receptor-1 (CB1-R) antagonism, or vehicle was combined with inflation to evaluate interaction between AGB and pharmacological treatments. GLP1-R agonism reduced BW in both sham and AGB rats (left un-inflated) compared to vehicle-treated animals. Subsequent band inflation was ineffective in vehicle-treated rats, but enhanced weight loss stimulated by GLP1-R agonism. In contrast, there were no additional BW loss when CB1-R antagonism was given with AGB. We found band inflation to trigger neural activation in areas of the nucleus of the solitary tract known to be targeted by GLP1-R agonism, offering potential mechanism for the interaction. These data show that GLP-1R agonism, but not CB1-R antagonism, improves weight loss achieved by AGB, and suggest an opportunity to optimize bariatric surgery with adjunctive pharmacotherapy. AU - Habegger, K.M.* AU - Kirchner, H.* AU - Yi, C.-X. AU - Heppner, K.M.* AU - Sweeney, D.* AU - Ottaway, N.* AU - Holland, J.* AU - Amburgy, S.* AU - Raver, C.* AU - Krishna, R.* AU - Müller, T.D. AU - Perez-Tilve, D.* AU - Pfluger, P.T. AU - Obici, S.* AU - DiMarchi, R.D.* AU - D'Alessio, D.A.* AU - Seeley, R.J.* AU - Tschöp, M.H. C1 - 24888 C2 - 31713 SP - 3261-3267 TI - GLP-1R agonism enhances adjustable gastric banding in diet-induced obese rats. JO - Diabetes VL - 62 IS - 9 PB - Amer. Diabetes Assoc. PY - 2013 SN - 0012-1797 ER - TY - JOUR AU - Heni, M. AU - Kullmann, S. AU - Fritsche, A. C1 - 26732 C2 - 32358 TI - Comment on: Teeuwisse et al. Short-term caloric restriction normalizes hypothalamic neuronal responsiveness to glucose ingestion in patients with type 2 diabetes. Diabetes 2012;61:3255-3259. JO - Diabetes VL - 62 IS - 6 PB - Amer. Diabetes Assoc. PY - 2013 SN - 0012-1797 ER - TY - JOUR AB - Islet autoimmunity precedes type 1 diabetes onset. We previously found that islet autoimmunity rarely starts before age six months but reaches its highest incidence already at around 1 year of age. We now examine whether homeostatic expansion and immune competence changes seen in a maturating immune system may account for this marked variation in islet autoimmunity risk in the first year of life. We found naïve proinsulin- and GAD65-responsive T cells in cord blood of healthy newborns, with highest responses observed in children with type 1 diabetes susceptible HLA-DRB1/DQB1 genotypes. Homeostatic expansion characteristics with increased IL-7 concentrations and enhanced T cell responsiveness to IL-7 were observed throughout the first year of life. However, the ability of antigen-presenting cells to activate naïve T cells was compromised at birth, and cord blood monocytes had low surface expression of CD40 and HLA class II. In contrast, antigen presentation and expression of these molecules had reached competent adult levels by the high incidence age of 8 months. We propose that temporal changes in islet autoimmunity seroconversion in infants are a consequence of the changing balance between homeostatic drive and antigen presentation competence. These findings are relevant for early prevention of type 1 diabetes. AU - Heninger, A.K.* AU - Monti, P.* AU - Wilhelm, C.* AU - Schwaiger, P.* AU - Kuehn, D.* AU - Ziegler, A.-G. AU - Bonifacio, E.* C1 - 24483 C2 - 31545 SP - 2059-2066 TI - Activation of islet autoreactive naive T cells in infants is influenced by homeostatic mechanisms and antigen presenting capacity. JO - Diabetes VL - 62 IS - 6 PB - Amer. Diabetes Assoc. PY - 2013 SN - 0012-1797 ER - TY - JOUR AB - Substantial progress has been made in identification of type 2 diabetes (T2D) risk loci in the past few years, but our understanding of the genetic basis of T2D in ethnically diverse populations remains limited. We performed a genome-wide association study and a replication study in Chinese Hans comprising 8,569 T2D case subjects and 8,923 control subjects in total, from which 10 single nucleotide polymorphisms were selected for further follow-up in a de novo replication sample of 3,410 T2D case and 3,412 control subjects and an in silico replication sample of 6,952 T2D case and 11,865 control subjects. Besides confirming seven established T2D loci (CDKAL1, CDKN2A/B, KCNQ1, CDC123, GLIS3, HNF1B, and DUSP9) at genome-wide significance, we identified two novel T2D loci, including G-protein-coupled receptor kinase 5 (GRK5) (rs10886471: P = 7.1 × 10(-9)) and RASGRP1 (rs7403531: P = 3.9 × 10(-9)), of which the association signal at GRK5 seems to be specific to East Asians. In nondiabetic individuals, the T2D risk-increasing allele of RASGRP1-rs7403531 was also associated with higher HbA(1c) and lower homeostasis model assessment of β-cell function (P = 0.03 and 0.0209, respectively), whereas the T2D risk-increasing allele of GRK5-rs10886471 was also associated with higher fasting insulin (P = 0.0169) but not with fasting glucose. Our findings not only provide new insights into the pathophysiology of T2D, but may also shed light on the ethnic differences in T2D susceptibility. AU - Li, H.* AU - Gan, W.* AU - Lu, L.* AU - Dong, X.* AU - Han, X.* AU - Hu, C.* AU - Yang, Z.* AU - Sun, L.* AU - Bao, W.* AU - Li, P.* AU - He, M.* AU - Wang, Y.* AU - Zhu, J.* AU - Ning, Q.* AU - Tang, Y.* AU - Zhang, R.* AU - Wen, J.* AU - Wang, D.* AU - Zhu, X.* AU - Guo, K.* AU - Zuo, X.* AU - Guo, X.* AU - Yang, H.* AU - Zhou, X.* AU - DIAGRAM Consortium (Huth, C. AU - Grallert, H. AU - Gieger, C. AU - Klopp, N. AU - Petersen, A.-K. AU - Thorand, B. AU - Wichmann, H.-E. AU - Illig, T. AU - Meitinger, T.) AU - AGEN-T2D Consortium (*) AU - Zhang, X.* AU - Qi, L.* AU - Loos, R.J.* AU - Hu, F.B.* AU - Wu, T.* AU - Liu, Y.* AU - Liu, L.* AU - Hu, R.* AU - Jia, W.* AU - Ji, L.* AU - Li, Y.* AU - Lin, X.* C1 - 22469 C2 - 30875 SP - 291-298 TI - A genome-wide association study identifies GRK5 and RASGRP1 as type 2 diabetes loci in Chinese Hans. JO - Diabetes VL - 62 IS - 1 PB - American Diabetes Assoc. PY - 2013 SN - 0012-1797 ER - TY - JOUR AB - Using a non-targeted metabolomics approach of 447 fasting plasma metabolites, we searched for novel molecular markers that arise before and after hyperglycaemia in a large population-based cohort of 2,204 females (115 Type 2 Diabetes-T2D cases, 192 individuals with impaired fasting glucose- IFG and 1,897 controls) from TwinsUK.Forty-two metabolites from three major fuel sources, carbohydrates, lipids and proteins, were found to significantly correlate with T2D after adjusting for multiple testing; of these, 22 were previously reported as associated with T2D or insulin resistance. Fourteen metabolites were found to be associated with IFG. Among the metabolites identified, the branched-chain-keto-acid metabolite 3-methyl-2-oxovalerate, was the strongest predictive biomarker for IFG after glucose (OR=1.65, 95%CI=1.39,1.95, P=8.46x10(-9)) and was moderately heritable (h(2)=0.20). The association was replicated in an independent population (n=720, OR=1.68, 95%CI=1.34, 2.11, P=6.52x10(-6)) and validated in 189 Twins with urine metabolomics taken at the same time as plasma (OR=1.87, 95%CI=1.27,2.75, P=1x10(-3)). Results confirm an important role for catabolism of branched-chain-amino-acids in T2D and IFG.In conclusion, this T2D-IFG biomarker study has surveyed the broadest panel of non-targeted metabolites to date, revealing both novel and known associated metabolites and providing potential novel targets for clinical prediction and a deeper understanding of causal mechanisms. AU - Menni, C.* AU - Fauman, E.* AU - Erte, I.* AU - Perry, J.R.* AU - Kastenmüller, G. AU - Shin, S.Y.* AU - Petersen, A.-K. AU - Hyde, C.* AU - Psatha, M.* AU - Ward, K.J.* AU - Yuan, W.* AU - Milburn, M.V.* AU - Palmer, C.N.* AU - Frayling, T.M.* AU - Trimmer, J.* AU - Bell, J.T.* AU - Gieger, C. AU - Mohney, R.P.* AU - Brosnan, M.J.* AU - Suhre, K. AU - Soranzo, N.* AU - Spector, T.D.* C1 - 28396 C2 - 33358 CY - Alexandria SP - 4270-4276 TI - Biomarkers for type 2 diabetes and impaired fasting glucose using a non-targeted metabolomics approach. JO - Diabetes VL - 62 IS - 12 PB - Amer. Diabetes Assoc. PY - 2013 SN - 0012-1797 ER - TY - JOUR AB - Soluble IL-7 receptor alpha (sCD127) is implicated in the pathogenesis of autoimmune diseases. We show that serum sCD127 concentrations are increased at the onset of type 1 diabetes (n=390) as compared to concentrations in age-matched islet autoantibody negative first degree relatives of patients (n=392; P=0.00001). sCD127 Concentration in patients was influenced by islet autoantibody status (P=0.003) and genotype of the rs6897932 single nucleotide polymorphism within theIL-7RA gene (P=0.006). Release of sCD127 in vitro was strongly up-regulated by activation of T lymphocytes, and affected by exposure to cytokines. sCD127 bound IL-7 and was antagonistic to IL-7 signaling and IL-7 mediated T cell proliferation suggesting a regulatory feedback mechanism on T cell expansion. Remarkably, high glucose led to a glycated form of sCD127 that was ineffective as an IL-7 antagonist. The finding of glycated sCD127 in the circulation of patients at onset of type 1 diabetes suggested that physiological regulation of IL-7 mediated T cell survival and expansion by sCD127 may be compromised in type 1 diabetes. The findings indicate that genetic, immunologic and metabolic factors contribute to a dysregulation of the IL-7/IL-7 receptor pathway in type 1 diabetes, and identify a novel hyperglycemia mediated interference of immune regulatory networks. AU - Monti, P.* AU - Brigatti, C.* AU - Krasmann, M. AU - Ziegler, A.-G. AU - Bonifacio, E.* C1 - 24487 C2 - 31547 SP - 2500-2508 TI - Concentration and activity of the soluble form of the interleukin-7 receptor α in type I diabetes identifies an interplay between hyperglycemia and immune function. JO - Diabetes VL - 62 IS - 7 PB - Amer. Diabetes Assoc. PY - 2013 SN - 0012-1797 ER - TY - JOUR AB - Experiments in animals suggest that the neuropeptide oxytocin acts as an anorexigenic signal in the central nervous control of food intake. In humans, however, research has almost exclusively focused on the involvement of oxytocin in the regulation of social behavior. We investigated the effect of intranasal oxytocin on ingestion and metabolic function in healthy men. Food intake in the fasted state was examined 45 min after neuropeptide administration, followed by the assessment of olfaction and reward-driven snack intake in the absence of hunger. Energy expenditure was registered by indirect calorimetry, and blood was repeatedly sampled to determine concentrations of blood glucose and hormones. Oxytocin markedly reduced snack consumption, restraining, in particular, the intake of chocolate cookies by 25%. Oxytocin, moreover, attenuated basal and postprandial levels of adrenocorticotropic hormone and cortisol and curbed the meal-related rise in plasma glucose. Energy expenditure and hunger-driven food intake as well as olfactory function were not affected. Our results indicate that oxytocin, beyond its role in social bonding, regulates nonhomeostatic, reward-related energy intake, hypothalamic-pituitary-adrenal axis activity, and the glucoregulatory response to food intake in humans. These effects can be assumed to converge with the psychosocial function of oxytocin and imply possible applications in the treatment of metabolic disorders. AU - Ott, V.* AU - Finlayson, G.* AU - Lehnert, H.* AU - Heitmann, B.* AU - Heinrichs, M.* AU - Born, J. AU - Hallschmid, M. C1 - 28049 C2 - 32918 SP - 3418-3425 TI - Oxytocin reduces reward-driven food intake in humans. JO - Diabetes VL - 62 IS - 10 PB - Amer. Diabetes Assoc. PY - 2013 SN - 0012-1797 ER - TY - JOUR AB - Mutations in the insulin (INS) gene may cause permanent neonatal diabetes mellitus (PNDM). Ins2 mutant mouse models provided important insights into the disease mechanisms of PNDM but have limitations for translational research. To establish a large animal model of PNDM, we generated INSC94Y transgenic pigs. A line expressing high levels of INSC94Y mRNA (70-86% of wildtype INS transcripts) exhibited elevated blood glucose soon after birth but unaltered beta-cell mass at the age of 8 days. At 4.5 months, INSC94Y transgenic pigs exhibited 41% reduced body weight, 72% decreased beta-cell mass (-53% relative to body weight), and 60% lower fasting insulin levels compared with littermate controls. beta-cells of INSC94Y transgenic pigs showed a marked reduction of insulin secretory granules and severe dilation of the endoplasmic reticulum. Cataract development was already visible in 8-day-old INSC94Y transgenic pigs and became more severe with increasing age. Diabetes-associated pathological alterations of kidney and nervous tissue were not detected during the observation period of 1 year. The stable diabetic phenotype and its rescue by insulin treatment make the INSC94Y transgenic pig an attractive model for insulin supplementation and islet transplantation trials, and for studying developmental consequences of maternal diabetes mellitus. AU - Renner, S.* AU - Braun-Reichhart, C.* AU - Blutke, A.* AU - Herbach, N.* AU - Emrich, D.* AU - Streckel, E.* AU - Wünsch, A.* AU - Kessler, B.* AU - Kurome, M.* AU - Bahr, A.* AU - Klymiuk, N.* AU - Krebs, S.* AU - Puk, O. AU - Nagashima, H.* AU - Graw, J. AU - Blum, H.* AU - Wanke, R.* AU - Wolf, E.* C1 - 24683 C2 - 31641 SP - 1505-1511 TI - Permanent neonatal diabetes in INSC94Y transgenic pigs. JO - Diabetes VL - 62 IS - 5 PB - Amer. Diabetes Assoc. PY - 2013 SN - 0012-1797 ER - TY - JOUR AB - We performed a genome-wide association study (GWAS) and a multistage meta-analysis of type 2 diabetes (T2D) in Punjabi Sikhs from India. Our discovery GWAS in 1,616 individuals (842 case subjects) was followed by in silico replication of the top 513 independent single nucleotide polymorphisms (SNPs) (P < 10⁻³) in Punjabi Sikhs (n = 2,819; 801 case subjects). We further replicated 66 SNPs (P < 10⁻⁴) through genotyping in a Punjabi Sikh sample (n = 2,894; 1,711 case subjects). On combined meta-analysis in Sikh populations (n = 7,329; 3,354 case subjects), we identified a novel locus in association with T2D at 13q12 represented by a directly genotyped intronic SNP (rs9552911, P = 1.82 × 10⁻⁸) in the SGCG gene. Next, we undertook in silico replication (stage 2b) of the top 513 signals (P < 10⁻³) in 29,157 non-Sikh South Asians (10,971 case subjects) and de novo genotyping of up to 31 top signals (P < 10⁻⁴) in 10,817 South Asians (5,157 case subjects) (stage 3b). In combined South Asian meta-analysis, we observed six suggestive associations (P < 10⁻⁵ to < 10⁻⁷), including SNPs at HMG1L1/CTCFL, PLXNA4, SCAP, and chr5p11. Further evaluation of 31 top SNPs in 33,707 East Asians (16,746 case subjects) (stage 3c) and 47,117 Europeans (8,130 case subjects) (stage 3d), and joint meta-analysis of 128,127 individuals (44,358 case subjects) from 27 multiethnic studies, did not reveal any additional loci nor was there any evidence of replication for the new variant. Our findings provide new evidence on the presence of a population-specific signal in relation to T2D, which may provide additional insights into T2D pathogenesis. AU - Saxena, R.* AU - Saleheen, D.* AU - Been, L.F.* AU - Garavito, M.L.* AU - Braun, T.* AU - Bjonnes, A.* AU - Young, R.* AU - Ho, W.K.* AU - Rasheed, A.* AU - Frossard, P.* AU - Sim, X.* AU - Hassanali, N.* AU - Radha, V.* AU - Chidambaram, M.* AU - Liju, S.* AU - Rees, S.D.* AU - Ng, D.P.* AU - Wong, T.Y.* AU - Yamauchi, T.* AU - Hara, K.* AU - Tanaka, Y.* AU - Hirose, H.* AU - McCarthy, M.I.* AU - Morris, A.P.* AU - DIAGRAM Consortium (Meitinger, T. AU - Huth, C. AU - Illig, T. AU - Thorand, B. AU - Wichmann, H.-E. AU - Petersen, A.-K. AU - Klopp, N. AU - Gieger, C. AU - Grallert, H.) AU - MuTHER Consortium (*) AU - AGEN Consortium (*) AU - Basit, A.* AU - Barnett, A.H.* AU - Katulanda, P.* AU - Matthews, D.* AU - Mohan, V.* AU - Wander, G.S.* AU - Singh, J.R.* AU - Mehra, N.K.* AU - Ralhan, S.* AU - Kamboh, M.I.* AU - Mulvihill, J.J.* AU - Maegawa, H.* AU - Tobe, K.* AU - Maeda, S.* AU - Cho, Y.S.* AU - Tai, E.S.* AU - Kelly, M.A.* AU - Chambers, J.C.* AU - Kooner, J.S.* AU - Kadowaki, T.* AU - Deloukas, P.* AU - Rader, D.J. AU - Danesh, J.* AU - Sanghera, D.K.* C1 - 28118 C2 - 32951 SP - 1746-1755 TI - Genome-wide association study identifies a novel locus contributing to type 2 diabetes susceptibility in Sikhs of Punjabi origin from India. JO - Diabetes VL - 62 IS - 5 PB - Amer. Diabetes Assoc. PY - 2013 SN - 0012-1797 ER - TY - JOUR AB - Indians undergoing socioeconomic and lifestyle transitions will be maximally affected by epidemic of type 2 diabetes (T2D). We conducted a two-stage genome-wide association study of T2D in 12,535 Indians, a less explored but high-risk group. We identified a new type 2 diabetes-associated locus at 2q21, with the lead signal being rs6723108 (odds ratio 1.31; P = 3.32 × 10(-9)). Imputation analysis refined the signal to rs998451 (odds ratio 1.56; P = 6.3 × 10(-12)) within TMEM163 that encodes a probable vesicular transporter in nerve terminals. TMEM163 variants also showed association with decreased fasting plasma insulin and homeostatic model assessment of insulin resistance, indicating a plausible effect through impaired insulin secretion. The 2q21 region also harbors RAB3GAP1 and ACMSD; those are involved in neurologic disorders. Forty-nine of 56 previously reported signals showed consistency in direction with similar effect sizes in Indians and previous studies, and 25 of them were also associated (P < 0.05). Known loci and the newly identified 2q21 locus altogether explained 7.65% variance in the risk of T2D in Indians. Our study suggests that common susceptibility variants for T2D are largely the same across populations, but also reveals a population-specific locus and provides further insights into genetic architecture and etiology of T2D. AU - Tabassum, R.* AU - Chauhan, G.* AU - Dwivedi, O.P.* AU - Mahajan, A.* AU - Jaiswal, A.* AU - Kaur, I.* AU - Bandesh, K.* AU - Singh, T.* AU - Mathai, B.J.* AU - Pandey, Y.* AU - Chidambaram, M.* AU - Sharma, A.* AU - Chavali, S.* AU - Sengupta, S.* AU - Ramakrishnan, L.* AU - Venkatesh, P.* AU - Aggarwal, S.K.* AU - Ghosh, S.* AU - Prabhakaran, D.* AU - Srinath, R.K.* AU - Saxena, M.* AU - Banerjee, M.* AU - Mathur, S.* AU - Bhansali, A.* AU - Shah, V.N.* AU - Madhu, S.V.* AU - Marwaha, R.K.* AU - Basu, A.* AU - Scaria, V.* AU - McCarthy, M.I.* AU - DIAGRAM Consortium (Gieger, C. AU - Grallert, H. AU - Huth, C. AU - Illig, T. AU - Klopp, N. AU - Meitinger, T. AU - Petersen, A.-K. AU - Thorand, B. AU - Wichmann, H.-E.) AU - INDICO Consortium (*) AU - Venkatesan, R.* AU - Mohan, V.* AU - Tandon, N.* AU - Bharadwaj, D.* C1 - 23002 C2 - 30979 SP - 977-986 TI - Genome-wide association study for type 2 diabetes in Indians identifies a new susceptibility locus at 2q21. JO - Diabetes VL - 62 IS - 3 PB - American Diabetes Assoc. PY - 2013 SN - 0012-1797 ER - TY - JOUR AB - The role of free fatty acid receptor 1 (FFAR1/GPR40) in glucose homeostasis is still incompletely understood. Small receptor agonists stimulating insulin secretion are undergoing investigation for the treatment of type 2 diabetes. Surprisingly, genome-wide association studies did not discover diabetes risk variants in FFAR1. We reevaluated the role of FFAR1 in insulin secretion using a specific agonist, FFAR1-knockout mice and human islets. Nondiabetic individuals were metabolically phenotyped and genotyped. In vitro experiments indicated that palmitate and a specific FFAR1 agonist, TUG-469, stimulate glucose-induced insulin secretion through FFAR1. The proapoptotic effect of chronic exposure of beta-cells to palmitate was independent of FFAR1. TUG-469 was protective, whereas inhibition of FFAR1 promoted apoptosis. In accordance with the proapoptotic effect of palmitate, in vivo cross-sectional observations demonstrated a negative association between fasting free fatty acids (NEFAs) and insulin secretion. Because NEFAs stimulate secretion through FFAR1, we examined the interaction of genetic variation in FFAR1 with NEFA and insulin secretion. The inverse association of NEFA and secretion was modulated by rs1573611 and became steeper for carriers of the minor allele. In conclusion, FFAR1 agonists support beta-cell function, but variation in FFAR1 influences NEFA effects on insulin secretion and therefore could affect therapeutic efficacy of FFAR1 agonists. AU - Wagner, R. AU - Kaiser, G.* AU - Gerst, F. AU - Christiansen, E.* AU - Due-Hansen, M.E.* AU - Grundmann, M.* AU - Machicao, F. AU - Peter, A. AU - Kostenis, E.* AU - Ulven, T.* AU - Fritsche, A. AU - Häring, H.-U. AU - Ullrich, S. C1 - 25746 C2 - 31914 SP - 2106-2111 TI - Reevaluation of fatty acid receptor 1 as a drug target for the stimulation of insulin secretion in humans. JO - Diabetes VL - 62 IS - 6 PB - Amer. Diabetes Assoc. PY - 2013 SN - 0012-1797 ER - TY - JOUR AB - Circulating metabolites associated with insulin sensitivity may represent useful biomarkers, but their causal role in insulin sensitivity and diabetes is less certain. We previously identified novel metabolites correlated with insulin sensitivity measured by the hyperinsulinemic-euglycemic clamp. The top-ranking metabolites were in the glutathione and glycine biosynthesis pathways. We aimed to identify common genetic variants associated with metabolites in these pathways and test their role in insulin sensitivity and type 2 diabetes. With 1,004 nondiabetic individuals from the RISC study, we performed a genome-wide association study (GWAS) of 14 insulin sensitivity-related metabolites and one metabolite ratio. We replicated our results in the Botnia study (n = 342). We assessed the association of these variants with diabetes-related traits in GWAS meta-analyses (GENESIS [including RISC, EUGENE2, and Stanford], MAGIC, and DIAGRAM). We identified four associations with three metabolites-glycine (rs715 at CPS1), serine (rs478093 at PHGDH), and betaine (rs499368 at SLC6A12; rs17823642 at BHMT)-and one association signal with glycine-to-serine ratio (rs1107366 at ALDH1L1). There was no robust evidence for association between these variants and insulin resistance or diabetes. Genetic variants associated with genes in the glycine biosynthesis pathways do not provide consistent evidence for a role of glycine in diabetes-related traits. AU - Xie, W.* AU - Wood, A.R.* AU - Lyssenko, V.* AU - Weedon, M.N.* AU - Knowles, J.W.* AU - Alkayyali, S.* AU - Assimes, T.L.* AU - Quertermous, T.* AU - Abbasi, F.* AU - Paananen, J.* AU - Häring, H.-U. AU - Hansen, T.* AU - Pedersen, O.* AU - Smith, U.* AU - Laakso, M.* AU - MAGIC Investigators (Gieger, C. AU - Wichmann, H.-E. AU - Grallert, H. AU - Thorand, B. AU - Illig, T. AU - Meisinger, C.) AU - DIAGRAM Consortium (Huth, C. AU - Grallert, H. AU - Meitinger, T. AU - Gieger, C. AU - Wichmann, H.-E. AU - Illig, T. AU - Thorand, B. AU - Petersen, A.-K. AU - Klopp, N.) AU - Dekker, J.M.* AU - Nolan, J.J.* AU - Groop, L.* AU - Ferrannini, E.* AU - Adam, K.-P.* AU - Gall, W.E.* AU - Frayling, T.M.* AU - Walker, M.* C1 - 28109 C2 - 32952 SP - 2141-2150 TI - Genetic variants associated with glycine metabolism and their role in insulin sensitivity and type 2 diabetes. JO - Diabetes VL - 62 IS - 6 PB - Amer. Diabetes Assoc. PY - 2013 SN - 0012-1797 ER - TY - JOUR AB - Exploring genetic pleiotropy can provide clues to a mechanism underlying the observed epidemiological association between type 2 diabetes and heightened fracture risk. We examined genetic variants associated with bone mineral density (BMD) for association with type 2 diabetes and glycemic traits in large well-phenotyped and -genotyped consortia. We undertook follow-up analysis in ∼19,000 individuals and assessed gene expression. We queried single nucleotide polymorphisms (SNPs) associated with BMD at levels of genome-wide significance, variants in linkage disequilibrium (r(2) > 0.5), and BMD candidate genes. SNP rs6867040, at the ITGA1 locus, was associated with a 0.0166 mmol/L (0.004) increase in fasting glucose per C allele in the combined analysis. Genetic variants in the ITGA1 locus were associated with its expression in the liver but not in adipose tissue. ITGA1 variants appeared among the top loci associated with type 2 diabetes, fasting insulin, β-cell function by homeostasis model assessment, and 2-h post-oral glucose tolerance test glucose and insulin levels. ITGA1 has demonstrated genetic pleiotropy in prior studies, and its suggested role in liver fibrosis, insulin secretion, and bone healing lends credence to its contribution to both osteoporosis and type 2 diabetes. These findings further underscore the link between skeletal and glucose metabolism and highlight a locus to direct future investigations. AU - Billings, L.K.* AU - Hsu, Y.H.* AU - Ackerman, R.J.* AU - Dupuis, J.* AU - Voight, B.F.* AU - Rasmussen-Torvik, L.J.* AU - Hercberg, S.* AU - Lathrop, M* AU - Barnes, D.* AU - Langenberg, C.* AU - Hui, J.* AU - Fu, M.* AU - Bouatia-Naji, N.* AU - Lecoeur, C.* AU - An, P.* AU - Magnusson, P.K.* AU - Surakka, I.* AU - Ripatti, S.* AU - Christiansen, L.* AU - Dalgård, C.* AU - Folkersen, L.* AU - Grundberg, E.* AU - MAGIC Investigators (Gieger, C. AU - Grallert, H. AU - Meisinger, C. AU - Wichmann, H.-E. AU - Thorand, B. AU - Illig, T.) AU - DIAGRAM Consortium (Huth, C. AU - Klopp, N. AU - Meitinger, T. AU - Thorand, B. AU - Grallert, H. AU - Gieger, C. AU - Wichmann, H.-E. AU - Illig, T. AU - Petersen, A.-K.) AU - MuTHER Consortium (*) AU - ASCOT Investigators (*) AU - GEFOS Consortium (*) AU - Eriksson, P.* AU - Kaprio, J.* AU - Ohm Kyvik, K.* AU - Pedersen, N.L.* AU - Borecki, I.B.* AU - Province, M.A.* AU - Balkau, B.* AU - Froguel, P.* AU - Shuldiner, A.R.* AU - Palmer, L.J.* AU - Wareham, N.J.* AU - Meneton, P.* AU - Johnson, T.* AU - Pankow, J.S.* AU - Karasik, D.* AU - Meigs, J.B.* AU - Kiel, D.P.* AU - Florez, J.C* C1 - 8457 C2 - 30115 SP - 2176-2186 TI - Impact of common variation in bone-related genes on type 2 diabetes and related traits. JO - Diabetes VL - 61 IS - 8 PB - American Diabetes Assoc. PY - 2012 SN - 0012-1797 ER - TY - JOUR AB - It has recently been suggested that the low-frequency c.136-14_136-13insC variant in high-mobility group A1 (HMGA1) may strongly contribute to insulin resistance and type 2 diabetes risk. In our study, we attempted to confirm that HMGA1 is a novel type 2 diabetes locus in French Caucasians. The gene was sequenced in 368 type 2 diabetic case subjects with a family history of type 2 diabetes and 372 normoglycemic control subjects without a family history of type 2 diabetes. None of the 41 genetic variations identified were associated with type 2 diabetes. The lack of association between the c.136-14_136-13insC variant and type 2 diabetes was confirmed in an independent French group of 4,538 case subjects and 4,015 control subjects and in a large meta-analysis of 16,605 case subjects and 46,179 control subjects. Finally, this variant had no effects on metabolic traits and was not involved in variations of HMGA1 and insulin receptor (INSR) expressions. The c.136-14_136-13insC variant was not associated with type 2 diabetes in individuals of European descent. Our study emphasizes the need to analyze a large number of subjects to reliably assess the association of low-frequency variants with the disease. AU - Marquez, M.* AU - Huyvaert, M.* AU - Perry, J.R.* AU - Pearson, R.D.* AU - Falchi, M.* AU - Morris, A.P.* AU - Vivequin, S.* AU - Lobbens, S.* AU - Yengo, L.* AU - Gaget, S.* AU - Pattou, F.* AU - Poulain-Godefroy, O.* AU - Charpentier, G.* AU - Carlsson, L.M.* AU - Jacobson, P.* AU - Sjöström, L.* AU - Lantieri, O.* AU - Heude, B.* AU - Walley, A.* AU - Balkau, B.* AU - Marre, M.* AU - Froguel, P.* AU - Cauchi, S* 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 - 7314 C2 - 29677 SP - 524-530 TI - Low-frequency variants in HMGA1 are not associated with type 2 diabetes risk. JO - Diabetes VL - 61 IS - 2 PB - American Diabetes Assoc. PY - 2012 SN - 0012-1797 ER - TY - JOUR AB - Diabetes is generally diagnosed too late. Therefore, biomarkers indicating early stages of beta-cell dysfunction and mass reduction would facilitate timely counteraction. Transgenic pigs expressing a dominant-negative glucose-dependent insulinotropic polypeptide receptor (GIPR(dn)) reveal progressive deterioration of glucose control and reduction of beta-cell mass, providing a unique opportunity to study metabolic changes during the prediabetic period. Plasma samples from intravenous glucose tolerance tests of 2.5- and 5-month-old GIPR(dn) transgenic and control animals were analyzed for 163 metabolites by targeted mass spectrometry. Analysis of variance revealed that 26 of 163 parameters were influenced by the interaction Genotype x Age (P <= 0.0001) and thus are potential markers for progression within the prediabetic state. Among them, the concentrations of seven amino acids (Phe, Orn, Val, xLeu, His, Arg, and Tyr) were increased in 2.5-month-old but decreased in 5-month-old GIPR(dn) transgenic pigs versus controls. Furthermore, specific sphingomyelins, diacylglycerols, and ether phospholipids were decreased in plasma of 5-month-old GIPR(dn) transgenic pigs. Alterations in plasma metabolite concentrations were associated with liver transcriptome changes in relevant pathways. The concentrations of a number of plasma amino acids and lipids correlated significantly with beta-cell mass of 5-monthold pigs. These metabolites represent candidate biomarkers of early phases of beta-cell dysfunction and mass reduction. Diabetes 61:2166-2175, 2012 AU - Renner, S.* AU - Römisch-Margl, W. AU - Prehn, C. AU - Krebs, S.* AU - Adamski, J. AU - Göke, B.* AU - Blum, H.* AU - Suhre, K. AU - Roscher, A.A.* AU - Wolf, E.* C1 - 8385 C2 - 30099 SP - 2166-2175 TI - Changing metabolic signatures of amino acids and lipids during the prediabetic period in a pig model with impaired incretin function and reduced β-cell mass. JO - Diabetes VL - 61 IS - 8 PB - Amer. Diabetes Assoc. PY - 2012 SN - 0012-1797 ER - TY - JOUR AB - no Abstract AU - Tschöp, M.H. AU - DiMarchi, R.D.* C1 - 8007 C2 - 30000 SP - 1309-1314 TI - Outstanding scientific achievement award lecture 2011: Defeating diabesity: The case for personalized combinatorial therapies. JO - Diabetes VL - 61 IS - 6 PB - Amer. Diabetes Assoc. PY - 2012 SN - 0012-1797 ER - TY - JOUR AB - Glucocorticoid receptors are highly expressed in the hypothalamic paraventricular nucleus (PVN) and arcuate nucleus (ARC). As glucocorticoids have pronounced effects on neuropeptide Y (NPY) expression and as NPY neurons projecting from the ARC to the PVN are pivotal for balancing feeding behavior and glucose metabolism, we investigated the effect of glucocorticoid signaling in these areas on endogenous glucose production (EGP) and insulin sensitivity by local retrodialysis of the glucocorticoid receptor agonist dexamethasone into the ARC or the PVN, in combination with isotope dilution and hyperinsulinemic-euglycemic clamp techniques. Retrodialysis of dexamethasone for 90 min into the ARC or the PVN did not have significant effects on basal plasma glucose concentration. During the hyperinsulinemic-euglycemic clamp, retrodialysis of dexamethasone into the ARC largely prevented the suppressive effect of hyperinsulinemia on EGP. Antagonizing the NPY1 receptors by intracerebroventricular infusion of its antagonist largely blocked the hepatic insulin resistance induced by dexamethasone in the ARC. The dexamethasone-ARC-induced inhibition of hepatic insulin sensitivity was also prevented by hepatic sympathetic denervation. These data suggest that glucocorticoid signaling specifically in the ARC neurons modulates hepatic insulin responsiveness via NPY and the sympathetic system, which may add to our understanding of the metabolic impact of clinical conditions associated with hypercortisolism. AU - Yi, C.-X. AU - Foppen, E.* AU - Abplanalp, W.* AU - Gao, Y.* AU - Alkemade, A.* AU - la Fleur, S.E.* AU - Serlie, M.J.* AU - Fliers, E.* AU - Buijs, R.M.* AU - Tschöp, M.H. AU - Kalsbeek, A.* C1 - 7189 C2 - 29534 SP - 339-345 TI - Glucocorticoid signaling in the arcuate nucleus modulates hepatic insulin sensitivity. JO - Diabetes VL - 61 IS - 2 PB - Amer. Diabetes Assoc. PY - 2012 SN - 0012-1797 ER - TY - JOUR AB - Women with gestational diabetes mellitus (GDM) have a high risk of developing postpartum type 2 diabetes. Strategies to prevent postpartum type 2 diabetes are important to reduce the epidemic of diabetes and its societal impact. Breastfeeding was reported to improve early postpartum glucose tolerance and reduce the subsequent risk of type 2 diabetes. To investigate whether breastfeeding influences short- and long-term postpartum diabetes outcomes, women with GDM (n = 304) participating in the prospective German GDM study were followed from delivery for up to 19 years postpartum for diabetes development. All participants were recruited between 1989 and 1999. Postpartum diabetes developed in 147 women and was dependent on the treatment received during pregnancy (insulin vs. diet), BMI, and presence/absence of islet autoantibodies. Among islet autoantibody-negative women, breastfeeding was associated with median time to diabetes of 12.3 years compared with 2.3 years in women who did not breastfeed. The lowest postpartum diabetes risk was observed in women who breastfed for >3 months. On the basis of these results, we recommend that breastfeeding should be encouraged among these women because it offers a safe and feasible low-cost intervention to reduce the risk of subsequent diabetes in this high-risk population. Diabetes 61:3167-3171, 2012 AU - Ziegler, A.-G. AU - Wallner, M. AU - Kaiser, I.* AU - Rossbauer, M. AU - Harsunen, M.H. AU - Lachmann, L.* AU - Maier, J.M.* AU - Winkler, C. AU - Hummel, S. C1 - 11540 C2 - 30721 SP - 3167-3171 TI - Long-term protective effect of lactation on the development of type 2 diabetes in women with recent gestational diabetes mellitus. JO - Diabetes VL - 61 IS - 12 PB - American Diabetes Assoc. PY - 2012 SN - 0012-1797 ER - TY - JOUR AB - OBJECTIVE The incidence of type 1 diabetes is increasing. Delivery by cesarean section is also more prevalent, and it is suggested that cesarean section is associated with type 1 diabetes risk. We examine associations between cesarean delivery, islet autoimmunity and type 1 diabetes, and genes involved in type 1 diabetes susceptibility. RESEARCH DESIGN AND METHODS Cesarean section was examined as a risk factor in 1,650 children born to a parent with type 1 diabetes and followed from birth for the development of islet autoantibodies and type 1 diabetes. RESULTS Children delivered by cesarean section (n = 495) had more than twofold higher risk for type 1 diabetes than children born by vaginal delivery (hazard ratio [HR] 2.5; 95% CI 1.4-4.3; P = 0.001). Cesarean section did not increase the risk for islet autoantibodies (P = 0.6) but was associated with a faster progression to diabetes after the appearance of autoimmunity (P = 0.015). Cesarean section-associated risk was independent of potential confounder variables (adjusted HR 2.7;1.5-5.0; P = 0.001) and observed in children with and without high-risk HLA genotypes. Interestingly, cesarean section appeared to interact with immune response genes, including CD25 and in particular the interferon-induced helicase 1 gene, where increased risk for type 1 diabetes was only seen in children who were delivered by cesarean section and had type 1 diabetes-susceptible IFIH1 genotypes (12-year risk, 9.1 vs. <3% for all other combinations; P < 0.0001). CONCLUSIONS These findings suggest that type 1 diabetes risk modification by cesarean section may be linked to viral responses in the preclinical autoantibody-positive disease phase. AU - Bonifacio, E. AU - Warncke, K. AU - Winkler, C. AU - Wallner, M.* AU - Ziegler, A.-G. C1 - 6715 C2 - 29306 CY - Alexandria SP - 3300-3306 TI - Cesarean section and interferon-induced helicase gene polymorphisms combine to increase childhood type 1 diabetes risk. JO - Diabetes VL - 60 IS - 12 PY - 2011 SN - 0012-1797 ER - TY - JOUR AB - Over 30 loci have been associated with risk of type 2 diabetes at genome-wide statistical significance. Genetic risk scores (GRSs) developed from these loci predict diabetes in the general population. We tested if a GRS based on an updated list of 34 type 2 diabetes-associated loci predicted progression to diabetes or regression toward normal glucose regulation (NGR) in the Diabetes Prevention Program (DPP). RESEARCH DESIGN AND METHODS: We genotyped 34 type 2 diabetes-associated variants in 2,843 DPP participants at high risk of type 2 diabetes from five ethnic groups representative of the U.S. population, who had been randomized to placebo, metformin, or lifestyle intervention. We built a GRS by weighting each risk allele by its reported effect size on type 2 diabetes risk and summing these values. We tested its ability to predict diabetes incidence or regression to NGR in models adjusted for age, sex, ethnicity, waist circumference, and treatment assignment.RESULTS: In multivariate-adjusted models, the GRS was significantly associated with increased risk of progression to diabetes (hazard ratio [HR] = 1.02 per risk allele [95% CI 1.00-1.05]; P = 0.03) and a lower probability of regression to NGR (HR = 0.95 per risk allele [95% CI 0.93-0.98]; P < 0.0001). At baseline, a higher GRS was associated with a lower insulinogenic index (P < 0.001), confirming an impairment in β-cell function. We detected no significant interaction between GRS and treatment, but the lifestyle intervention was effective in the highest quartile of GRS (P < 0.0001). CONCLUSIONS: A high GRS is associated with increased risk of developing diabetes and lower probability of returning to NGR in high-risk individuals, but a lifestyle intervention attenuates this risk. AU - Hivert, M.F.* AU - Jablonski, K.A.* AU - Perreault, L.* AU - Saxena, R.* AU - McAteer, J.B.* AU - Franks, P.W.* AU - Hamman, R.F.* AU - Kahn, S.E.* AU - Haffner, S* 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 - Meigs, J.B.* AU - Altshuler, D.* AU - Knowler, W.C.* AU - Florez, J.C* C1 - 6449 C2 - 28703 SP - 1340-1348 TI - Updated genetic score based on 34 confirmed type 2 diabetes loci is associated with diabetes incidence and regression to normoglycemia in the diabetes prevention program. JO - Diabetes VL - 60 IS - 4 PB - Amer Diabetes Assoc. PY - 2011 SN - 0012-1797 ER - TY - JOUR AB - Many genetic variants have been associated with glucose homeostasis and type 2 diabetes in genome-wide association studies. Zinc is an essential micronutrient that is important for β-cell function and glucose homeostasis. We tested the hypothesis that zinc intake could influence the glucose-raising effect of specific variants. RESEARCH DESIGN AND METHODS: We conducted a 14-cohort meta-analysis to assess the interaction of 20 genetic variants known to be related to glycemic traits and zinc metabolism with dietary zinc intake (food sources) and a 5-cohort meta-analysis to assess the interaction with total zinc intake (food sources and supplements) on fasting glucose levels among individuals of European ancestry without diabetes. RESULTS: We observed a significant association of total zinc intake with lower fasting glucose levels (β-coefficient ± SE per 1 mg/day of zinc intake: -0.0012 ± 0.0003 mmol/L, summary P value = 0.0003), while the association of dietary zinc intake was not significant. We identified a nominally significant interaction between total zinc intake and the SLC30A8 rs11558471 variant on fasting glucose levels (β-coefficient ± SE per A allele for 1 mg/day of greater total zinc intake: -0.0017 ± 0.0006 mmol/L, summary interaction P value = 0.005); this result suggests a stronger inverse association between total zinc intake and fasting glucose in individuals carrying the glucose-raising A allele compared with individuals who do not carry it. None of the other interaction tests were statistically significant. CONCLUSIONS: Our results suggest that higher total zinc intake may attenuate the glucose-raising effect of the rs11558471 SLC30A8 (zinc transporter) variant. Our findings also support evidence for the association of higher total zinc intake with lower fasting glucose levels. AU - Kanoni, S.* AU - Nettleton, J.A.* AU - Hivert, M.F.* AU - Ye, Z.* AU - van Rooij, F.J.* AU - Shungin, D.* AU - Sonestedt, E.* AU - Ngwa, J.S.* AU - Wojczynski, M.K.* AU - Lemaitre, R.N.* AU - Gustafsson, S.* AU - Anderson, J.S.* AU - Tanaka, T.* AU - Hindy, G.* AU - Saylor, G.* AU - Renström, F.* AU - Bennett, A.J.* AU - van Duijn, C.M.* AU - Florez, J.C* AU - Fox, C.S.* AU - Hofman, A.* AU - Hoogeveen, R.C.* AU - Houston, D.K.* AU - Hu, F.B.* AU - Jacques, P.F.* AU - Johansson, I.* AU - Lind, L.* AU - Liu, Y.* AU - McKeown, N.* AU - Ordovas, J.* AU - Pankow, J.S.* AU - Sijbrands, E.J.* AU - Syvanen, A.C.* AU - Uitterlinden, A.G.* AU - Yannakoulia, M.* AU - Zillikens, M.C.* AU - MAGIC Investigators (Gieger, C. AU - Grallert, H. AU - Meisinger, C. AU - Wichmann, H.-E. AU - Illig, T.) AU - Wareham, N.J.* AU - Prokopenko, I.* AU - Bandinelli, S.* AU - Forouhi, N.G.* AU - Cupples, L.A.* AU - Loos, R.J.* AU - Hallmans, G.* AU - Dupuis, J.* AU - Langenberg, C.* AU - Ferrucci, L.* AU - Kritchevsky, S.B.* AU - McCarthy, M.I.* AU - Ingelsson, E.* AU - Borecki, I.B.* AU - Witteman, J.C.* AU - Orho-Melander, M.* AU - Siscovick, D.S.* AU - Meigs, J.B.* AU - Franks, P.W.* AU - Dedoussis, G.V.* C1 - 6865 C2 - 29368 SP - 2407-2416 TI - Total zinc intake may modify the glucose-raising effect of a zinc transporter (SLC30A8) variant: A 14-cohort meta-analysis. JO - Diabetes VL - 60 IS - 9 PB - Amer Diabetes Assoc. PY - 2011 SN - 0012-1797 ER - TY - JOUR AB - OBJECTIVE: Islet autoimmunity precedes type 1 diabetes and often initiates in childhood. Phenotypic variation in islet autoimmunity relative to the age of its development suggests heterogeneous mechanisms of autoimmune activation. To support this notion, we examined whether serum metabolite profiles differ between children with respect to islet autoantibody status and the age of islet autoantibody development. RESEARCH DESIGN AND METHODS: The study analyzed 29 metabolites of amino acid metabolism and 511 lipids assigned to 12 lipid clusters in children, with a type 1 diabetic parent, who first developed autoantibodies at age 2 years or younger (n = 13), at age 8 years or older (n = 22), or remained autoantibody-negative, and were matched for age, date of birth, and HLA genotypes (n = 35). Ultraperformance liquid chromatography and mass spectroscopy were used to measure metabolites and lipids quantitatively in the first autoantibody-positive and matched autoantibody-negative serum samples and in a second sample after 1 year of follow-up. RESULTS: Differences in the metabolite profiles were observed relative to age and islet autoantibody status. Independent of age-related differences, autoantibody-positive children had higher levels of odd-chain triglycerides and polyunsaturated fatty acid-containing phospholipids than autoantibody-negative children and independent of age at first autoantibody appearance (P < 0.0001). Consistent with our hypothesis, children who developed autoantibodies by age 2 years had twofold lower concentration of methionine compared with those who developed autoantibodies in late childhood or remained autoantibody-negative (P < 0.0001). CONCLUSIONS :Distinct metabolic profiles are associated with age and islet autoimmunity. Pathways that use methionine are potentially relevant for developing islet autoantibodies in early infancy. AU - Pflueger, M. AU - Seppänen-Laakso, T.* AU - Suortti, T.* AU - Hyötyläinen, T.* AU - Achenbach, P. AU - Bonifacio, E.* AU - Oresič, M.* AU - Ziegler, A.-G. C1 - 6875 C2 - 29378 CY - Alexandria, VA SP - 2740-2747 TI - Age- and islet autoimmunity-associated differences in amino acid and lipid metabolites in children at risk for type 1 diabetes. JO - Diabetes VL - 60 IS - 11 PB - American Diabetes Assoc. PY - 2011 SN - 0012-1797 ER - TY - JOUR AB - OBJECTIVE: To assess whether recently discovered genetic loci associated with hyperglycemia also predict long-term changes in glycemic traits. RESEARCH DESIGN AND METHODS: Sixteen fasting glucose-raising loci were genotyped in middle-aged adults from the Gene x Lifestyle interactions And Complex traits Involved in Elevated disease Risk (GLACIER) Study, a population-based prospective cohort study from northern Sweden. Genotypes were tested for association with baseline fasting and 2-h postchallenge glycemia (N = 16,330), and for changes in these glycemic traits during a 10-year follow-up period (N = 4,059).RESULTS: Cross-sectional directionally consistent replication with fasting glucose concentrations was achieved for 12 of 16 variants; 10 variants were also associated with impaired fasting glucose (IFG) and 7 were independently associated with 2-h postchallenge glucose concentrations. In prospective analyses, the effect alleles at four loci (GCK rs4607517, ADRA2A rs10885122, DGKB-TMEM195 rs2191349, and G6PC2 rs560887) were nominally associated with worsening fasting glucose concentrations during 10-years of follow-up. MTNR1B rs10830963, which was predictive of elevated fasting glucose concentrations in cross-sectional analyses, was associated with a protective effect on postchallenge glucose concentrations during follow-up; however, this was only when baseline fasting and 2-h glucoses were adjusted for. An additive effect of multiple risk alleles on glycemic traits was observed: a weighted genetic risk score (80th vs. 20th centiles) was associated with a 0.16 mmol/l (P = 2.4 × 10⁻⁶) greater elevation in fasting glucose and a 64% (95% CI: 33-201%) higher risk of developing IFG during 10 years of follow-up. CONCLUSIONS: Our findings imply that genetic profiling might facilitate the early detection of persons who are genetically susceptible to deteriorating glucose control; studies of incident type 2 diabetes and discrete cardiovascular end points will help establish whether the magnitude of these changes is clinically relevant. AU - Renström, F.* AU - Shungin, D.* AU - Johansson, I* AU - MAGIC Investigators (Grallert, H. AU - Gieger, C. AU - Meisinger, C. AU - Thorand, B. AU - Wichmann, H.-E. AU - Illig, T.) AU - Florez, J.C* AU - Hallmans, G.* AU - Hu, F.B.* AU - Franks, P.W.* C1 - 6902 C2 - 29408 SP - 345-354 TI - Genetic predisposition to long-term nondiabetic deteriorations in glucose homeostasis: Ten-year follow-up of the GLACIER study. JO - Diabetes VL - 60 IS - 1 PB - Amer Diabetes Assoc PY - 2011 SN - 0012-1797 ER - TY - JOUR AB - OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis. AU - Strawbridge, R.J.* AU - Dupuis, J.* AU - Prokopenko, I.* AU - Barker, A.* AU - Ahlqvist, E.* AU - Rybin, D.* AU - Petrie, J.R.* AU - Travers, M.E.* AU - Bouatia-Naji, N.* AU - Dimas, A.S.* AU - Nica, A.* AU - Wheeler, E.* AU - Chen, H.* AU - Voight, B.F.* AU - Taneera, J.* AU - Kanoni, S.* AU - Peden, J.F.* AU - Turrini, F.* AU - Gustafsson, S.* AU - Zabena, C.* AU - Almgren, P.* AU - Barker, D.J.* AU - Barnes, D.* AU - Dennison, E.M.* AU - Eriksson, J.G.* AU - Eriksson, P.* AU - Eury, E.* AU - Folkersen, L.* AU - Fox, C.S.* AU - Frayling, T.M.* AU - Goel, A.* AU - Gu, H.F.* AU - Horikoshi, M.* AU - Isomaa, B.* AU - Jackson, A.U.* AU - Jameson, K.A.* AU - Kajantie, E.* AU - Kerr-Conte, J.* AU - Kuulasmaa, T.* AU - Kuusisto, J.* AU - Loos, R.J.* AU - Luan, J.* AU - Makrilakis, K.* AU - Manning, A.K.* AU - Martinez-Larrad, M.T.* AU - Narisu, N.* AU - Nastase, Mannila, M.* AU - Ohrvik, J.* AU - Osmond, C.* AU - Pascoe, L.* AU - Payne, F.* AU - Sayer, A.A.* AU - Sennblad, B.* AU - Silveira, A.* AU - Stancáková, A.* AU - Stirrups, K.* AU - Swift, A.J.* AU - Syvanen, A.C.* AU - Tuomi, T.* AU - van't Hooft, F.M.* AU - Walker, M.* AU - Weedon, M.N.* AU - Xie, W.* AU - Zethelius, B* AU - DIAGRAM Consortium (Huth, C. AU - Grallert, H. AU - Gieger, C. AU - Klopp, N. AU - Meitinger, T. AU - Petersen, A.-K. AU - Wichmann, H.-E. AU - Illig, T.) AU - GIANT Consortium (Heid, I.M. AU - Lamina, C. AU - Thiering, E. AU - Illig, T. AU - Peters, A. AU - Wichmann, H.-E. AU - Grallert, H. AU - Heinrich, J. AU - Gieger, C.) AU - MuTHER Consortium (*) AU - CARDIoGRAM Consortium (Wichmann, H.-E. AU - Illig, T. AU - Döring, A. AU - Peters, A. AU - Klopp, N. AU - Meisinger, C. AU - Meitinger, T.) AU - C4D Consortium (*) AU - Ongen, H.* AU - Mälarstig, A.* AU - Hopewell, J.C.* AU - Saleheen, D.* AU - Chambers, J.* AU - Parish, S.* AU - Danesh, J.* AU - Kooner, J.* AU - Ostenson, C.G.* AU - Lind, L.* AU - Cooper, C.C.* AU - Serrano-Rios, M.* AU - Ferrannini, E.* AU - Forsen, T.J.* AU - Clarke, R.* AU - Franzosi, M.G.* AU - Seedorf, U.* AU - Watkins, H.* AU - Froguel, P.* AU - Johnson, P.* AU - Deloukas, P.* AU - Collins, F.S.* AU - Laakso, M.* AU - Dermitzakis, E.T.* AU - Boehnke, M.* AU - McCarthy, M.I.* AU - Wareham, N.J.* AU - Groop, L.* AU - Pattou, F.* AU - Gloyn, A.L.* AU - Dedoussis, G.V.* AU - Lyssenko, V.* AU - Meigs, J.B.* AU - Barroso, I.* AU - Watanabe, R.M.* AU - Ingelsson, E.* AU - Langenberg, C.* AU - Hamsten, A.* AU - Florez, J.C* C1 - 6770 C2 - 29249 SP - 2624-2634 TI - Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes. JO - Diabetes VL - 60 IS - 10 PB - Amer Diabetes Assoc. PY - 2011 SN - 0012-1797 ER - TY - JOUR AB - OBJECTIVE: Genome-wide association studies have identified gene regions associated with the development of type 1 diabetes. The aim of this study was to determine whether these associations are with the development of autoimmunity and/or progression to diabetes. RESEARCH DESIGN AND METHODS: Children (n = 1,650) of parents with type 1 diabetes were prospectively followed from birth (median follow-up 10.20 years) for the development of islet autoantibodies, thyroid peroxidase antibodies, tissue transglutaminase antibodies, and diabetes. Genotyping for single-nucleotide polymorphisms of the PTPN22, ERBB3, PTPN2, KIAA0350, CD25, and IFIH1 genes was performed using the MassARRAY system with iPLEX chemistry. RESULTS: Islet autoantibodies developed in 137 children and diabetes developed in 47 children. Type 1 diabetes risk was associated with the IFIH1 rs2111485 single-nucleotide polymorphism (hazard ratio 2.08; 95% CI 1.16-3.74; P = 0.014). None of the other genes were significantly associated with diabetes development in this cohort. IFIH1 genotypes did not associate with the development of islet autoantibodies (P = 0.80) or autoantibodies against thyroid peroxidase (P = 0.55) and tissue transglutaminase (P = 0.66). Islet autoantibody-positive children with the IFIH1 rs2111485 GG genotype had a faster progression to diabetes (31% within 5 years) than children with the type 1 diabetes protective GA or AA genotypes (11% within 5 years; P = 0.006). CONCLUSIONS: The findings indicate that IFIH1 genotypes influence progression from autoimmunity to diabetes development, consistent with the notion that protective genotypes downregulate responses to environmental insults after initiation of autoimmunity. AU - Winkler, C. AU - Lauber, C. AU - Adler, K.* AU - Grallert, H. AU - Illig, T. AU - Ziegler, A.-G. AU - Bonifacio, E.* C1 - 6316 C2 - 28481 CY - Alexandria SP - 685-690 TI - An interferon-induced helicase (IFIH1) gene polymorphism associates with different rates of progression from autoimmunity to type 1 diabetes. JO - Diabetes VL - 60 IS - 2 PB - Amer Diabetes Assoc PY - 2011 SN - 0012-1797 ER - TY - JOUR AB - OBJECTIVE: Glycated hemoglobin (HbA₁(c)), used to monitor and diagnose diabetes, is influenced by average glycemia over a 2- to 3-month period. Genetic factors affecting expression, turnover, and abnormal glycation of hemoglobin could also be associated with increased levels of HbA₁(c). We aimed to identify such genetic factors and investigate the extent to which they influence diabetes classification based on HbA₁(c) levels. RESEARCH DESIGN AND METHODS: We studied associations with HbA₁(c) in up to 46,368 nondiabetic adults of European descent from 23 genome-wide association studies (GWAS) and 8 cohorts with de novo genotyped single nucleotide polymorphisms (SNPs). We combined studies using inverse-variance meta-analysis and tested mediation by glycemia using conditional analyses. We estimated the global effect of HbA₁(c) loci using a multilocus risk score, and used net reclassification to estimate genetic effects on diabetes screening. RESULTS: Ten loci reached genome-wide significant association with HbA(1c), including six new loci near FN3K (lead SNP/P value, rs1046896/P = 1.6 × 10⁻²⁶), HFE (rs1800562/P = 2.6 × 10⁻²⁰), TMPRSS6 (rs855791/P = 2.7 × 10⁻¹⁴), ANK1 (rs4737009/P = 6.1 × 10⁻¹²), SPTA1 (rs2779116/P = 2.8 × 10⁻⁹) and ATP11A/TUBGCP3 (rs7998202/P = 5.2 × 10⁻⁹), and four known HbA₁(c) loci: HK1 (rs16926246/P = 3.1 × 10⁻⁵⁴), MTNR1B (rs1387153/P = 4.0 × 10⁻¹¹), GCK (rs1799884/P = 1.5 × 10⁻²⁰) and G6PC2/ABCB11 (rs552976/P = 8.2 × 10⁻¹⁸). We show that associations with HbA₁(c) are partly a function of hyperglycemia associated with 3 of the 10 loci (GCK, G6PC2 and MTNR1B). The seven nonglycemic loci accounted for a 0.19 (% HbA₁(c)) difference between the extreme 10% tails of the risk score, and would reclassify ∼2% of a general white population screened for diabetes with HbA₁(c). CONCLUSIONS: GWAS identified 10 genetic loci reproducibly associated with HbA₁(c). Six are novel and seven map to loci where rarer variants cause hereditary anemias and iron storage disorders. Common variants at these loci likely influence HbA₁(c) levels via erythrocyte biology, and confer a small but detectable reclassification of diabetes diagnosis by HbA₁(c). AU - Soranzo, N.* AU - Sanna, S.* AU - Wheeler, E.* AU - Gieger, C. AU - Radke, D.* AU - Dupuis, J. AU - Boutaia-Naji, N.* AU - Langenberg, C.* AU - Prokopenko, I.* AU - Stolerman, E.* AU - Sandhu, M.S.* AU - Heeney, M.M.* AU - Devaney, J.M.* AU - Reilly, M.P.* AU - Ricketts, S.L.* AU - Stewart, A.F.R.* AU - Voight, B.F.* AU - Willenborg, C.* AU - Wright, B.* AU - Altshuler, D.* AU - Arking, D.* AU - Balkau, B.* AU - Barnes, D.* AU - Boerwinkle, E. AU - Bohm, B.* AU - Bonnefond, A.* AU - Bonnycastle, L.L.* AU - Boomsma, D.I.* AU - Bornstein, S.R.* AU - Böttcher, Y.* AU - Bumpstead, S.* AU - Burnett-Miller, M.S.* AU - Campbell, H.* AU - Cao, A.* AU - Chambers, J.* AU - Clark, R.* AU - Collins, F.S.* AU - Coresh, J.* AU - Geus, E.J.C.* AU - Die, M.* AU - Deloukas, P.* AU - Döring, A.* AU - Egan, J.M.* AU - Elosua, R.* AU - Ferrucci, L.* AU - Forouhi, N.* AU - Fox, C.S.* AU - Franklin, C.* AU - Franzosi, M.G.* AU - Gallina, S.* AU - Goel, A.* AU - Graessler, J. AU - Grallert, H. AU - Greinacher, A.* AU - Hadley, D.* AU - Hall, A.* AU - Hamsten, A.* AU - Hayward, C.* AU - Heath, S.* AU - Herder, C.* AU - Homuth, V.* AU - Hottenga, J.-J.* AU - Hunter-Merril, R.* AU - Illig, T. AU - Jackson, A.U.* AU - Jula, A.* AU - Kleber, M.* AU - Knouff, C.W.* AU - Kong, A.* AU - Kooner, J.* AU - Köttgen, A.* AU - Kovacs, P.* AU - Krohn, K.* AU - Kühne, B.* AU - Kuusisto, J.* AU - Laakso, M.* AU - Lecoeur, C.* AU - Li, M.* AU - Loos, R.J.F.* AU - Luan, J.* AU - Lyssenko, V.* AU - Mägi, R.* AU - Magnusson, P.K.E.* AU - Mälastig, A.* AU - Mangino, M. AU - Martinez-Larrad, M.T.* AU - Marz, W.* AU - McArdle, W.L.* AU - McPherson, R.* AU - Meisinger, C. AU - Meitinger, T. AU - Melander, O.* AU - Wichmann, H.-E. AU - Winkelmann, J.* AU - Peltonen, L. AU - Rathmann, W. AU - Wild, S.H. AU - Procardis Consortium (*) AU - Wellcome Trust Case Consortium (WTCCC) (*) C1 - 5298 C2 - 28129 SP - 3229-3239 TI - Common variants at 10 genomic loci influence hemoglobin A₁C levels via glycemic and nonglycemic pathways. JO - Diabetes VL - 59 IS - 12 PB - Amer. Diabetes Assoc. PY - 2010 SN - 0012-1797 ER - TY - JOUR AB - OBJECTIVE: To determine whether HHEX-IDE and CDKAL1 genes, which are associated with birth weight and susceptibility to type 2 diabetes, continue to influence growth during childhood. RESEARCH DESIGN AND METHODS: BMI, weight, and height at age 8 years expressed as age- and sex-corrected standard deviation scores (SDS) against national reference data and single-nucleotide polymorphism genotyping of HHEX-IDE and CDKAL1 loci were analyzed in 646 prospectively followed children in the German BABYDIAB cohort. All children were singleton full-term births; 386 had mothers with type 1 diabetes, and 260 had fathers with type 1 diabetes and a nondiabetic mother. RESULTS: Type 2 diabetes risk alleles at the HHEX-IDE locus were associated with reduced BMI-SDS at age 8 years (0.17 SDS per allele; P = 0.004). After stratification for birth weight, both HHEX-IDE and CDKAL1 risk alleles were associated with reduced BMI-SDS (0.45 SDS, P = 0.0002; 0.52 SDS, P = 0.0001) and weight-SDS (0.22 SDS, P = 0.04; 0.56 SDS, P = 0.0002) in children born large for gestational age (>90th percentile) but not children born small or appropriate for gestational age. Within children born large for gestational age, BMI and weight decreased with each additional type 2 diabetes risk allele ( approximately -2 kg per allele; >8 kg overall). Findings were consistent in children of mothers with type 1 diabetes (P < 0.0001) and children of nondiabetic mothers (P = 0.008). CONCLUSIONS: The type 2 diabetes susceptibility alleles at HHEX-IDE and CDKAL1 loci are associated with low BMI at age 8 years in children who were born large for gestational age. AU - Winkler, C. AU - Bonifacio, E.* AU - Grallert, H. AU - Henneberger, L. AU - Illig, T. AU - Ziegler, A.-G. C1 - 4339 C2 - 27462 SP - 2063-2067 TI - BMI at age 8 years is influenced by the type 2 diabetes susceptibility genes HHEX-IDE and CDKAL1. JO - Diabetes VL - 59 IS - 8 PB - American Diabetes Assoc. PY - 2010 SN - 0012-1797 ER - TY - JOUR AB - OBJECTIVE-Adiponectin (APM1, ACDC) is an adipocyte-derived protein with downregulated expression in obesity and insulin-resistant states. Several potentially regulatory single nucleotide polymorphisms (SNPs) within the APM1 gene promoter region have been associated with circulating adiponectin levels. None of them have been functionally characterized in adiponectin-expressing cells. Hence, we investigated three SNPs (rs16861194, rs17300539, and rs266729) for their influence on adiponectin promoter activity and their association with circulating adiponectin levels. RESEARCH DESIGN AND METHODS-Basal and rosiglitazone-induced promoter activity of different SNP combinations (haplotypes) was analyzed in 3T3-L1 adipocytes using luciferase reporter gene assays and DANN binding studies comparing all possible APM1 haplotypes. This functional approach was complemented with analysis of epidemiological population-based data of 1,692 participants of the MONICA/KORA S123 cohort and 696 participants from the KORA S4 cohort for SNP and haplotype association with circulating adiponectin levels. RESULTS-Major to minor allele replacements of the three SNPs revealed significant effects on promoter activity in luciferase assays. Particularly, a minor variant in rs16861194 resulted in reduced basal and rosiglitazone-induced promoter activity and hypoadiponectinemia in the epidemiological datasets. The haplotype with the minor allele in all three SNPs showed a complete loss of promoter activity, and no subject carried this haplotype in either of the epidemiological samples (combined P value for statistically significant difference from a random sample was 0.006). CONCLUSIONS-Our results clearly demonstrate that promoter variants associated with hypoadiponectinemia in humans substantially affect adiponectin promoter activity in adipocytes. Our combination of functional experiments with epidemiological data overcomes the drawback of each approach alone. AU - Laumen, H.* AU - Saningong, A.D.* AU - Heid, I.M. AU - Hess J.* AU - Herder, C.* AU - Claussnitzer, M.* AU - Baumert, J.J. AU - Lamina, C. AU - Rathmann, W.* AU - Sedlmeier, E.-M.* AU - Klopp, N. AU - Thorand, B. AU - Wichmann, H.-E. AU - Illig, T. AU - Hauner, H.* C1 - 561 C2 - 26126 SP - 984-991 TI - Functional characterization of promoter variants of the adiponectin gene complemented by epidemiological data. JO - Diabetes VL - 58 IS - 4 PB - Amer Diabetes Assoc PY - 2009 SN - 0012-1797 ER - TY - JOUR AB - Lipin, a novel molecular protein expressed by adipocytes, has marked effects on adipose tissue mass, insulin sensitivity, and glucose homeostasis. Thus, we hypothesized that genetic variants within LPIN1 are associated with traits of the metabolic syndrome. RESEARCH DESIGN AND METHODS: A total of 15 single nucleotide polymorphisms (SNPs) covering the LPIN1 gene region were genotyped in an age- and sex-stratified sample of the general population (Monitoring Trends and Determinants on Cardiovascular Diseases Study Augsburg; DNA and phenotypes of 1,416 Caucasians). Ten SNPs were also genotyped for replication in an independent sample of 1,030 subjects recruited throughout Germany. The metabolic syndrome was defined via the sum of its core components and, additionally, by a factor score derived from factor analysis. Permutation-based methods were used to test the association between genetic LPIN1 variants and metabolic traits for empirical significance. RESULTS: Linkage disequilibrium (LD) analysis revealed three LD blocks encompassing LPIN1. We identified three associated three-marker haplotypes: one common haplotype (26.8% frequency) increases the risk for the metabolic syndrome (odds ratio 1.6 [95% CI 1.2-2.2]), while the other two, being less common (5.7 and 4.0%), are strongly associated with lower blood pressure levels (systolic blood pressure 127 +/- 18 vs. 135 +/- 20 mmHg; P = 0.0001), a lower BMI (24.6 +/- 3.6 vs. 26.9 +/- 4.1 kg/m(2); P = 3.7 x 10(-7)) and waist circumference (82 +/- 12 vs. 90 +/- 12 cm; P = 3.2 x 10(-8)), lower A1C levels (5.1 +/- 0.7 vs. 5.3 +/- 0.9%; P = 0.0002), as well as a lower metabolic syndrome factor score (-0.67 +/- 1.00 vs. 0.04 +/- 1.24; P = 1.4 x 10(-7)). Furthermore, the frequencies of arterial hypertension (23.7 vs. 46.4%; P = 0.00001), obesity (12.9 vs. 30.8%; P = 0.0003), diabetes (2.2 vs. 8.2%; P = 0.041), and the presence of three or more metabolic syndrome components (3.3 vs. 13.7%; P = 0.002) were significantly lower than in subjects not carrying one of these protective haplotypes. Strong associations were also observed in the replication sample using the same haplotypes but with effects in the opposite direction. CONCLUSIONS These data suggest that allelic variants of the LPIN1 gene have significant effects in human metabolic traits and thus implicate lipin in the pathophysiology of the metabolic syndrome. AU - Wiedmann, S.* AU - Fischer, M.* AU - Koehler, M.* AU - Neureuther, K.* AU - Riegger, G.* AU - Döring, A. AU - Schunkert, H.* AU - Hengstenberg, C.* AU - Baessler, A.* C1 - 3311 C2 - 25231 SP - 209-217 TI - Genetic variants within the LPIN1 gene, encoding lipin, are influencing phenotypes of the metabolic syndrome in humans. JO - Diabetes VL - 57 IS - 1 PB - American Diabetes Assoc. PY - 2008 SN - 0012-1797 ER - TY - JOUR AB - The novel diabetic mouse model Munich Ins2C95S was discovered within the Munich N-ethyl-N-nitrosourea mouse mutagenesis screen. These mice exhibit a T->A transversion in the insulin 2 (Ins2) gene at nucleotide position 1903 in exon 3, which leads to the amino acid exchange C95S and loss of the A6-A11 intrachain disulfide bond. From 1 month of age onwards, blood glucose levels of heterozygous Munich Ins2C95S mutant mice were significantly increased compared with controls. The fasted and postprandial serum insulin levels of the heterozygous mutants were indistinguishable from those of wild-type littermates. However, serum insulin levels after glucose challenge, pancreatic insulin content, and homeostasis model assessment (HOMA) ß-cell indices of heterozygous mutants were significantly lower than those of wild-type littermates. The initial blood glucose decrease during an insulin tolerance test was lower and HOMA insulin resistance indices were significantly higher in mutant mice, indicating the development of insulin resistance in mutant mice. The total islet volume, the volume density of ß-cells in the islets, and the total ß-cell volume of heterozygous male mutants was significantly reduced compared with wild-type mice. Electron microscopy of the ß-cells of male mutants showed virtually no secretory insulin granules, the endoplasmic reticulum was severely enlarged, and mitochondria appeared swollen. Thus, Munich Ins2C95S mutant mice are considered a valuable model to study the mechanisms of ß-cell dysfunction and death during the development of diabetes. AU - Herbach, N.* AU - Rathkolb, B.* AU - Kemter, E.* AU - Pichl, L.* AU - Klaften, M. AU - Hrabě de Angelis, M. AU - Halban, P. A.* AU - Wolf, E.* AU - Aigner, B.* AU - Wanke, R.* C1 - 3503 C2 - 24397 SP - 1268-1276 TI - Dominant-Negative Effects of a Novel Mutated Ins2 Allele Causes Early-Onset Diabetes and Severe ß-Cell Loss in Munich Ins2C95S Mutant Mice. JO - Diabetes VL - 56 IS - 5 PB - American Diabetes Assoc. PY - 2007 SN - 0012-1797 ER - TY - JOUR AU - Endl, J.* AU - Rosinger, S.* AU - Schwarz, B.* AU - Friedrich, S.-O.* AU - Rothe, G.* AU - Karges, W.* AU - Schlosser, M.* AU - Eiermann, T.* AU - Schendel, D.J. AU - Boehm, B.O.* C1 - 4209 C2 - 23936 SP - 50-60 TI - Co-expression of CD25 and Ox40 (CD134) receptors delineates autoreactive T-cells in type 1 diabetes. JO - Diabetes VL - 55 PY - 2006 SN - 0012-1797 ER - TY - JOUR AB - Peroxisome proliferator-activated receptor (PPAR)γ is a key transcription factor facilitating fat deposition in adipose tissue through its proadipogenic and lipogenic actions. Human patients with dominant-negative mutations in PPARγ display lipodystrophy and extreme insulin resistance. For this reason it was completely unexpected that mice harboring an equivalent mutation (P465L) in PPARγ developed normal amounts of adipose tissue and were insulin sensitive. This finding raised important doubts about the interspecies translatability of PPARγ-related findings, bringing into question the relevance of other PPARγ murine models. Here, we demonstrate that when expressed on a hyperphagic ob/ob background, the P465L PPARγ mutant grossly exacerbates the insulin resistance and metabolic disturbances associated with leptin deficiency, yet reduces whole-body adiposity and adipocyte size. In mouse, coexistence of the P465L PPARγ mutation and the leptin-deficient state creates a mismatch between insufficient adipose tissue expandability and excessive energy availability, unmasking the deleterious effects of PPARγ mutations on carbohydrate metabolism and replicating the characteristic clinical symptoms observed in human patients with dominant-negative PPARγ mutations. Thus, adipose tissue expandability is identified as an important factor for the development of insulin resistance in the context of positive energy balance. © 2006 by the American Diabetes Association. AU - Gray, S.L.* AU - Nora, E.D.* AU - Grosse, J.* AU - Manieri, M.* AU - Stöger, T. AU - Medina-Gomez, G.* AU - Burling, K.* AU - Wattler, S.* AU - Russ, A.* AU - Yeo, G.S.* AU - Chatterjee, V.K.* AU - O'Rahilly, S.* AU - Voshol, P.J.* AU - Cinti, S.* AU - Vidal-Puig, A.* C1 - 5344 C2 - 23907 SP - 2669-2677 TI - Leptin deficiency unmasks the deleterious effects of impaired peroxisome proliferator-activated receptor gamma function (P465L PPARgamma) in mice. JO - Diabetes VL - 55 IS - 10 PY - 2006 SN - 0012-1797 ER - TY - JOUR AU - Heid, I.M. AU - Wagner, S.A.* AU - Gohlke, H. AU - Iglseder, B.* AU - Mueller, J.C.* AU - Cip, P.* AU - Ladurner, G.* AU - Reiter, R.* AU - Stadlmayr, A.* AU - Mackevics, V.* AU - Illig, T. C1 - 859 C2 - 23686 SP - 375-384 TI - Genetic architecture of the APM1 gene and its influence on adiponectin plasma levels anmd parameters of the metabolic syndrome in 1,727 healthy Caucasians. JO - Diabetes VL - 55 PY - 2006 SN - 0012-1797 ER - TY - JOUR AB - Several lines of evidence indicate a causal role of the cytokine interleukin (IL)-6 in the development of type 2 diabetes in humans. Two common polymorphisms in the promoter of the IL-6 encoding gene IL6, -174G>C (rs1800795) and -573G>C (rs1800796), have been investigated for association with type 2 diabetes in numerous studies but with results that have been largely equivocal. To clarify the relationship between the two IL6 variants and type 2 diabetes, we analyzed individual data on >20,000 participants from 21 published and unpublished studies. Collected data represent eight different countries, making this the largest association analysis for type 2 diabetes reported to date. The GC and CC genotypes of IL6 -174G>C were associated with a decreased risk of type 2 diabetes (odds ratio 0.91, P = 0.037), corresponding to a risk modification of nearly 9%. No evidence for association was found between IL6 -573G>C and type 2 diabetes. The observed association of the IL6 -174 C-allele with a reduced risk of type 2 diabetes provides further evidence for the hypothesis that immune mediators are causally related to type 2 diabetes; however, because the association is borderline significant, additional data are still needed to confirm this finding. © 2006 by the American Diabetes Association. AU - Huth, C. AU - Heid, I.M. AU - Vollmert, C. AU - Gieger, C. AU - Grallert, H. AU - Wolford, J.K.* AU - Langer, B. AU - Thorand, B. AU - Klopp, N. AU - Hamid, Y.H.* AU - Pedersen, O.* AU - Hansen, T.* AU - Lyssenko, V.* AU - Groop, L.* AU - Meisinger, C. AU - Döring, A. AU - Löwel, H. AU - Lieb, W.* AU - Hengstenberg, C.* AU - Rathmann, W.* AU - Martin, S.* AU - Stephens, J.W.* AU - Ireland, H.* AU - Mather, H.* AU - Miller, G.J.* AU - Stringham, H.M.* AU - Boehnke, M.* AU - Tuomilehto, J.* AU - Boeing, H.* AU - Möhlig, M.* AU - Spranger, J.* AU - Pfeiffer, A.* AU - Wernstedt, I.* AU - Niklason, A.* AU - Lopez-Bermejo, A.* AU - Fernández-Real, J.M.* AU - Hanson, R.L.* AU - Gallart, L.* AU - Vendrell, J.* AU - Tsiavou, A.* AU - Hatziagelaki, E.* AU - Humphries, S.E.* AU - Wichmann, H.-E. AU - Herder, C.* AU - Illig, T. C1 - 2933 C2 - 24053 SP - 2915-2921 TI - IL6 gene promoter polymorphisms and type 2 diabetes: Joint analysis of individual participants' data from 21 studies. JO - Diabetes VL - 55 IS - 10 PY - 2006 SN - 0012-1797 ER - TY - JOUR AU - Schoenborn, V.* AU - Heid, I.M. AU - Vollmert, C. AU - Lingenhel, A.* AU - Adams, T.D.* AU - Hopkins, P.N.* AU - Illig, T. AU - Zimmermann, R.* AU - Zechner, R.* AU - Hunt, S.C.* AU - Kronenberg, F.* C1 - 4713 C2 - 23614 SP - 1270-1275 TI - The ATGL gene is associated with free fatty acids, triglycerides and type 2 diabetes. JO - Diabetes VL - 55 PY - 2006 SN - 0012-1797 ER - TY - JOUR AB - The growth hormone secretagogue receptor (GHSR) (ghrelin receptor) plays an important role in the regulation of food intake and energy homeostasis. The GHSR gene lies on human chromosome 3q26 within a quantitative trait locus strongly linked to multiple phenotypes related to obesity and the metabolic syndrome. Because the biological function and location of the GHSR gene make it an excellent candidate gene, we tested the relation between common single nucleotide polymorphisms (SNPs) in the GHSR gene and human obesity. We performed a comprehensive analysis of SNPs, linkage disequilibrium (LD), and haplotype structure across the entire GHSR gene region (99.3 kb) in 178 pedigrees with multiple obese members (DNA of 1,095 Caucasians) and in an independent sample of the general population (MONICA Augsburg left ventricular hypertrophy substudy; DNA of 1,418 Caucasians). The LD analysis revealed a disequilibrium block consisting of five SNPs, consistent in both study cohorts. We found linkage among all five SNPs, their haplotypes, and BMI. Further, we found suggestive evidence for transmission disequilibrium for the minor SNP alleles (P < 0.05) and the two most common haplotypes with the obesity affection status ("susceptible" P = 0.025, "nonsusceptible" P = 0.045) in the family cohort using the family-based association test program. Replication of these findings in the general population resulted in stronger evidence for an association of the SNPs (best P = 0.00001) and haplotypes with the disease ("susceptible" P = 0.002, "nonsusceptible" P = 0.002). To our knowledge, these data are the first to demonstrate linkage and association of SNPs and haplotypes within the GHSR gene region and human obesity. This linkage, together with significant transmission disequilibrium in families and replication of this association in an independent population, provides evidence that common SNPs and haplotypes within the GHSR region are involved in the pathogenesis of human obesity. AU - Baessler, A.* AU - Döring, A. C1 - 2729 C2 - 22679 SP - 259-267 TI - Genetic linkage and association of the growth hormone secretagogue receptor (Ghrelin receptor) gene in human obesity. JO - Diabetes VL - 54 IS - 1 PY - 2005 SN - 0012-1797 ER - TY - JOUR AB - Chemokines are crucial immune mediators in many physiological and pathophysiological conditions. Chemokines have been hypothesized to be involved in macrophage infiltration into adipose tissue in obesity and might therefore play an important role in the development of obesity-related disorders like type 2 diabetes. Out of 1,653 individuals aged 55–74 years participating in a population-based survey in southern Germany (the Kooperative Gesundheitsforschung in der Region Augsburg [KORA] [Cooperative Health Research in the Region of Augsburg] Survey S4, 1999–2001), 236 individuals with type 2 diabetes, 242 subjects with impaired glucose tolerance (IGT), and 244 normoglycemic control subjects were studied for circulating concentrations of interleukin (IL)-8; RANTES (regulated on activation, normal T-cell expressed, and secreted); interferon-γ–inducible protein-10 (IP-10), and eotaxin. Systemic concentrations of RANTES were higher in individuals with IGT or type 2 diabetes than in control subjects, whereas IL-8 levels were elevated in type 2 diabetic patients only (P < 0.001 for all comparisons). IP-10 and eotaxin were not significantly associated with IGT or type 2 diabetes. Adjustment for age, sex, BMI, hypertension, LDL cholesterol, HDL cholesterol, uric acid, C-reactive protein, and IL-6 did not alter these findings. Our findings indicate that RANTES and IL-8 may be involved in the development of type 2 diabetes independent of metabolic syndrome–related risk factors and of each other. There is no general upregulation of chemokine production in type 2 diabetes, but rather an association of the disease with specific members of the chemokine family. AU - Herder, Ch.* AU - Haastert, B.* AU - Müller-Scholze, S.* AU - König, W.* AU - Thorand, B. AU - Holle, R. AU - Wichmann, H.-E. AU - Scherbaum, W.A.* AU - Martin, S.* AU - Kolb, H.* C1 - 868 C2 - 23285 SP - 11-17 TI - Association of Systemic Chemokine Concentrations with Impaired Glucose Tolerance and Type 2 Diabetes: Results from the Cooperative Health Research in the Region of Augsburg Survey S4 (KORA S4). JO - Diabetes VL - 54 PY - 2005 SN - 0012-1797 ER - TY - JOUR AB - We investigated prospectively the association between serum levels of interleukin (IL)-18 and the risk of type 2 diabetes in a case-cohort study conducted in middle-aged men and women who represented 7,936 participants of the three MONItoring of trends and determinants in CArdiovascular disease (MONICA)/Cooperative Research in the Region of Augsburg (KORA) surveys. Levels of IL-18 were measured in stored samples of 527 case subjects with incident type 2 diabetes and 1,698 noncase subjects. Elevated levels of IL-18 were associated with a significantly increased risk of type 2 diabetes after adjustment for age, sex, survey, BMI, systolic blood pressure, ratio of total cholesterol to HDL cholesterol, physical activity, alcohol intake, smoking status, and parental history of diabetes. Hazard ratios and 95% confidence intervals comparing quartile extremes were 1.73 (1.25–2.40). Further adjustment for C-reactive protein and IL-6 had no impact on the observed associations. However, the risk of developing type 2 diabetes was highest among subjects with elevated levels of both IL-18 and CRP or IL-18 and IL-6, respectively. In conclusion, elevated levels of IL-18 are associated with a considerably increased risk of type 2 diabetes. This association is independent of a generalized proinflammatory state, but subjects with elevated levels of several inflammatory markers seem to be particularly prone to develop type 2 diabetes. AU - Thorand, B. AU - Kolb, H.* AU - Baumert, J.J. AU - König, W.* AU - Chambless, L.* AU - Meisinger, C. AU - Illig, T. AU - Martin, S.* AU - Herder, C.* C1 - 1852 C2 - 23116 SP - 2932-2938 TI - Elevated levels of interleukin-18 predict the development of type 2 diabetes: Results from the MONICA/KORA Augsburg Study, 1984-2002. JO - Diabetes VL - 54 IS - 10 PY - 2005 SN - 0012-1797 ER - TY - JOUR AB - Diabetes is associated with an enhanced collagen-mediated platelet activation that contributes significantly to thromboischemic complications. In this study, the platelet collagen receptor glycoprotein VI (GPVI) was studied in 385 patients with type 2 diabetes. Surface expression of the platelet Fc receptor that forms a functional complex with GPVI was significantly increased in patients with diabetes compared with those without diabetes (P = 0.02). Fc receptor expression correlated with GPVI expression and was found to be independently associated with diabetes (r = 0.529, P < 0.001). Stimulation of GPVI through a specific anti-GPVI monoclonal antibody significantly enhanced surface expression of CD40L (P = 0.006). Because CD40L is a potent platelet-derived cytokine that is involved in thrombosis and atherosclerosis, we evaluated the effect of GPVI-mediated release of CD40L on activation of endothelial cells. Coincubation of GPVI-stimulated platelets resulted in substantial enhanced endothelial surface expression of CD62P, αvβ3, and intercellular adhesion molecule 1 (P < 0.05) and secretion of monocyte chemoattractant protein 1 of cultured human umbilical vein endothelial cells (P < 0.01). These results suggest that the function of collagen receptor GPVI is altered in type 2 diabetes and may play an important role in atherothrombotic complications. Inhibition of GPVI may be a promising pharmacological target in the treatment of high-risk diabetic patients. AU - Cabeza, N.* AU - Li, Z.* AU - Schulz, C.* AU - Kremmer, E. AU - Massberg, S.* AU - Bültmann, A.* AU - Gawaz, M.* C1 - 3369 C2 - 22327 SP - 2117-2121 TI - Surface expression of collagen receptor Fc receptor-gamma/glycoprotein VI is enhanced on platelets in type 2 diabetes and mediates release of CD40 ligand and activation of endothelial cells. JO - Diabetes VL - 53 IS - 8 PY - 2004 SN - 0012-1797 ER - TY - JOUR AU - Illig, T. AU - Bongardt, F. AU - Schöpfer, A. AU - Holle, R. AU - Müller, S.* AU - Rathmann, W.* AU - Koenig, W.* AU - Meisinger, C. AU - Wichmann, H.-E. AU - Kolb, H.* AU - KORA Study Group (John, J. AU - Peters, A. AU - Illig, T. AU - Holle, R. AU - Meisinger, C. AU - Wichmann, H.-E.) C1 - 10246 C2 - 21521 SP - 2861-2864 TI - The endotoxin receptor TLR4 polymorphism is not associated with diabetes or components of the metabolic syndrome. JO - Diabetes VL - 52 IS - 11 PY - 2003 SN - 0012-1797 ER - TY - JOUR AU - Ruprecht, L. AU - Illini, P. AU - Funke, H. C1 - 18967 C2 - 11364 TI - Investigations on Sheep and Dog Concerning the Correlation of Subcutaneous Glucose Concentration and Plasma Glucose Concentration. JO - Diabetes PY - 1986 SN - 0012-1797 ER -