TY  - JOUR
AB  - BACKGROUND/AIM: Type 1 diabetes is an autoimmune disease that involves the development of autoantibodies against pancreatic islet beta-cell antigens, preceding clinical diagnosis by a period of preclinical disease activity. As screening activity to identify autoantibody-positive individuals increases, a rise in presymptomatic type 1 diabetes individuals seeking medical attention is expected. Current guidance on how to monitor these individuals in a safe but minimally invasive way is limited. This article aims to provide clinical guidance for monitoring individuals with presymptomatic type 1 diabetes to reduce the risk of diabetic ketoacidosis (DKA) at diagnosis. METHODS: Expert consensus was obtained from members of the Fr1da, GPPAD, and INNODIA consortia, three European diabetes research groups. The guidance covers both specialist and primary care follow-up strategies. RESULTS: The guidance outlines recommended monitoring approaches based on age, disease stage and clinical setting. Individuals with presymptomatic type 1 diabetes are best followed up in specialist care. For stage 1, biannual assessments of random plasma glucose and HbA1c are suggested for children, while annual assessments are recommended for adolescents and adults. For stage 2, 3-monthly clinic visits with additional home monitoring are advised. The value of repeat OGTT in stage 1 and the use of continuous glucose monitoring in stage 2 are discussed. Primary care is encouraged to monitor individuals who decline specialist care, following the guidance presented. CONCLUSIONS: As type 1 diabetes screening programs become more prevalent, effective monitoring strategies are essential to mitigate the risk of complications such as DKA. This guidance serves as a valuable resource for clinicians, providing practical recommendations tailored to an individual's age and disease stage, both within specialist and primary care settings.
AU  - Hendriks, A.E.J.*
AU  - Marcovecchio, M.L.*
AU  - Besser, R.E.J.*
AU  - Bonifacio, E.*
AU  - Casteels, K.*
AU  - Elding Larsson, H.*
AU  - Gemulla, G.*
AU  - Lundgren, M.*
AU  - Kordonouri, O.*
AU  - Mallone, R.*
AU  - Pociot, F.*
AU  - Szypowska, A.*
AU  - Toppari, J.*
AU  - Berge, T.V.D.*
AU  - Ziegler, A.-G.
AU  - Mathieu, C.*
AU  - Achenbach, P.
AU  - INNODIA consortium (Rodriguez-Calvo, T.)
C1  - 70058
C2  - 55388
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Clinical care advice for monitoring of islet autoantibody positive individuals with presymptomatic type 1 diabetes.
JO  - Diabetes Metab. Res. Rev.
VL  - 40
IS  - 2
PB  - Wiley
PY  - 2024
SN  - 1520-7552
ER  - 

TY  - JOUR
AB  - AIMS: The aim of this study was to assess associations between neurological biomarkers and distal sensorimotor polyneuropathy (DSPN). MATERIALS AND METHODS: Cross-sectional analyses were based on 1032 participants aged 61-82 years from the population-based KORA F4 survey, 177 of whom had DSPN at baseline. The prevalence of type 2 diabetes was 20%. Prospective analyses used data from 505 participants without DSPN at baseline, of whom 125 had developed DSPN until the KORA FF4 survey. DSPN was defined based on the examination part of the Michigan Neuropathy Screening Instrument. Serum levels of neurological biomarkers were measured using proximity extension assay technology. Associations between 88 biomarkers and prevalent or incident DSPN were estimated using Poisson regression with robust error variance and are expressed as risk ratios (RR) and 95% CI per 1-SD increase. Results were adjusted for multiple confounders and multiple testing using the Benjamini-Hochberg procedure. RESULTS: Higher serum levels of CTSC (cathepsin C; RR [95% CI] 1.23 (1.08; 1.39), pB-H = 0.044) and PDGFRα (platelet-derived growth factor receptor A; RR [95% CI] 1.21 (1.08; 1.35), pB-H = 0.044) were associated with prevalent DSPN in the total study sample. CDH3, JAM-B, LAYN, RGMA and SCARA5 were positively associated with DSPN in the diabetes subgroup, whereas GCP5 was positively associated with DSPN in people without diabetes (all pB-H for interaction <0.05). None of the biomarkers showed an association with incident DSPN (all pB-H>0.05). CONCLUSIONS: This study identified multiple novel associations between neurological biomarkers and prevalent DSPN, which may be attributable to functions of these proteins in neuroinflammation, neural development and myelination.
AU  - Herder, C.*
AU  - Thorand, B.
AU  - Strom, A.*
AU  - Rathmann, W.*
AU  - Heier, M.
AU  - Koenig, W.*
AU  - Morrison, H.*
AU  - Ziegler, D.*
AU  - Roden, M.*
AU  - Peters, A.
AU  - Bönhof, G.J.*
AU  - Maalmi, H.*
C1  - 70838
C2  - 55785
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Associations between multiple neurological biomarkers and distal sensorimotor polyneuropathy: KORA F4/FF4 study.
JO  - Diabetes Metab. Res. Rev.
VL  - 40
IS  - 5
PB  - Wiley
PY  - 2024
SN  - 1520-7552
ER  - 

TY  - JOUR
AB  - BACKGROUND: Diabetic sensorimotor polyneuropathy (DSPN) is often asymptomatic and remains undiagnosed. The ability of clinical and anthropometric variables to identify individuals likely to have DSPN might be limited. Here, we aimed to integrate protein biomarkers for reliably predicting present DSPN. METHODS: Using the proximity extension assay, we measured 135 neurological and protein biomarkers of inflammation in blood samples of 423 individuals with recent-onset diabetes from the German Diabetes Study (GDS). DSPN was diagnosed based on the Toronto Consensus Criteria. We constructed (i) a protein-based prediction model using LASSO logistic regression, (ii) an optimised traditional risk model with age, sex, waist circumference, height and diabetes type and (iii) a model combining both. All models were bootstrapped to assess the robustness, and optimism-corrected AUCs (95% CI) were reported. RESULTS: DSPN was present in 16% of the study population. LASSO logistic regression selected the neurofilament light chain (NFL) and fibroblast growth factor-19 (FGF-19) as the most predictive protein biomarkers for detecting DSPN in individuals with recent-onset diabetes. The protein-based model achieved an AUC of 0.66 (0.59, 0.73), while the traditional risk model had an AUC of 0.66 (0.61, 0.74). However, combined features boosted the model performance to an AUC of 0.72 (0.67, 0.79). CONCLUSION: We developed a prediction model for DSPN in recent-onset diabetes based on two protein biomarkers and five standard anthropometric, demographic and clinical variables. The model has a fair discrimination performance and might be used to inform the referral of patients for further testing.
AU  - Maalmi, H.*
AU  - Nguyen, B.H.P.
AU  - Strom, A.*
AU  - Bönhof, G.J.*
AU  - Rathmann, W.*
AU  - Ziegler, D.*
AU  - Menden, M.P.
AU  - Roden, M.*
AU  - Herder, C.*
C1  - 72540
C2  - 56624
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Prediction model for polyneuropathy in recent-onset diabetes based on serum neurofilament light chain, fibroblast growth factor-19 and standard anthropometric and clinical variables.
JO  - Diabetes Metab. Res. Rev.
VL  - 40
IS  - 8
PB  - Wiley
PY  - 2024
SN  - 1520-7552
ER  - 

TY  - JOUR
AB  - AIMS: We recently reported that genetic variability in the TKT gene encoding transketolase, a key enzyme in the pentose phosphate pathway, is associated with measures of diabetic sensorimotor polyneuropathy (DSPN) in recent-onset diabetes. Here, we aimed to substantiate these findings in a population-based KORA F4 study. MATERIALS AND METHODS: In this cross-sectional study, we assessed seven single nucleotide polymorphisms (SNPs) in the transketolase gene in 952 participants from the KORA F4 study with normal glucose tolerance (NGT; n = 394), prediabetes (n = 411), and type 2 diabetes (n = 147). DSPN was defined by the examination part of the Michigan Neuropathy Screening Instrument (MNSI) using the original MNSI > 2 cut-off and two alternative versions extended by touch/pressure perception (TPP) (MNSI > 3) and by TPP plus cold perception (MNSI > 4). RESULTS: After adjustment for sex, age, BMI, and HbA1c, in type 2 diabetes participants, four out of seven transketolase SNPs were associated with DSPN for all three MNSI versions (all p ≤ 0.004). The odds ratios of these associations increased with extending the MNSI score, for example, OR (95% CI) for SNP rs62255988 with MNSI > 2: 1.99 (1.16-3.41), MNSI > 3: 2.27 (1.26-4.09), and MNSI > 4: 4.78 (2.22-10.26); SNP rs9284890 with MNSI > 2: 2.43 (1.42-4.16), MNSI > 3: 3.46 (1.82-6.59), and MNSI > 4: 4.75 (2.15-10.51). In contrast, no associations were found between transketolase SNPs and the three MNSI versions in the NGT and prediabetes groups. CONCLUSIONS: The link of genetic variation in transketolase enzyme to diabetic polyneuropathy corroborated at the population level strengthens the concept suggesting an important role of pathways metabolising glycolytic intermediates in the evolution of diabetic polyneuropathy.
AU  - Ziegler, D.*
AU  - Thorand, B.
AU  - Strom, A.*
AU  - Bönhof, G.J.*
AU  - Knebel, B.*
AU  - Schleicher, E.*
AU  - Rathmann, W.*
AU  - Herder, C.*
AU  - Maalmi, H.*
AU  - Gieger, C.
AU  - Heier, M.
AU  - Meisinger, C.*
AU  - Roden, M.*
AU  - Peters, A.
AU  - Grallert, H.
C1  - 71047
C2  - 55860
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Association of transketolase polymorphisms with diabetic polyneuropathy in the general population: The KORA F4 study.
JO  - Diabetes Metab. Res. Rev.
VL  - 40
IS  - 5
PB  - Wiley
PY  - 2024
SN  - 1520-7552
ER  - 

TY  - JOUR
AB  - OBJECTIVES: The aim of this study was to asses adrenal gland volume by magnetic resonance imaging (MRI) and to study its role as an indirect marker of impaired glucose metabolism and hypothalamic-pituitary-adrenal (HPA) axis activation in a population-based cohort. METHODS: Asymptomatic participants were enrolled in a nested case-control study and underwent a 3-T MRI, including T1w-VIBE-Dixon sequences. For assessment of adrenal gland volume, adrenal glands were manually segmented in a blinded fashion. Impaired glucose metabolism was determined using fasting glucose and oral glucose tolerance test. Cardiometabolic risk factors were also obtained. Inter- and intrareader reliability as well as univariate and multivariate associations were derived. RESULTS: Among 375 subjects included in the analysis (58.5% male, 56.1 ± 9.1 years), 25.3% participants had prediabetes and 13.6% had type 2 diabetes (T2DM). Total adrenal gland volume was 11.2 ± 4.2 ml, and differed significantly between impaired glucose metabolism and healthy controls with largest total adrenal gland volume in T2DM (healthy controls: 10.0 ± 3.9 ml, prediabetes: 12.5 ± 3.8 ml, T2DM: 13.9 ± 4.6 ml; p<0.001). In multivariate analysis, association of T2DM and increased adrenal gland volume was independent of age, sex, hypertension, triglycerides and body mass index (BMI), but was attenuated in subjects with prediabetes after adjustment for BMI. CONCLUSIONS: T2DM is significantly associated with increased adrenal gland volume by MRI in an asymptomatic cohort, independent of age, sex, dyslipidemia, hypertension and BMI. Adrenal gland volume may represent an indirect marker of impaired glucose metabolism and HPA axis dysfunction.
AU  - Askani, E.*
AU  - Rospleszcz, S.
AU  - Lorbeer, R.*
AU  - Kulka, C.*
AU  - von Krüchten, R.*
AU  - Müller-Peltzer, K.*
AU  - Hasic, D.*
AU  - Kellner, E.*
AU  - Reisert, M.*
AU  - Rathmann, W.*
AU  - Peters, A.
AU  - Schlett, C.L.*
AU  - Bamberg, F.*
AU  - Storz, C.*
C1  - 64630
C2  - 52359
TI  - Association of MRI-based adrenal gland volume and impaired glucose metabolism in a population-based cohort study.
JO  - Diabetes Metab. Res. Rev.
VL  - 38
IS  - 5
PY  - 2022
SN  - 1520-7552
ER  - 

TY  - JOUR
AB  - AIMS: Immunomodulation with autoantigens potentially constitutes a specific and safe treatment for type 1 diabetes (T1D). Studies with GAD-alum administrated subcutaneously have shown to be safe, but its efficacy has been inconclusive. Administration of GAD-alum into the lymph nodes, aimed to optimise antigen presentation, has shown promising results in an open-label clinical trial. Herein, we compared the immune response of the individuals included in the trial with a group who received GAD-alum subcutaneously in a previous study. MATERIALS AND METHODS: Samples from T1D individuals collected 15 months after administration of either three doses 1 month apart of 4 μg GAD-alum into lymph nodes (LN, n = 12) or two doses 1 month apart of 20 μg subcutaneously (SC, n = 12) were studied. GADA, GADA subclasses, GAD65 -induced cytokines, peripheral blood mononuclear cell proliferation, and T cells markers were analysed. RESULTS: Low doses of GAD-alum into the lymph nodes induced higher GADA levels than higher doses administrated subcutaneously. Immune response in the LN group was characterised by changes in GADA subclasses, with a relative reduction of IgG1 and enhanced IgG2, IgG3, and IgG4 proportion, higher GAD65 -induced secretion of IL-5, IL-10, and TNF-α, and reduction of cell proliferation and CD8+ T cells. These changes were not observed after subcutaneous (SC) injections of GAD-alum. CONCLUSIONS: GAD-specific immune responses 15 months after lymph node injections of GAD-alum differed from the ones induced by SC administration of the same autoantigen.
AU  - Dietrich, F.*
AU  - Barcenilla, H.*
AU  - Tavira, B.*
AU  - Wahlberg, J.*
AU  - Achenbach, P.
AU  - Ludvigsson, J.*
AU  - Casas, R.*
C1  - 63300
C2  - 51464
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Immune response differs between intralymphatic or subcutaneous administration of GAD-alum in individuals with recent onset type 1 diabetes.
JO  - Diabetes Metab. Res. Rev.
PB  - Wiley
PY  - 2022
SN  - 1520-7552
ER  - 

TY  - JOUR
AB  - Background There is limited knowledge about mortality risk in persons with increased haemoglobin A(1c)(HbA(1c)) levels below the diabetes threshold. Moreover, little is known about how associations between increased HbA(1c)and mortality depend on the length of follow-up. Therefore, we studied associations between HbA(1c)and mortality over long-term follow-up in persons with and without known diabetes. Methods We used data from two German population-based cohort studies: KORA S4 Study (Southern Germany, n = 1458, baseline visits in 1999 to 2001, baseline age 55 to 74 years, mortality follow-up 16.8 years) and Heinz Nixdorf Recall (HNR) Study (Ruhr area, n = 4613, baseline visits in 2000 to 2003, baseline age 45 to 75 years, mortality follow-up 17.8 years). Adjusted log-linear models were fitted to estimate relative risks (RRs) with 95% confidence intervals (CI). Results In both cohorts, participants with HbA(1c)39 to 41 mmol/mol (5.7%-5.9%) and HbA(1c)42 to 46 mmol/mol (6.0% to 6.4%) did not have a larger overall mortality risk than participants with HbA(1c) < 39 mmol/mol (5.7%): the corresponding adjusted RRs were 1.00 (95% CI: 0.83-1.21) and 1.01 (0.80-1.27) in KORA and 0.99 (0.82-1.21) and 0.83 (0.65-1.07) in the HNR Study. For the pooled cohorts, the RR for HbA(1c)39 to 46 mmol/mol (5.7%-6.4%) was 0.96 (0.85-1.07). Associations between newly detected diabetes (HbA(1c) >= 6.5%) and mortality were weak after 4 and 8 years of follow-up, but were stronger after 12 years of follow-up, whereas associations between previously known diabetes (baseline) and mortality decreased. Conclusions HbA(1c)-defined pre-diabetes is not associated with overall mortality. For newly detected and previously known diabetes, mortality risks vary with length of follow-up.
AU  - Kowall, B.*
AU  - Rathmann, W.*
AU  - Kuss, O.*
AU  - Herder, C.*
AU  - Roden, M.*
AU  - Stang, A.*
AU  - Erbel, R.*
AU  - Huth, C.
AU  - Thorand, B.
AU  - Meisinger, C.
AU  - Jöckel, K.H.*
AU  - Peters, A.
C1  - 59420
C2  - 48807
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Associations between haemoglobin A(1c)and mortality rate in the KORA S4 and the Heinz Nixdorf Recall population-based cohort studies.
JO  - Diabetes Metab. Res. Rev.
VL  - 37
IS  - 2
PB  - Wiley
PY  - 2021
SN  - 1520-7552
ER  - 

TY  - JOUR
AB  - Aims Experimental and epidemiological studies reported controversial data on the role of omentin in type 2 diabetes and cardiovascular diseases. This study aimed to characterise the impact of omentin on the secretome of human adipocytes to analyse the enrichment of these proteins in metabolic and cellular signalling pathways underlying its physiological function. Material/methods Differentiated primary human adipocytes were treated without or with 500 or 2000 ng/mL omentin for 24 hours. The secretome was analysed by liquid chromatography coupled tandem-mass spectrometry. Differences in protein secretion between untreated and omentin-treated adipocytes were compared using a paired t-test. Other potential upstream regulators and the overrepresentation in canonical pathways of omentin-stimulated proteins were analysed using Ingenuity Pathway Analysis. Results The supernatant of adipocytes contained 3493 proteins, of which 140 were differentially secreted by both concentrations of omentin compared with untreated adipocytes. Among the most strongly increased proteins, tumour necrosis factor-inducible gene 6 protein (TNFAIP6) was increased by 140-fold in the supernatant. Omentin-regulated proteins were overrepresented in seven canonical pathways including eukaryotic initiation factor 2 signalling, complement system, and inhibition of matrix metalloproteases. We further identified 25 other potential upstream activators of omentin-regulated proteins, mainly pro-inflammatory cytokines and transcription regulators including NF kappa B. Conclusions In differentiated human adipocytes, the release of the anti-inflammatory TNFAIP6 might be part of a counterregulatory response to the pro-inflammatory action of omentin. Omentin-regulated proteins were overrepresented in pathways indicating cellular stress, a pro-inflammatory environment and a crosstalk with other organs. Other potential activators of omentin-regulated proteins point towards a central role of NF kappa B activation in the omentin-induced secretory process.
AU  - Niersmann, C.*
AU  - Hauck, S.M.
AU  - Kannenberg, J.M.*
AU  - Röhrig, K.*
AU  - von Toerne, C.
AU  - Roden, M.*
AU  - Herder, C.*
AU  - Carstensen-Kirberg, M.*
C1  - 54499
C2  - 45634
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Omentin-regulated proteins combine a pro-inflammatory phenotype with an anti-inflammatory counterregulation in human adipocytes: A proteomics analysis.
JO  - Diabetes Metab. Res. Rev.
VL  - 35
IS  - 1
PB  - Wiley
PY  - 2019
SN  - 1520-7552
ER  - 

TY  - JOUR
AB  - Aims Subclinical systemic inflammation may contribute to the development of type 2 diabetes, but its association with early progression of glycaemic deterioration in persons without diabetes has not been fully investigated. Our primary aim was to assess longitudinal associations of changes in pro-inflammatory (leukocytes, high-sensitivity C-reactive protein (hsCRP)) and anti-inflammatory (adiponectin) markers with changes in markers that assessed glycaemia, insulin resistance, and secretion (HbA(1c), HOMA-IR, and HOMA-beta). Furthermore, we aimed to directly compare longitudinal with cross-sectional associations. Materials and methods Results This study includes 819 initially nondiabetic individuals with repeated measurements from the Cooperative Health Research in the Region of Augsburg (KORA) S4/F4 cohort study (median follow-up: 7.1 years). Longitudinal and cross-sectional associations were simultaneously examined using linear mixed growth models. Changes in markers of inflammation were used as independent and changes in markers of glycaemia/insulin resistance/insulin secretion as dependent variables. Models were adjusted for age, sex, major lifestyle and metabolic risk factors for diabetes using time-varying variables in the final model. Changes of leukocyte count were positively associated with changes in HbA(1c) and HOMA-beta while changes in adiponectin were inversely associated with changes in HbA(1c). All examined cross-sectional associations were statistically significant; they were generally stronger and mostly directionally consistent to the longitudinal association estimates. Conclusions Adverse changes in low-grade systemic inflammation go along with glycaemic deterioration and increased insulin secretion independently of changes in other risk factors, suggesting that low-grade inflammation may contribute to the development of hyperglycaemia and a compensatory increase in insulin secretion.
AU  - de Las Heras Gala, T.
AU  - Herder, C.*
AU  - Rutters, F.*
AU  - Carstensen-Kirberg, M.*
AU  - Huth, C.
AU  - Stehouwer, C.D.A.*
AU  - Nijpels, G.*
AU  - Schalkwijk, C.*
AU  - Flyvbjerg, A.*
AU  - Franks, P.W.*
AU  - Dekker, J.*
AU  - Meisinger, C.
AU  - Koenig, W.*
AU  - Roden, M.*
AU  - Rathmann, W.*
AU  - Peters, A.
AU  - Thorand, B.
C1  - 54432
C2  - 45531
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Association of changes in inflammation with variation in glycaemia, insulin resistance and secretion based on the KORA study.
JO  - Diabetes Metab. Res. Rev.
VL  - 34
IS  - 8
PB  - Wiley
PY  - 2018
SN  - 1520-7552
ER  - 

TY  - JOUR
AB  - Aims On the basis of the Diabetes Versorgungs-Evaluation (DIVE) and Diabetes-Patienten-Verlaufsdokumentation (DPV) datasets, we aimed to explore the impact of differences in treatment modalities on outcomes in Germany and put these into a global context. Methods Results The 2014 to 2016 DIVE and DPV databases were combined, and a total of 127 838 patients 18 years and older was analysed with respect to demographics, cardiovascular risk factors, comorbidities, treatments, and outcomes, separately for each German state. Estimates were expressed as adjusted least squares means together with 95% confidence intervals. Saarland dataset recorded the lowest mean HbA(1c) (6.7%; 6.6%-6.8%; 50 mmol/mol, 49-51 mmol/mol), Saxony-Anhalt showed the highest (8.3%; 8.2%-8.3%; 67 mmol/mol, 66-67 mmol/mol). The highest percentage of hypoglycaemic events was reported in Mecklenburg-West Pomerania (MWP) (4.7%; 3.9%-5.7%), the lowest in Thuringia (0.9%; 0.2%-3.4%). Metformin and sulfonylurea accounted for 36.4% to 53.3% of anti-diabetic treatments across states; other antihyperglycaemic drugs such as DPP-4 inhibitors, SGLT2 inhibitors, and GLP-1 analogues were used most often in MWP (40.0%; 37.8%-42.1%) and least in Rhineland-Palatinate (13.6%; 13.0%-14.2%). Treatment with insulin (alone or in combination) was reported most often in MWP (78.2%; 76.4%-80.0%) and least in Thuringia (26.0%; 20.1%-32.9%). Conclusions Federal states in Germany are heterogeneous concerning diabetes treatment and associated outcomes. These data should stimulate further discussion about how optimal diabetes care can be implemented in all areas of Germany, to achieve good treatment outcomes in all federal states.
AU  - Hartmann, B.*
AU  - Bramlage, P.*
AU  - Lanzinger, S.*
AU  - Danne, T.*
AU  - Hummel, M.
AU  - Kaltheuner, M.*
AU  - Raddatz, D.*
AU  - Rathmann, W.*
AU  - Reuter, H.M.*
AU  - Seufert, J.*
AU  - Holl, R.W.*
C1  - 54018
C2  - 45207
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Regional differences in type 2 diabetes treatment and outcomes in Germany-An analysis of the German DPV and DIVE registries.
JO  - Diabetes Metab. Res. Rev.
VL  - 34
IS  - 8
PB  - Wiley
PY  - 2018
SN  - 1520-7552
ER  - 

TY  - JOUR
AB  - BackgroundOxidative stress has been proposed as important pathomechanism of cardiometabolic diseases and distal sensorimotor polyneuropathy (DSPN). However, the relevance of biomarkers of oxidative stress has not been investigated in this context. Therefore, this study aimed to assess the association of the prooxidant myeloperoxidase (MPO) and the antioxidant extracellular superoxide dismutase (SOD3) with cardiometabolic risk factors and with prevalence and incidence of DSPN.MethodsCross-sectional analyses comprised 1069 participants (40.3% with prediabetes and 20.5% with type 2 diabetes) of the population-based Cooperative Health Research in the Region of Augsburg (KORA) F4 study (2006-2008), 181 of whom had DSPN at baseline. Prospective analyses included 524 individuals without DSPN at baseline who also participated in the KORA FF4 study (2013-2014), 132 of whom developed DSPN during the 6.5-year follow-up. Serum MPO and SOD3 were measured by ELISA, and their association with cardiometabolic risk factors and DSPN were estimated by using linear and logistic regression analyses.ResultsHigher MPO and SOD levels showed multiple positive associations with cardiometabolic risk factors including age, indices of obesity, insulin resistance, serum lipids, renal dysfunction, and biomarkers of inflammation. Higher MPO levels were associated with prevalent DSPN (fully adjusted OR 1.38 [95% CI 1.10; 1.72] per doubling of MPO). Higher baseline SOD3 levels were related to incident DSPN (age and sex-adjusted OR 2.14 [1.02; 4.48] per doubling of SOD3), which was partially explained by cardiometabolic risk factors.ConclusionsSystemic levels of both pro- and antioxidant enzymes appear involved in cardiometabolic risk and development of DSPN.
AU  - Herder, C.*
AU  - Kannenberg, J.M.*
AU  - Huth, C.
AU  - Carstensen-Kirberg, M.*
AU  - Rathmann, W.*
AU  - Koenig, W.*
AU  - Strom, A.*
AU  - Bönhof, G.J.*
AU  - Heier, M.
AU  - Thorand, B.
AU  - Peters, A.
AU  - Roden, M.*
AU  - Meisinger, C.
AU  - Ziegler, D.*
C1  - 53321
C2  - 44691
CY  - 111 River St, Hoboken 07030-5774, Nj Usa
TI  - Myeloperoxidase, superoxide dismutase-3, cardiometabolic risk factors, and distal sensorimotor polyneuropathy: The KORA F4/FF4 study.
JO  - Diabetes Metab. Res. Rev.
VL  - 34
IS  - 5
PB  - Wiley
PY  - 2018
SN  - 1520-7552
ER  - 

TY  - JOUR
AB  - Background: Prediabetes often occurs together with dyslipidaemia, which is paradoxically treated with statins predisposing to type 2 diabetes mellitus. We examined peripheral blood pathway profiles in prediabetic subjects with (PR D ) and without dyslipidaemia (PR 0 ) and compared these to nonprediabetic controls without dyslipidaemia (C 0 ). Methods: The participants were from the Cardiovascular Risk in Young Finns Study, including 1240 subjects aged 34 to 49 years. Genome-wide expression data of peripheral blood and gene set enrichment analysis were used to investigate the differentially expressed genes and enriched pathways between different subtypes of prediabetes. Results: Pathways for cholesterol synthesis, interleukin-12-mediated signalling events, and downstream signalling in naïve CD8+ T-cells were upregulated in the PR 0 group in comparison with controls (C 0 ). The upregulation of these pathways was independent of waist circumference, blood pressure, smoking status, and insulin. Adjustment for CRP left the CD8+ T-cell signalling and interleukin-12-mediated signalling event pathway upregulated. The cholesterol synthesis pathway was also upregulated when all prediabetic subjects (PR 0 and PR D ) were compared with the nonprediabetic control group. No pathways were upregulated or downregulated when the PR D group was compared with the C 0 group. Five genes in the PR 0 group and 1 in the PR D group were significantly differentially expressed in comparison with the C 0 group. Conclusions: Blood cell gene expression profiles differ significantly between prediabetic subjects with and without dyslipidaemia. Whether this classification may be used in detection of prediabetic individuals at a high risk of cardiovascular complications remains to be examined.
AU  - Laaksonen, J.*
AU  - Taipale, T.*
AU  - Seppälä, I.*
AU  - Raitoharju, E.*
AU  - Mononen, N.*
AU  - Lyytikäinen, L.-P.*
AU  - Waldenberger, M.
AU  - Illig, T.
AU  - Hutri-Kähönen, N.*
AU  - Rönnemaa, T.*
AU  - Juonala, M.*
AU  - Viikari, J.*
AU  - Kähönen, M.*
AU  - Raitakari, O.*
AU  - Lehtimäki, T.*
C1  - 51702
C2  - 43368
CY  - Hoboken
TI  - Blood pathway analyses reveal differences between prediabetic subjects with or without dyslipidaemia. The Cardiovascular Risk in Young Finns Study.
JO  - Diabetes Metab. Res. Rev.
VL  - 33
IS  - 7
PB  - Wiley
PY  - 2017
SN  - 1520-7552
ER  - 

TY  - JOUR
AB  - BACKGROUND: Shunting of glycolytic intermediates into the pentose phosphate pathway (PPP) has been suggested to protect from hyperglycaemia-induced microvascular damage. We hypothesised that genetic variability in the gene encoding transketolase, a key PPP enzyme, contributes to early nerve dysfunction in recent-onset diabetes. METHODS: In this cross-sectional study, we assessed nine single nucleotide polymorphisms (SNPs) in the transketolase gene, plasma methylglyoxal concentrations, and clinical and quantitative measures of peripheral nerve function in 165 type 1 and 373 type 2 diabetic patients with a diabetes duration up to 1 year. RESULTS: The Total Symptom Score (TSS) was associated with transketolase SNPs rs7648309, rs62255988, and rs7633966, while peroneal motor nerve conduction velocity (MNCV) correlated only with rs7648309 (P < 0.01). Cold thermal detection threshold (TDT) (foot) was associated with transketolase SNPs rs11130362 and rs7648309, while warm TDT (hand) correlated with rs62255988 and rs7648309 (P < 0.01). After Bonferroni correction, the correlations of transketolase SNP rs7648309 with TSS and rs62255988 with warm TDT (hand) remained statistically significant. Among subgroups, men with type 2 diabetes showed the strongest associations. No associations were observed between each of the nine tagged transketolase SNPs and plasma methylglyoxal concentrations. CONCLUSIONS: The observed associations of genetic variation in transketolase enzyme with neuropathic symptoms and reduced thermal sensation in recent-onset diabetes suggest a role of pathways metabolizing glycolytic intermediates in early diabetic neuropathy.
AU  - Ziegler, D.*
AU  - Schleicher, E.
AU  - Strom, A.*
AU  - Knebel, B.*
AU  - Fleming, T.*
AU  - Nawroth, P.P.*
AU  - Häring, H.-U.
AU  - Papanas, N.*
AU  - Szendrödi, J.*
AU  - Müssig, K.*
AU  - Al-Hasani, H.*
AU  - Roden, M.*
C1  - 48608
C2  - 41213
TI  - Association of transketolase polymorphisms with measures of polyneuropathy in patients with recently diagnosed diabetes.
JO  - Diabetes Metab. Res. Rev.
VL  - 33
IS  - 4
PY  - 2017
SN  - 1520-7552
ER  - 

TY  - JOUR
AB  - Aims The Environmental Determinants of Diabetes in the Young (TEDDY) planned biomarker discovery studies on longitudinal samples for persistent confirmed islet cell autoantibodies and type 1 diabetes (T1D) using dietary biomarkers, metabolomics, microbiome/viral metagenomics and gene expression. Methods This paper describes the details of planning the TEDDY biomarker discovery studies using a nested case-control design that was chosen as an alternative to the full cohort analysis. In the frame of a nested case-control design, it guides the choice of matching factors, selection of controls, preparation of external quality control samples, and reduction of batch effects along with proper sample allocation. Results and Conclusion Our design is to reduce potential bias and retain study power while reduce the costs by limiting the numbers of samples requiring laboratory analyses. It also covers two primary end points (the occurrence of diabetes-related autoantibodies and the diagnosis of T1D). The resulting list of case-control matched samples for each laboratory was augmented with external quality control (QC) samples.
AU  - Lee, H.S.*
AU  - Burkhardt, B.R.*
AU  - McLeod, W.*
AU  - Smith, S.*
AU  - Eberhard, C.*
AU  - Lynch, K.*
AU  - Hadley, D.*
AU  - Rewers, M.*
AU  - Simell, O.*
AU  - She, J.X.*
AU  - Hagopian, B.*
AU  - Lernmark, A.*
AU  - Akolkar, B.*
AU  - Ziegler, A.-G.
AU  - Krischer, J.P.*
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  - 28982
C2  - 33596
CY  - Hoboken
SP  - 424-434
TI  - Biomarker discovery study design for type 1 diabetes in The Environmental Determinants of Diabetes in the Young (TEDDY) study.
JO  - Diabetes Metab. Res. Rev.
VL  - 30
IS  - 5
PB  - Wiley-blackwell
PY  - 2014
SN  - 1520-7552
ER  - 

TY  - JOUR
AB  - BACKGROUND/PURPOSE: The literature on the role of body iron status in the development of type 2 diabetes in humans is inconsistent. We aimed to assess the association between iron indices and type 2 diabetes by a metaanalysis of previously published studies. METHODS: A systematic literature search was conducted in PubMed and EMBASE. Observational studies on the association of ferritin (if controlled for age and sex), transferrin saturation, soluble transferrin receptor, and transferrin with type 2 diabetes were included. Pooled association estimates were calculated using a random effects model. RESULTS: Forty-seven eligible studies were identified. The pooled multivariable adjusted relative risks of type 2 diabetes in the highest versus lowest quartile of ferritin levels were significantly elevated in both, cross-sectional as well as prospective studies and after restriction to inflammation-adjusted studies (overall: 1.67 (95%CI 1.41-1.99)). The mean difference indicated 43.54 ng/ml (95%CI 28.14-58.94) higher ferritin levels in type 2 diabetic individuals. The relative risk for a transferrin saturation ≥50% was 1.59 (95%CI 1.28-1.97), the mean difference was 1.92% (95%CI 2.99-(-0.85)). Study-specific results of soluble transferrin receptor and transferrin levels were extremely heterogeneous. CONCLUSIONS: Ferritin and clinically elevated transferrin saturation were strongly associated with an increased risk of type 2 diabetes, overall and in prospective studies. Ferritin was also significantly associated after multivariable adjustment including inflammation. Thus, the current evidence hints at a causal effect, however, publication bias and unmeasured confounding cannot be excluded. The study protocol was registered in PROSPERO, number CRD42012002362.
AU  - Orban, E.
AU  - Schwab, S.
AU  - Thorand, B.
AU  - Huth, C.
C1  - 28722
C2  - 33517
CY  - Hoboken
SP  - 372-394
TI  - Association of iron indices and type 2 diabetes: A meta-analysis of observational studies.
JO  - Diabetes Metab. Res. Rev.
VL  - 30
IS  - 5
PB  - Wiley-Blackwell
PY  - 2013
SN  - 1520-7552
ER  - 

TY  - JOUR
AB  - BackgroundInsulin resistance has been postulated to be linked to the frequent onset of type 1 diabetes (T1D) during puberty. Very few studies have investigated the time course of insulin resistance in childhood. To address the question of how insulin resistance develops with age and how this is related to puberty onset, we examined insulin resistance and pubertal development over time in children at increased risk for T1D. MethodsHomeostasis model assessment of insulin resistance (HOMA-IR) was measured in 1848 fasting samples of 1177 children (aged 5-15years) in a cross-sectional analysis. All children had a first degree relative with T1D, 120 developed islet autoantibodies. Pubertal development was determined by Tanner staging. ResultsInsulin resistance rose continuously from age 5 to 13years in girls and from age 5 to 14years in boys with an average increase of 0.09 (95 % confidence interval [CI]: 0.08-0.10) per year for girls and 0.07 (95 % CI: 0.06-0.08) for boys. The rise preceded the onset of puberty (Tanner stage 2), which was reported between 10 and 12years of age in 80.4 % of the children (mean age: 11.20.06years). No difference was seen between children with or without islet autoantibodies. ConclusionsThere was a constant age-dependent rise of insulin resistance during childhood without observed associations to the onset of puberty or the presence of islet autoimmunity in children at increased risk for T1D. Our data show that insulin resistance emerges well before the initiation of physical changes of puberty.
AU  - Raab, J.
AU  - Haupt, F.
AU  - Kordonouri, O.*
AU  - Scholz, M.*
AU  - Wosch, A.
AU  - Ried, C.*
AU  - Aschemeier, B.*
AU  - Danne, T.*
AU  - Ziegler, A.-G.
AU  - Winkler, C.
C1  - 28584
C2  - 33468
SP  - 631-635
TI  - Continuous rise of insulin resistance before and after the onset of puberty in children at increased risk for type 1 diabetes - a cross-sectional analysis.
JO  - Diabetes Metab. Res. Rev.
VL  - 29
IS  - 8
PB  - Wiley-Blackwell
PY  - 2013
SN  - 1520-7552
ER  - 

TY  - JOUR
AB  - BACKGROUND: The vast array and quantity of longitudinal samples collected in The Environmental Determinants of Diabetes in the Young study present a series of challenges in terms of quality control procedures and data validity. To address this, pilot studies have been conducted to standardize and enhance both biospecimen collection and sample obtainment in terms of autoantibody collection, stool sample preservation, RNA, biomarker stability, metabolic biomarkers and T-cell viability. RESEARCH DESIGN AND METHODS: The Environmental Determinants of Diabetes in the Young is a multicentre, international prospective study (n = 8677) designed to identify environmental triggers of type 1 diabetes (T1D) in genetically at-risk children from ages 3 months until 15 years. The study is conducted through six primary clinical centres located in four countries. RESULTS: As of May 2012, over three million biological samples and 250 million total data points have been collected, which will be analysed to assess autoimmunity status, presence of inflammatory biomarkers, genetic factors, exposure to infectious agents, dietary biomarkers and other potentially important environmental exposures in relation to autoimmunity and progression to T1D. CONCLUSIONS: Detailed procedures were utilized to standardize both data harmonization and management when handling a large quantity of longitudinal samples obtained from multiple locations. In addition, a description of the available specimens is provided that serve as an invaluable repository for the elucidation of determinants in T1D focusing on autoantibody concordance and harmonization, transglutaminase autoantibody, inflammatory biomarkers (T-cells), genetic proficiency testing, RNA lab internal quality control testing, infectious agents (monitoring cross-contamination, virus preservation and nasal swab collection validity) and HbA1c testing.
AU  - Vehik, K.*
AU  - Fiske, S.W.*
AU  - Logan, C.A.*
AU  - Agardh, D.*
AU  - Cilio, C.M.*
AU  - Hagopian, W.*
AU  - Simell, O.*
AU  - Roivainen, M.*
AU  - She, J.X.*
AU  - Briese, T.*
AU  - Oikarinen, S.*
AU  - Hyoty, H.*
AU  - Ziegler, A.-G.
AU  - Rewers, M.*
AU  - Lernmark, A.*
AU  - Akolkar, B.*
AU  - Krischer, J.P.*
AU  - Burkhardt, B.R.*
C1  - 27907
C2  - 32852
SP  - 557-567
TI  - Methods, quality control and specimen management in an international multicentre investigation of type 1 diabetes: TEDDY.
JO  - Diabetes Metab. Res. Rev.
VL  - 29
IS  - 7
PB  - Wiley-Blackwell
PY  - 2013
SN  - 1520-7552
ER  - 

TY  - JOUR
AB  - Background Neuropad is a novel indicator test for sudomotor dysfunction, which has not been validated as a screening tool in a population-based study. This study aimed to evaluate the utility of Neuropad as a screening tool for distal symmetric polyneuropathy among elderly subjects with diabetes and pre-diabetes in the general population. Methods Eligible subjects aged 61-82 years (n = 940) from the KORA F4 survey were examined, 201 of whom had diabetes and 231 had pre-diabetes (WHO 1999 criteria). Polyneuropathy was defined by the Michigan Neuropathy Screening Instrument (MNSI) score >3. Results Polyneuropathy was diagnosed in 60 (29.9%) subjects with diabetes and in 45 (19.5%) subjects with pre-diabetes, respectively (p = 0.013). The sensitivity and negative predictive value of Neuropad (reading time: 10 min) for the diagnosis of polyneuropathy were moderately high, reaching 76.7% and 78.1% in subjects with diabetes and 57.8% and 76.5% in those with pre-diabetes, respectively. Conversely, the specificity and positive predictive value for the diagnosis of polyneuropathy were rather low: 35.5% and 33.6% in diabetic individuals and 33.3% and 17.3% in subjects with pre-diabetes, respectively. Use of the >2 cut-off and MNSI combined with monofilament examination did not improve the diagnostic performance of Neuropad. Conclusions In the elderly general population with diabetes and pre-diabetes, Neuropad has reasonable sensitivity but rather low specificity for the diagnosis of polyneuropathy. It is a useful simple and inexpensive tool to screen for and to exclude polyneuropathy as desired, while its low specificity implies that a longer reading time merits consideration.
AU  - Ziegler, D.*
AU  - Papanas, N.*
AU  - Rathmann, W.*
AU  - Heier, M.
AU  - Scheer, M.*
AU  - Meisinger, C.
C1  - 11259
C2  - 30594
SP  - 692-697
TI  - Evaluation of the Neuropad sudomotor function test as a screening tool for polyneuropathy in the elderly population with diabetes and pre-diabetes: The KORA F4 survey.
JO  - Diabetes Metab. Res. Rev.
VL  - 28
IS  - 8
PB  - Wiley-Blackwell
PY  - 2012
SN  - 1520-7552
ER  - 

TY  - JOUR
AB  - OBJECTIVE: Type 2 diabetes disease management programmes (DDMPs) are offered by German social health insurance to promote healthcare consistent with evidence-based medical guidelines. The aim of this study was to compare healthcare quality and medical endpoints between diabetes management programme participants and patients receiving usual care designated as controls. METHODS: All patients with type 2 diabetes (age range: 36-81) in a cross-sectional survey of a cohort study, performed by the Cooperative Health Research in the Region of Augsburg, received a self-administered questionnaire regarding their diabetes care. Physical examination and laboratory tests were also performed. The analysis only included patients with social health insurance and whose participation status in a diabetes disease management program was validated by the primary physician (n = 166). Regression analyses, adjusting for age, sex, education, diabetes duration, baseline waist circumference and clustering regarding primary physician were conducted. RESULTS: Evaluation of healthcare processes showed that those in diabetes disease management programmes (n = 89) reported medical examination of eyes and feet and medical advice regarding diet [odds ratio (OR): 2.39] and physical activity (OR: 2.87) more frequently, received anti-diabetic medications (OR: 3.77) and diabetes education more often (OR: 2.66) than controls. Both groups had satisfactory HbA(1c) control but poor low-density lipoprotein cholesterol control. Blood pressure goals (<140/90 mmHg) were achieved more frequently by patients in diabetes disease management programmes (OR: 2.21). CONCLUSIONS: German diabetes disease management programmes are associated with improved healthcare processes and blood pressure control. Low-density lipoprotein cholesterol control must be improved for all patients with diabetes. Further research will be required to assess the long-term effects of this diabetes disease management programme.
AU  - Stark, R.G.
AU  - Schunk, M.
AU  - Meisinger, C.
AU  - Rathmann, W.*
AU  - Leidl, R.
AU  - Holle, R.
C1  - 6523
C2  - 28906
SP  - 383-391
TI  - Medical care of type 2 diabetes in German disease management programmes: A population-based evaluation.
JO  - Diabetes Metab. Res. Rev.
VL  - 27
IS  - 4
PB  - Wiley-Blackwell
PY  - 2011
SN  - 1520-7552
ER  -