TY - JOUR AB - OBJECTIVE: This secondary analysis of the Semaglutide Treatment Effect in People with obesity (STEP) TEENS (NCT04102189) study investigated the effect of semaglutide 2.4 mg versus placebo on insulin sensitivity and cardiometabolic risk factors. RESEARCH DESIGN AND METHODS: The STEP TEENS phase 3a randomized study in adolescents (aged 12 to <18 years) with obesity demonstrated that once-weekly subcutaneous semaglutide 2.4 mg provided a significantly greater percentage reduction in BMI than placebo at week 68 (estimated difference -16.7 percentage points; P = 0.0001). This analysis investigated changes in insulin sensitivity and cardiometabolic risk factors from baseline to week 68. RESULTS: Overall, 193 participants without type 2 diabetes were included in the analysis. Participants receiving semaglutide 2.4 mg (n = 129) compared with those receiving placebo (n = 64) had greater reductions from baseline in fasting serum insulin (-33.6% vs. -10.1%; P = 0.0012), homeostatic model assessment for insulin resistance (HOMA-IR) score (-35.0% vs. -5.3%; P = 0.0002), glycemic measures (glycated hemoglobin: P < 0.0001; fasting plasma glucose: P = 0.0181), alanine aminotransferase (ALT; -17.9% vs. -3.3%; P = 0.0232), waist-to-height ratio (P < 0.0001), triglycerides (P < 0.0001), LDL cholesterol (P = 0.0105), and total cholesterol (P < 0.0001). Moreover, greater improvements in insulin sensitivity, glycemic measures, and cardiometabolic risk factors were seen in semaglutide 2.4 mg recipients with BMI reductions of ≥20% versus <20%. CONCLUSIONS: These novel data support semaglutide 2.4 mg as an efficacious obesity treatment in adolescents with obesity and advance its application by showing associated improvements in insulin sensitivity, glycemic measures, ALT, and other cardiometabolic risk factors. AU - Arslanian, S.* AU - Gies, I.* AU - Goldman, B.* AU - Karlsson, T.* AU - Kelly, A.S.* AU - Skalshøi Kjær, M.* AU - Körner, A. AU - Noureddin, M.* AU - Wabitsch, M.* AU - Harder-Lauridsen, N.M.* AU - Weghuber, D.* C1 - 76136 C2 - 58430 TI - Effect of semaglutide on insulin sensitivity and cardiometabolic risk factors in adolescents with obesity: The STEP TEENS study. JO - Diabetes Care PY - 2025 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE: Progression of prediabetes to type 2 diabetes has been associated with β-cell dysfunction, whereas its remission to normoglycemia has been related to improvement of insulin sensitivity. To understand the mechanisms and identify potential biomarkers related to prediabetes trajectories, we compared the proteomics and metabolomics profile of people with prediabetes progressing to diabetes or reversing to normoglycemia within 1 year. RESEARCH DESIGN AND METHODS: The fasting plasma concentrations of 1,389 proteins and the fasting, 30-min, and 120-min post-oral glucose tolerance test (OGTT) plasma concentrations of 152 metabolites were measured in up to 134 individuals with new-onset diabetes, prediabetes, or normal glucose tolerance. For 108 participants, the analysis was repeated with samples from 1 year before, when all had prediabetes. RESULTS: The plasma concentrations of 14 proteins were higher in diabetes compared with normoglycemia in a population with prediabetes 1 year before, and they correlated with indices of insulin sensitivity. Higher levels of dicarbonyl/L-xylulose reductase and glutathione S-transferase A3 in the prediabetic state were associated with an increased risk of diabetes 1 year later. Pathway analysis pointed toward differences in immune response between diabetes and normoglycemia that were already recognizable in the prediabetic state 1 year prior at baseline. The area under the curve during OGTT of the concentrations of IDL particles, IDL apolipoprotein B, and IDL cholesterol was higher in new-onset diabetes compared with normoglycemia. The concentration of glutamate increased in prediabetes progressing to diabetes. CONCLUSIONS: We identify new candidates associated with the progression of prediabetes to diabetes or its remission to normoglycemia. Pathways regulating the immune response are related to prediabetes trajectories. AU - Barovic, M.* AU - Hahn, J.J. AU - Heinrich, A. AU - Adhikari, T. AU - Schwarz, P.E. AU - Mirtschink, P.* AU - Funk, A.* AU - Kabisch, S.* AU - Pfeiffer, A.F.H.* AU - Blüher, M.* AU - Seissler, J.* AU - Stefan, N. AU - Wagner, R.* AU - Fritsche, A. AU - Jumpertz von Schwartzenberg, R. AU - Chlamydas, S.* AU - Harb, H.* AU - Mantzoros, C.S.* AU - Chavakis, T. AU - Schürmann, A.* AU - Birkenfeld, A.L. AU - Roden, M.* AU - Solimena, M. AU - Bornstein, S.R. AU - Perakakis, N. C1 - 72920 C2 - 56916 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 405-415 TI - Proteomic and metabolomic signatures in prediabetes progressing to diabetes or reversing to normoglycemia within 1 Year. JO - Diabetes Care VL - 48 IS - 3 PB - Amer Diabetes Assoc PY - 2025 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE: This study aimed to identify metabolites characterizing the progression from normal glucose metabolism (NORM) to prediabetes (PreT2D) and type 2 diabetes (T2D), focusing on stage-specific metabolic shifts (early: NORM to PreT2D; late: PreT2D to T2D) and mechanistic relevance. RESEARCH DESIGN AND METHODS: We analyzed 8,240 observations from the KORA cohort, profiling 104 targeted and 312 non-targeted metabolites across three time points: baseline (S4) and follow-ups (F4 and FF4) spanning 14 years. Trajectory analyses of 1,050 individuals identified 211 incident PreT2D and 112 incident T2D cases. Linear mixed-effects models (basic: adjusted for age, sex, BMI, lifestyle; sensitivity: additionally adjusted for glycemic factors like fasting glucose, and cardiovascular factors such as systolic blood pressure (BP) were used to evaluate metabolic differences across glycemic states. Mediation and Mendelian randomization (MR) analyses examined mechanistic and causal relationships. RESULTS: We identified 140 Bonferroni-significant metabolites (45 targeted, 109 non-targeted, 14 overlapping), including 68 early-stage metabolites (significant in PreT2D/T2D vs. NORM), primarily energy metabolism markers such as fatty acid oxidation metabolites (e.g., 37 lipids) and TCA cycle metabolites (e.g., citrate). Twenty late-stage metabolites (significant in T2D vs. PreT2D/NORM) included amino acids like BCAAs and γ-glutamyl derivatives. Fewer significant associations were observed in incident cases. Sensitivity models validated 50% of early-stage but not late-stage metabolites. Fasting glucose mediated 35.1% of the γ-glutamyl-valine-T2D association, while MR analysis found no causal roles for C2, BCAAs, or γ-glutamyl-valine. CONCLUSIONS: Energy metabolism shifts occur early, while amino acid alterations emerge later stages. These stage-specific signatures may guide diabetes prevention strategies. AU - Ge, J. AU - Han, S. AU - Shi, M. AU - Harada, M. AU - Yu, S. AU - Zheng, J. AU - Prehn, C. AU - Adamski, J. AU - Kastenmüller, G. AU - Schlesinger, S.* AU - Koenig, W.* AU - Linkohr, B. AU - Thorand, B. AU - Suhre, K.* AU - Gieger, C. AU - Peters, A. AU - Wang-Sattler, R. C1 - 76179 C2 - 58455 TI - Integrative metabolomics of targeted and non-targeted analyses in T2D progression. JO - Diabetes Care PY - 2025 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE: In the TrialNet 10 Anti-CD3 Prevention (TN-10) trial, teplizumab delayed onset of stage 3 type 1 diabetes in U.S. and Canadian individuals with stage 2 disease who had a relative with type 1 diabetes. Here, the generalizability of the population risk in TN-10 to a European population with or without first-degree relatives (FDRs) with type 1 diabetes was investigated. RESEARCH DESIGN AND METHODS: This retrospective study used data from participants with stage 2 type 1 diabetes from the TN-10 placebo arm and the Fr1da population-based screening program in Germany (Fr1da group) to investigate time to progression from stages 2-3 type 1 diabetes. The study only had sufficient power to detect large differences. RESULTS: Risk of progression to stage 3 type 1 diabetes was comparable between the TN-10 placebo arm (n = 32) and the Fr1da group (n = 152; hazard ratio [HR] = 1.3 [95% CI 0.8-2.1]). Once prognostic factors significantly associated with progression in this study (anti-IA-2 antibodies, HbA1c >5.7%, and 120-min oral glucose tolerance test) were included in the model, the adjusted HR was 1.1 (95% CI 0.6-2.1). Fr1da group participants with (n = 45) and without (n = 107) FDRs with type 1 diabetes had similar time to progression to stage 3. Age-based subanalysis demonstrated minimal impact of age on progression time. CONCLUSIONS: Time to progression to stage 3 appeared similar between the TN-10 placebo arm and the Fr1da group and between participants with and without FDRs with disease. Results suggest progression risk from the TN-10 trial may be generalizable to European populations with or without FDRs with type 1 diabetes. AU - Köger, M. AU - Winkler, C. AU - Hummel, S. AU - Weiss, A. AU - Koutangni, T.* AU - Yates, M.* AU - Bonnemaire, M.* AU - Guenther, O.* AU - Zaccai, J.* AU - Ziegler, A.-G. C1 - 75820 C2 - 58065 TI - Generalizability of progression risk in the TN-10 trial to a European population with or without a first-degree relative with type 1 diabetes. JO - Diabetes Care PY - 2025 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE: Childhood obesity may impact the risk of islet autoimmunity (IA). The trajectory of BMI through childhood resembles the early peak incidence of first-appearing autoantibodies against insulin (IAA-first) but not GAD65 (GADA-first). We studied whether a child's BMI can impact the age-related risk of first-appearing IA phenotypes. RESEARCH DESIGN AND METHODS: We identified 7,724 children at risk for IA with at least three BMI measurements in The Environmental Determinants of Diabetes in the Young (TEDDY) study. We modeled the risk of IAA-first, GADA-first, and IA overall on a child's BMI z score and change in BMI during infancy (age 2 weeks to 1.5 years, n = 7,724), early childhood (age 1.5-8.5 years, n = 6,396), and puberty (age 8.5-15 years, n = 4,732) using joint modeling of longitudinal BMI and time-to-event IA. RESULTS: An infant's BMI z score was not associated with IA risk before 18 months of age (n = 185, hazard ratio [HR] 1.03 [95% CI 0.88, 1.19]). In contrast, a child's BMI correlated with an increased risk of IA from 1.5 to 8.5 years of age (n = 470, HR 1.20 [95% CI 1.04, 1.32]) and from 8.5 to 15 years of age (n = 209, HR 1.27 [95% CI 1.09, 1.49]). No interactions with first-appearing IA phenotypes were observed. However, high BMI z score (SD >0.5) from age 9 months increased the risk of IA in early childhood, specifically for children with HLA-DR4/4 or HLA-DR4/8 and not with HLA-DR3/3 or HLA-DR3/4 (HLA * BMI interaction, P < 0.005). CONCLUSIONS: The contribution of BMI to risk of IA during early childhood is dependent on the HLA-DR-DQ genotype more so than the first-appearing IA phenotype. AU - Koskenniemi, J.J.* AU - Clasen, J.L.* AU - You, L.* AU - Parikh, H.M.* AU - Vehik, K.* AU - Yang, J.* AU - Uusitalo, U.* AU - Veijola, R.* AU - Haller, M.J.* AU - Ziegler, A.-G. AU - Rewers, M.J.* AU - Hagopian, W.A.* AU - Akolkar, B.* AU - Lernmark, A.* AU - Toppari, J.* AU - Larsson, H.E.* AU - Krischer, J.P.* AU - Lynch, K.F.* AU - Germany clinical center (Sanverdi, C. AU - Heublein, A. AU - Hummel, S. AU - Knopff, A. AU - Köger, M. AU - Koletzko, S. AU - Ramminger, C. AU - Roth, R. AU - Schmidt, J. AU - Scholz, M. AU - Stock, J. AU - Warncke, K. AU - Müller, L. AU - Winkler, C.) C1 - 75741 C2 - 57977 SP - 2103-2110 TI - The contribution of BMI to a young child's risk of islet autoimmunity is dependent on HLA-DR4-DQ8 without HLA-DR3-DQ2. JO - Diabetes Care VL - 48 IS - 12 PY - 2025 SN - 0149-5992 ER - TY - JOUR AB - BACKGROUND: There is uncertainty regarding effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors on the risk of major adverse liver-related outcomes (MALOs). PURPOSE: We performed a meta-analysis of observational cohort studies to quantify the magnitude of the association between SGLT2 inhibitor use and risk of developing MALOs for people with type 2 diabetes mellitus (T2DM). DATA SOURCES: We systematically reviewed three large electronic databases from inception to January 2025. STUDY SELECTION: We included active-comparator, new-user cohort studies with comparison of SGLT2 inhibitors versus other glucose-lowering medications in patients with T2DM. DATA EXTRACTION: The primary outcome was incidence rate of MALOs defined as a composite of hepatic decompensation events, hepatocellular carcinoma, liver transplantation, or liver-related deaths. Secondary outcomes included each of the above as individual events. Meta-analysis was performed with random-effects models. DATA SYNTHESIS: We identified eight cohort studies with aggregate data on 626,104 patients with T2DM (397,806 SGLT2 inhibitor new users and 228,298 new users of other glucose-lowering agents). During a median of 2.7 years, SGLT2 inhibitor use was associated with significantly lower risk of MALOs (random-effects hazard ratio 0.83, 95% CI 0.72-0.95; I2 = 83.1%) and liver-related deaths (0.64, 0.50-0.82; I2 = 0%). The significant risk reduction in MALOs was observed in comparisons of SGLT2 inhibitors with dipeptidyl peptidase 4 inhibitors, metformin, or pioglitazone but not glucagon-like peptide 1 receptor agonists. Sensitivity analyses did not modify these results. A funnel plot did not show significant publication bias. LIMITATIONS: Observational design of the cohort studies and high level of heterogeneity are the main limitations. CONCLUSIONS: SGLT2 inhibitor use was associated with lower risk of MALOs for patients with T2DM. AU - Mantovani, A.* AU - Morandin, R.* AU - Lando, M.G.* AU - Fiorio, V.* AU - Pennisi, G.* AU - Petta, S.* AU - Stefan, N. AU - Tilg, H.* AU - Byrne, C.D.* AU - Targher, G.* C1 - 74669 C2 - 57543 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 1042-1052 TI - Sodium-glucose cotransporter 2 inhibitor use and risk of liver-related events in patients with type 2 diabetes: A meta-analysis of observational cohort studies. JO - Diabetes Care VL - 48 IS - 6 PB - Amer Diabetes Assoc PY - 2025 SN - 0149-5992 ER - TY - JOUR AB - In 2025, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at the National Institutes of Health celebrates 75 years of leadership in diabetes research. The NIDDK serves people of the U.S. affected by or at risk for many chronic diseases, including diabetes and other endocrine, metabolic, and digestive disorders, by funding innovative research to develop better treatment and prevention and a cure for these conditions. Autoimmunity that leads to type 1 diabetes or celiac disease or thyroid autoimmunity affects 1 in 20 children and adolescents in the U.S. While treatments are available, prevention of these common autoimmune diseases has been elusive due to poor understanding of the environmental causes and their interactions with common predisposing or protective genetic variants. In 2002, the NIDDK established The Environmental Determinants of Diabetes in the Young (TEDDY) consortium to advance understanding of the causes and the natural history of type 1 diabetes and other autoimmune diseases. The overarching goal of TEDDY is to inform novel approaches to primary prevention of autoimmunity. In this large international prospective birth cohort study, standardized information has been collected concerning candidate environmental exposures along with serial blood, stool, nasal swab, and other biosamples, with creation of a central repository of data and biologic samples for hypothesis-based research. This review summarizes TEDDY's major contributions to our understanding of environmental triggers, drivers, and modifiers of autoimmunity, and gene-environment interactions, leading to type 1 diabetes. AU - Rewers, M.* AU - Agardh, D.* AU - Johnson, S.B.* AU - Bonifacio, E.* AU - Larsson, H.E.* AU - Gesualdo, P.* AU - Hagopian, W.* AU - Haller, M.J.* AU - Hyöty, H.* AU - Johnson, R.* AU - McIndoe, R.* AU - McKinney, E.F.* AU - Melin, J.* AU - Lernmark, Å.* AU - Lloyd, R.E.* AU - Lynch, K.F.* AU - Norris, J.M.* AU - Rich, S.S.* AU - Roth, R. AU - Schatz, D.* AU - Toppari, J.* AU - Triplett, E.W.* AU - Vehik, K.* AU - Virtanen, S.M.* AU - Ziegler, A.-G. AU - Akolkar, B.* AU - Krischer, J.P.* C1 - 74192 C2 - 57363 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 1125-1135 TI - Unfolding the mystery of autoimmunity: The environmental determinants of diabetes in the young (TEDDY) study. JO - Diabetes Care VL - 48 IS - 7 PB - Amer Diabetes Assoc PY - 2025 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE: Bariatric surgery is an effective treatment option for individuals with obesity and type 2 diabetes (T2D). However, whether outcomes in subtypes of individuals at risk for T2D and/or comorbidities (Tübingen Clusters) differ, is unknown. Of these, cluster 5 (C5) and cluster 6 (C6) are high-risk clusters for developing T2D and/or comorbidities, while cluster 4 (C4) is a low-risk cluster. We investigated bariatric surgery outcomes, hypothesizing that high-risk clusters benefit most due to great potential for metabolic improvement. RESEARCH DESIGN AND METHODS: We allocated participants without T2D but at risk for T2D, defined by elevated BMI, to the Tübingen Clusters. Participants had normal glucose regulation or prediabetes according to American Diabetes Association criteria. Two cohorts underwent bariatric surgery: a discovery (Lille, France) and a replication cohort (Rome, Italy). A control cohort (Tübingen, Germany) received behavioral modification counseling. Main outcomes included alteration of glucose regulation parameters and prediabetes remission. RESULTS: In the discovery cohort, 15.0% of participants (n = 121) were allocated to C4, 22.3% (n = 180) to C5, and 62.4% (n = 503) to C6. Relative body weight loss was similar among all clusters; however, reduction of insulin resistance and improvement of β-cell function were strongest in C5. Prediabetes remission rate was lowest in low-risk C4 and highest in high-risk C5. Individuals from high-risk clusters changed to low-risk clusters in both bariatric surgery cohorts but not in the control cohort. CONCLUSIONS: Participants in C5 had the highest benefit from bariatric surgery in terms of improvement in insulin resistance, β-cell function, and prediabetes remission. This novel classification might help identify individuals who will benefit specifically from bariatric surgery. AU - Sandforth, L. AU - Raverdy, V.* AU - Sandforth, A. AU - Bauvin, P.* AU - Chatelain, E.* AU - Verkindt, H.* AU - Mingrone, G.* AU - Guidone, C.* AU - Verrastro, O.* AU - Zhou, K. AU - Archid, R.* AU - Mihaljevic, A.L.* AU - Caiazzo, R.* AU - Baud, G.* AU - Marciniak, C.* AU - Chetboun, M.* AU - Ganslmeier, M. AU - Minelli Faiao, V. AU - Heni, M.* AU - Fritsche, L. AU - Moller, A. AU - Kantartzis, K. AU - Peter, A. AU - Lehmann, R. AU - Wagner, R. AU - Prystupa, K. AU - Fritsche, A. AU - Stefan, N. AU - Preissl, H. AU - Birkenfeld, A.L. AU - Jumpertz von Schwartzenberg, R. AU - Pattou, F.* C1 - 74056 C2 - 57316 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 996-1006 TI - Subphenotype-dependent benefits of bariatric surgery for individuals at risk for type 2 diabetes. JO - Diabetes Care VL - 48 IS - 6 PB - Amer Diabetes Assoc PY - 2025 SN - 0149-5992 ER - TY - JOUR AB - Prediabetes affects more than one-third of U.S. adults, yet represents a biologically heterogeneous state that is only partly captured by traditional glycemic categories (impaired fasting glucose, impaired glucose tolerance, or borderline elevated HbA1c). Leveraging unsupervised clustering in comprehensively phenotyped cohorts has identified six reproducible prediabetes subtypes integrating insulin sensitivity, insulin secretion, visceral and hepatic fat, and genetic risk. Three high-risk subtypes (progressing prediabetes with fatty liver, progressing prediabetes with β-cell failure, and slow progressors with hyperinsulinemic insulin resistance) show distinct trajectories toward diabetes and unique complication patterns. For example, "slow progressors" develop albuminuria and face excess mortality, despite only modest glycemic deterioration over 10-15 years, showing that complications can arise before diabetes diagnosis. Recognizing these subtypes sharpens risk stratification and opens a path toward precision prevention. Intensive lifestyle modification and bariatric surgery offer the greatest glycemic benefit in the fatty liver subtype, whereas early pharmacologic β-cell protection may be required for the β-cell failure cluster. GLP-1-based therapies offer promising subtype-specific options and should be tested in randomized controlled studies. Future prediabetes intervention trials should move beyond diabetes incidence as the sole end point and systematically evaluate kidney, nerve, eye, and cardiovascular outcomes. While testing for long-term clinical end points might not be feasible in studies where individuals with prediabetes are recruited, the use of surrogate end points could facilitate the assessment of early complications. Such complication-focused, subtype-guided studies will determine whether early, tailored therapy can halt tissue damage and reduce the public health burden linked to prediabetes. AU - Wagner, R. AU - Selvin, E.* AU - Sehgal, R.* AU - Prystupa, K. AU - Misra, S.* AU - Fritsche, A. AU - Heni, M.* C1 - 75542 C2 - 58037 TI - Beyond glucose-rethinking prediabetes for precision prevention. JO - Diabetes Care PY - 2025 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE: To explore whether insulin resistance, assessed by estimated glucose disposal rate (eGDR), is associated with cardiorenal risk and whether it modifies finerenone efficacy. RESEARCH DESIGN AND METHODS: In FIDELITY (N = 13,026), patients with type 2 diabetes, either 1) urine albumin-to-creatinine ratio (UACR) of ≥30 to <300 mg/g and estimated glomerular filtration rate (eGFR) of ≥25 to ≤90 mL/min/1.73 m2 or 2) UACR of ≥300 to ≤5,000 mg/g and eGFR of ≥25 mL/min/1.73 m2, who also received optimized renin-angiotensin system blockade, were randomized to finerenone or placebo. Outcomes included cardiovascular (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) and kidney (kidney failure, sustained decrease of ≥57% in eGFR from baseline, or renal death) composites. eGDR was calculated using waist circumference, hypertension status, and glycated hemoglobin for 12,964 patients. RESULTS: Median eGDR was 4.1 mg/kg/min. eGDR AU - Ebert, T.* AU - Anker, S.D.* AU - Ruilope, L.M.* AU - Fioretto, P.* AU - Fonseca, V.* AU - Umpierrez, G.E.* AU - Birkenfeld, A.L. AU - Lawatscheck, R.* AU - Scott, C.* AU - Rohwedder, K.* AU - Rossing, P.* C1 - 69029 C2 - 53814 SP - 362-370 TI - Outcomes with finerenone in patients with chronic kidney disease and type 2 diabetes by baseline insulin resistance. JO - Diabetes Care VL - 47 IS - 3 PY - 2024 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE: To characterize distinct islet autoantibody profiles preceding stage 3 type 1 diabetes. RESEARCH DESIGN AND METHODS: The T1DI (Type 1 Diabetes Intelligence) study combined data from 1,845 genetically susceptible prospectively observed children who were positive for at least one islet autoantibody: insulin autoantibody (IAA), GAD antibody (GADA), or islet antigen 2 antibody (IA-2A). Using a novel similarity algorithm that considers an individual's temporal autoantibody profile, age at autoantibody appearance, and variation in the positivity of autoantibody types, we performed an unsupervised hierarchical clustering analysis. Progression rates to diabetes were analyzed via survival analysis. RESULTS: We identified five main clusters of individuals with distinct autoantibody profiles characterized by seroconversion age and sequence of appearance of the three autoantibodies. The highest 5-year risk from first positive autoantibody to type 1 diabetes (69.9%; 95% CI 60.0-79.2) was observed in children who first developed IAA in early life (median age 1.6 years) followed by GADA (1.9 years) and then IA-2A (2.1 years). Their 10-year risk was 89.9% (95% CI 81.9-95.4). A high 5-year risk was also found in children with persistent IAA and GADA (39.1%) and children with persistent GADA and IA-2A (30.9%). A lower 5-year risk (10.5%) was observed in children with a late appearance of persistent GADA (6.1 years). The lowest 5-year diabetes risk (1.6%) was associated with positivity for a single, often reverting, autoantibody. CONCLUSIONS: The novel clustering algorithm identified children with distinct islet autoantibody profiles and progression rates to diabetes. These results are useful for prediction, selection of individuals for prevention trials, and studies investigating various pathways to type 1 diabetes. AU - Ghalwash, M.* AU - Anand, V.* AU - Ng, K.* AU - Dunne, J.L.* AU - Lou, O.* AU - Lundgren, M.* AU - Hagopian, W.A.* AU - Rewers, M.* AU - Ziegler, A.-G. AU - Veijola, R.* C1 - 70821 C2 - 55755 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 1424-1431 TI - Data-driven phenotyping of presymptomatic type 1 diabetes using longitudinal autoantibody profiles. JO - Diabetes Care VL - 47 IS - 8 PB - Amer Diabetes Assoc PY - 2024 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE: This study was conducted to evaluate the effects of early clinical diagnosis of type 1 diabetes by comparison of clinical parameters at diagnosis and during follow-up in patients with pediatric type 1 diabetes with early, intermediate, and late diagnosis. RESEARCH DESIGN AND METHODS: In a population-based analysis, data on 14,292 pediatric patients with type 1 diabetes diagnosed between 2015 and 2019 were retrieved from the Diabetes Prospective Documentation (DPV) registry in March 2023. Patients were divided into four groups: one with diabetic ketoacidosis (DKA) at diagnosis and three with early, intermediate, or late diagnosis based on age-dependent HbA1c terciles. Laboratory-measured HbA1c values and those estimated from continuous glucose monitoring were aggregated as a combined glucose indicator (CGI). Insulin-dose adjusted CGI values <9% were defined as partial remission. RESULTS: At diagnosis, patients had a median age of 9.8 years (IQR = 6.8; 13.0). Three years later, patients with early diagnosis had lower CGI than patients with late diagnosis or DKA (mean [95% CI] 7.46% [7.40; 7.53] vs. 7.81% [7.75; 7.87] or 7.74% [7.68; 7.79], respectively; each P < 0.001). More patients experienced partial remission (12.6% [11.0; 14.4] vs. 9.1% [7.7; 10.7] or 8.6% [7.3; 10.0]; each P < 0.001), and 11.7% [10.2; 13.5] of patients with intermediate diagnosis were in partial remission. CONCLUSIONS: Early clinical diagnosis of type 1 diabetes may be beneficial for metabolic control and remission after 3 years of follow-up. Patients diagnosed early may represent a distinct group with better resources or with a different disease biology and slower β-cell destruction, which needs further evaluation. AU - Hammersen, J.* AU - Tittel, S.R.* AU - Kamrath, C.* AU - Warncke, K. AU - Galler, A.* AU - Menzel, U.* AU - Hess, M.* AU - Meißner, T.* AU - Karges, B.* AU - Holl, R.W.* C1 - 71518 C2 - 56230 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 1808-1817 TI - Clinical outcomes in pediatric patients with type 1 diabetes with early versus late diagnosis: Analysis from the DPV registry. JO - Diabetes Care VL - 47 IS - 10 PB - Amer Diabetes Assoc PY - 2024 SN - 0149-5992 ER - TY - JOUR AB - Given the proven benefits of screening to reduce diabetic ketoacidosis (DKA) likelihood at the time of stage 3 type 1 diabetes diagnosis, and emerging availability of therapy to delay disease progression, type 1 diabetes screening programs are being increasingly emphasized. Once broadly implemented, screening initiatives will identify significant numbers of islet autoantibody-positive (IAb+) children and adults who are at risk for (confirmed single IAb+) or living with (multiple IAb+) early-stage (stage 1 and stage 2) type 1 diabetes. These individuals will need monitoring for disease progression; much of this care will happen in nonspecialized settings. To inform this monitoring, JDRF, in conjunction with international experts and societies, developed consensus guidance. Broad advice from this guidance includes the following: 1) partnerships should be fostered between endocrinologists and primary care providers to care for people who are IAb+; 2) when people who are IAb+ are initially identified, there is a need for confirmation using a second sample; 3) single IAb+ individuals are at lower risk of progression than multiple IAb+ individuals; 4) individuals with early-stage type 1 diabetes should have periodic medical monitoring, including regular assessments of glucose levels, regular education about symptoms of diabetes and DKA, and psychosocial support; 5) interested people with stage 2 type 1 diabetes should be offered trial participation or approved therapies; and 6) all health professionals involved in monitoring and care of individuals with type 1 diabetes have a responsibility to provide education. The guidance also emphasizes significant unmet needs for further research on early-stage type 1 diabetes to increase the rigor of future recommendations and inform clinical care. AU - Phillip, M.* AU - Achenbach, P. AU - Addala, A.* AU - Albanese-O'Neill, A.* AU - Battelino, T.* AU - Bell, K.J.* AU - Besser, R.E.J.* AU - Bonifacio, E. AU - Colhoun, H.M.* AU - Couper, J.J.* AU - Craig, M.E.* AU - Danne, T.* AU - de Beaufort, C.* AU - Dovc, K.* AU - Driscoll, K.A.* AU - Dutta, S.* AU - Ebekozien, O.* AU - Elding Larsson, H.* AU - Feiten, D.J.* AU - Frohnert, B.I.* AU - Gabbay, R.A.* AU - Gallagher, M.P.* AU - Greenbaum, C.J.* AU - Griffin, K.J.* AU - Hagopian, W.* AU - Haller, M.J.* AU - Hendrieckx, C.* AU - Hendriks, E.* AU - Holt, R.I.G.* AU - Hughes, L.* AU - Ismail, H.M.* AU - Jacobsen, L.M.* AU - Johnson, S.B.* AU - Kolb, L.E.* AU - Kordonouri, O.* AU - Lange, K.* AU - Lash, R.W.* AU - Lernmark, Å.* AU - Libman, I.M.* AU - Lundgren, M.* AU - Maahs, D.M.* AU - Marcovecchio, M.L.* AU - Mathieu, C.* AU - Miller, K.M.* AU - O'Donnell, H.K.* AU - Oron, T.* AU - Patil, S.P.* AU - Pop-Busui, R.* AU - Rewers, M.J.* AU - Rich, S.S.* AU - Schatz, D.A.* AU - Schulman-Rosenbaum, R.* AU - Simmons, K.M.* AU - Sims, E.K.* AU - Skyler, J.S.* AU - Smith, L.B.* AU - Speake, C.* AU - Steck, A.K.* AU - Thomas, N.P.B.* AU - Tonyushkina, K.N.* AU - Veijola, R.* AU - Wentworth, J.M.* AU - Wherrett, D.K.* AU - Wood, J.R.* AU - Ziegler, A.-G. AU - Dimeglio, L.A.* C1 - 70903 C2 - 55975 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 1276-1298 TI - Consensus guidance for monitoring individuals with islet autoantibody-positive pre-stage 3 type 1 diabetes. JO - Diabetes Care VL - 47 IS - 8 PB - Amer Diabetes Assoc PY - 2024 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE: Prolonged catabolic states in type 2 diabetes (T2D), exacerbated by excess substrate flux and hyperglycemia, can challenge metabolic flexibility and antioxidative capacity. We investigated cellular responses to glucose load after prolonged fasting in T2D. RESEARCH DESIGN AND METHODS: Glucose-tolerant individuals (CON, n = 10), T2D individuals with (T2D+, n = 10) and without diabetes complications (T2D-, n = 10) underwent oral glucose tolerance test before and after a 5-day fasting-mimicking diet. Peripheral blood mononuclear cells' (PBMC) resistance to ex vivo dicarbonyl methylglyoxal (MG) exposure after glucose load was assessed. Markers of dicarbonyl detoxification, oxidative stress, and mitochondrial biogenesis were analyzed by quantitative PCR, with mitochondrial complex protein expression assessed by western blotting. RESULTS: T2D+ exhibited decreased PBMC resistance against MG, while T2D- resistance remained unchanged, and CON improved postglucose load and fasting (-19.0% vs.-1.7% vs. 12.6%; all P = 0.017). T2D+ showed increased expression in dicarbonyl detoxification (mRNA glyoxalase-1, all P = 0.039), oxidative stress (mRNA glutathione-disulfide-reductase, all P = 0.006), and mitochondrial complex V protein (all P = 0.004) compared with T2D- and CON postglucose load and fasting. Citrate synthase activity remained unchanged, indicating no change in mitochondrial number. Mitochondrial biogenesis increased in T2D- compared with CON postglucose load and fasting (mRNA HspA9, P = 0.032). T2D-, compared with CON, exhibited increased oxidative stress postfasting, but not postglucose load, with increased mRNA expression in antioxidant defenses (mRNA forkhead box O4, P = 0.036, and glutathione-peroxidase-2, P = 0.034), and compared with T2D+ (glutathione-peroxidase-2, P = 0.04). CONCLUSIONS: These findings suggest increased susceptibility to glucose-induced oxidative stress in individuals with diabetes complications after prolonged fasting and might help in diet interventions for diabetes management. AU - von Rauchhaupt, E.* AU - Rodemer, C.* AU - Kliemank, E.* AU - Bulkescher, R.* AU - Campos, M.* AU - Kopf, S.* AU - Fleming, T.* AU - Herzig, S. AU - Nawroth, P.P. AU - Szendroedi, J. AU - Zemva, J.* AU - Sulaj, A.* C1 - 70910 C2 - 55802 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 1584-1592 TI - Glucose load following prolonged fasting increases oxidative stress-linked response in individuals with diabetic complications. JO - Diabetes Care VL - 47 IS - 9 PB - Amer Diabetes Assoc PY - 2024 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE: To assess the cost-effectiveness of collaborative versus usual care in adults with poorly controlled type 2 diabetes and depression in India. RESEARCH DESIGN AND METHODS: We performed a within-trial cost-effectiveness analysis of a 24-month parallel, open-label, pragmatic randomized clinical trial at four urban clinics in India from multipayer and societal perspectives. The trial randomly assigned 404 patients with poorly controlled type 2 diabetes (HbA1c ≥8.0%, systolic blood pressure ≥140 mmHg, or LDL cholesterol ≥130 mg/dL) and depressive symptoms (9-item Patient Health Questionnaire score ≥10) to collaborative care (support from nonphysician care coordinators, electronic registers, and specialist-supported case review) for 12 months, followed by 12 months of usual care or 24 months of usual care. We calculated incremental cost-effectiveness ratios (ICERs) in Indian rupees (INR) and international dollars (Int'l-$) and the probability of cost-effectiveness using quality-adjusted life-years (QALYs) and depression-free days (DFDs). RESULTS: From a multipayer perspective, collaborative care costed an additional INR309,558 (Int'l-$15,344) per QALY and an additional INR290.2 (Int'l-$14.4) per DFD gained compared with usual care. The probability of cost-effectiveness was 56.4% using a willingness to pay of INR336,000 (Int'l-$16,654) per QALY (approximately three times per-capita gross domestic product). The willingness to pay per DFD to achieve a probability of cost-effectiveness >95% was INR401.6 (Int'l-$19.9). From a societal perspective, cost-effectiveness was marginally lower. In sensitivity analyses, integrating collaborative care in clinical workflows reduced incremental costs by ∼47% (ICER 162,689 per QALY, cost-effectiveness probability 89.4%), but cost-effectiveness decreased when adjusting for baseline values. CONCLUSIONS: Collaborative care for patients with type 2 diabetes and depression in urban India can be cost-effective, especially when integrated in clinical workflows. Long-term cost-effectiveness might be more favorable. Scalability across lower- and middle-income country settings depends on heterogeneous contextual factors. AU - Emmert-Fees, K. AU - Laxy, M. AU - Patel, S.A.* AU - Singh, K.* AU - Poongothai, S.* AU - Mohan, V.* AU - Chwastiak, L.* AU - Narayan, K.M.V.* AU - Sagar, R.* AU - Sosale, A.R.* AU - Anjana, R.M.* AU - Sridhar, G.R.* AU - Tandon, N.* AU - Ali, M.K.* C1 - 66879 C2 - 53342 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 11-19 TI - Cost-effectiveness of a collaborative care model among patients with type 2 diabetes and depression in India. JO - Diabetes Care VL - 46 IS - 1 PB - Amer Diabetes Assoc PY - 2023 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE: To estimate the risk of progression to stage 3 type 1 diabetes based on varying definitions of multiple islet autoantibody positivity (mIA). RESEARCH DESIGN AND METHODS: Type 1 Diabetes Intelligence (T1DI) is a combined prospective data set of children from Finland, Germany, Sweden, and the U.S. who have an increased genetic risk for type 1 diabetes. Analysis included 16,709 infants-toddlers enrolled by age 2.5 years and comparison between groups using Kaplan-Meier survival analysis. RESULTS: Of 865 (5%) children with mIA, 537 (62%) progressed to type 1 diabetes. The 15-year cumulative incidence of diabetes varied from the most stringent definition (mIA/Persistent/2: two or more islet autoantibodies positive at the same visit with two or more antibodies persistent at next visit; 88% [95% CI 85-92%]) to the least stringent (mIA/Any: positivity for two islet autoantibodies without co-occurring positivity or persistence; 18% [5-40%]). Progression in mIA/Persistent/2 was significantly higher than all other groups (P < 0.0001). Intermediate stringency definitions showed intermediate risk and were significantly different than mIA/Any (P < 0.05); however, differences waned over the 2-year follow-up among those who did not subsequently reach higher stringency. Among mIA/Persistent/2 individuals with three autoantibodies, loss of one autoantibody by the 2-year follow-up was associated with accelerated progression. Age was significantly associated with time from seroconversion to mIA/Persistent/2 status and mIA to stage 3 type 1 diabetes. CONCLUSIONS: The 15-year risk of progression to type 1 diabetes risk varies markedly from 18 to 88% based on the stringency of mIA definition. While initial categorization identifies highest-risk individuals, short-term follow-up over 2 years may help stratify evolving risk, especially for those with less stringent definitions of mIA. AU - Frohnert, B.I.* AU - Ghalwash, M.* AU - Li, Y.* AU - Ng, K.* AU - Dunne, J.L.* AU - Lundgren, M.* AU - Hagopian, W.* AU - Lou, O.* AU - Winkler, C. AU - Toppari, J.* AU - Veijola, R.* AU - Anand, V.* C1 - 67564 C2 - 53593 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 1753-1761 TI - Refining the definition of stage 1itype 1 diabetes: An ontology-driven analysis of the heterogeneity of multiple Islet autoimmunity. JO - Diabetes Care VL - 46 IS - 10 PB - Amer Diabetes Assoc PY - 2023 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE This study investigated physical activity and its association with the development of islet autoimmunity and type 1 diabetes in genetically at-risk children aged 5–15 years. RESEARCH DESIGN AND METHODS As part of the longitudinal Environmental Determinants of Diabetes in the Young (TEDDY) study, annual assessment of activity using accelerometry was conducted from age 5 years. Time-to-event analyses using Cox proportional hazard models were used to assess the association between time spent in moderate to vigorous physical activity per day and the appearance of one or several autoantibodies and progression to type 1 diabetes in three risk groups: 1) 3,869 islet autoantibody (IA)-negative children, of whom 157 became single IA positive; 2) 302 single IA–positive children, of whom 73 became multiple IA positive; and 3) 294 multiple IA–positive children, of whom 148 developed type 1 diabetes. RESULTS No significant association was found in risk group 1 or risk group 2. A significant association was seen in risk group 3 (hazard ratio 0.920 [95% CI 0.856, 0.988] per 10-min increase; P = 0.021), particularly when glutamate decarboxylase autoantibody was the first autoantibody (hazard ratio 0.883 [95% CI 0.783, 0.996] per 10-min increase; P = 0.043). CONCLUSIONS More daily minutes spent in moderate to vigorous physical activity was associated with a reduced risk of progression to type 1 diabetes in children aged 5–15 years who had developed multiple IAs. AU - Liu, X.* AU - Johnson, S.B.* AU - Lynch, K.F.* AU - Cordan, K.* AU - Pate, R.* AU - Butterworth, M.D.* AU - Lernmark, Å.* AU - Hagopian, W.A.* AU - Rewers, M.J.* AU - McIndoe, R.A.* AU - Toppari, J.* AU - Ziegler, A.-G. AU - Akolkar, B.* AU - Krischer, J.P.* AU - Yang, J.* C1 - 68457 C2 - 53653 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 1409-1416 TI - Physical activity and the development of islet autoimmunity and type 1 diabetes in 5-to 15-year-old children followed in the TEDDY study. JO - Diabetes Care VL - 46 IS - 7 PB - Amer Diabetes Assoc PY - 2023 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE: To investigate gastrointestinal infection episodes (GIEs) in relation to the appearance of islet autoantibodies in The Environmental Determinants of Diabetes in the Young (TEDDY) cohort. RESEARCH DESIGN AND METHODS: GIEs on risk of autoantibodies against either insulin (IAA) or GAD (GADA) as the first-appearing autoantibody were assessed in a 10-year follow-up of 7,867 children. Stool virome was characterized in a nested case-control study. RESULTS: GIE reports (odds ratio [OR] 2.17 [95% CI 1.39-3.39]) as well as Norwalk viruses found in stool (OR 5.69 [1.36-23.7]) at <1 year of age were associated with an increased IAA risk at 2-4 years of age. GIEs reported at age 1 to <2 years correlated with a lower risk of IAA up to 10 years of age (OR 0.48 [0.35-0.68]). GIE reports at any other age were associated with an increase in IAA risk (OR 2.04 for IAA when GIE was observed 12-23 months prior [1.41-2.96]). Impacts on GADA risk were limited to GIEs <6 months prior to autoantibody development in children <4 years of age (OR 2.16 [1.54-3.02]). CONCLUSIONS: Bidirectional associations were observed. GIEs were associated with increased IAA risk when reported before 1 year of age or 12-23 months prior to IAA. Norwalk virus was identified as one possible candidate factor. GIEs reported during the 2nd year of life were associated with a decreased IAA risk. AU - Lönnrot, M.* AU - Lynch, K.F.* AU - Rewers, M.* AU - Lernmark, * AU - Vehik, K.* AU - Akolkar, B.* AU - Hagopian, W.* AU - Krischer, J.* AU - McIndoe, R.A.* AU - Toppari, J.* AU - Ziegler, A.-G. AU - Petrosino, J.F.* AU - Lloyd, R.* AU - Hyoty, H.* AU - TEDDY Study Group (Gezginci, C. AU - Heublein, A. AU - Hummel, S. AU - Knopff, A. AU - Köger, M. AU - Koletzko, S. AU - Roth, R. AU - Schmidt, J. AU - Scholz, M. AU - Stock, J. AU - Warncke, K. AU - Wendel, L. AU - Winkler, C.) C1 - 67971 C2 - 54449 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 1908-1915 TI - Gastrointestinal infections modulate the risk for insulin autoantibodies as the first-appearing autoantibody in the TEDDY Study. JO - Diabetes Care VL - 46 IS - 11 PB - Amer Diabetes Assoc PY - 2023 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE: Dietary glycemic index (GI) and glycemic load (GL) are associated with cardiometabolic health in children and adolescents, with potential distinct effects in people with increased BMI. DNA methylation (DNAm) may mediate these effects. Thus, we conducted meta-analyses of epigenome-wide association studies (EWAS) between dietary GI and GL and blood DNAm of children and adolescents. RESEARCH DESIGN AND METHODS: We calculated dietary GI and GL and performed EWAS in children and adolescents (age range: 4.5-17 years) from six cohorts (N = 1,187). We performed stratified analyses of participants with normal weight (n = 801) or overweight or obesity (n = 386). We performed look-ups for the identified cytosine-phosphate-guanine (CpG) sites (false discovery rate [FDR] <0.05) with tissue-specific gene expression of 832 blood and 223 subcutaneous adipose tissue samples from children and adolescents. RESULTS: Dietary GL was positively associated with DNAm of cg20274553 (FDR <0.05), annotated to WDR27. Several CpGs were identified in the normal-weight (GI: 85; GL: 17) and overweight or obese (GI: 136; GL: 298; FDR <0.05) strata, and none overlapped between strata. In participants with overweight or obesity, identified CpGs were related to RNA expression of genes associated with impaired metabolism (e.g., FRAT1, CSF3). CONCLUSIONS: We identified 537 associations between dietary GI and GL and blood DNAm, mainly in children and adolescents with overweight or obesity. High-GI and/or -GL diets may influence epigenetic gene regulation and thereby promote metabolic derangements in young people with increased BMI. AU - Ott, R. AU - Stein, R. AU - Hauta-Alus, H.H.* AU - Ronkainen, J.* AU - Fernández-Barrés, S.* AU - Spielau, U.* AU - Kirsten, H.* AU - Poulain, T.* AU - Melton, P.E.* AU - Küpers, L.K.* AU - Azaryah, H.* AU - Colombo, M.* AU - Landgraf, K.* AU - Tobi, E.W.* AU - O'Sullivan, T.* AU - Huang, R.C.* AU - Campoy, C.* AU - Winkler, C. AU - Vioque, J.* AU - Vrijheid, M.* AU - Kiess, W.* AU - Körner, A. AU - Sebert, S.* AU - Jarvelin, M.R.* AU - Ziegler, A.-G. AU - Hummel, S. C1 - 68640 C2 - 54834 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 2067-2075 TI - Epigenome-wide meta-analysis reveals associations between dietary glycemic index and glycemic load and DNA methylation in children and adolescents of different body sizes. JO - Diabetes Care VL - 46 IS - 11 PB - Amer Diabetes Assoc PY - 2023 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE: Previous studies showed that inhibiting lymphocyte costimulation reduces declining β-cell function in individuals newly diagnosed with type 1 diabetes. We tested whether abatacept would delay or prevent progression of type 1 diabetes from normal glucose tolerance (NGT) to abnormal glucose tolerance (AGT) or to diabetes and the effects of treatment on immune and metabolic responses. RESEARCH DESIGN AND METHODS: We conducted a phase 2, randomized, placebo-controlled, double-masked trial of abatacept in antibody-positive participants with NGT who received monthly abatacept/placebo infusions for 12 months. The end point was AGT or diabetes, assessed by oral glucose tolerance tests. RESULTS: A total of 101 participants received abatacept and 111 placebo. Of these, 81 (35 abatacept and 46 placebo) met the end point of AGT or type 1 diabetes diagnosis (hazard ratio 0.702; 95% CI 0.452, 1.09; P = 0.11) The C-peptide responses to oral glucose tolerance tests were higher in the abatacept arm (P < 0.03). Abatacept reduced the frequency of inducible T-cell costimulatory (ICOS)+ PD1+ T-follicular helper (Tfh) cells during treatment (P < 0.0001), increased naive CD4+ T cells, and also reduced the frequency of CD4+ regulatory T cells (Tregs) from the baseline (P = 0.0067). Twelve months after treatment, the frequency of ICOS+ Tfh, naive CD4+ T cells, and Tregs returned to baseline. CONCLUSIONS: Although abatacept treatment for 1 year did not significantly delay progression to glucose intolerance in at-risk individuals, it impacted immune cell subsets and preserved insulin secretion, suggesting that costimulation blockade may modify progression of type 1 diabetes. AU - Russell, W.E.* AU - Bundy, B.N.* AU - Anderson, M.S.* AU - Cooney, L.A.* AU - Gitelman, S.E.* AU - Goland, R.S.* AU - Gottlieb, P.A.* AU - Greenbaum, C.J.* AU - Haller, M.J.* AU - Krischer, J.P.* AU - Libman, I.M.* AU - Linsley, P.S.* AU - Long, S.A.* AU - Lord, S.M.* AU - Moore, D.J.* AU - Moore, W.V.* AU - Moran, A.M.* AU - Muir, A.B.* AU - Raskin, P.* AU - Skyler, J.S.* AU - Wentworth, J.M.* AU - Wherrett, D.K.* AU - Wilson, D.M.* AU - Ziegler, A.-G. AU - Herold, K.C.* C1 - 67726 C2 - 54034 SP - 1005-1013 TI - Abatacept for delay of type 1 diabetes progression in stage 1 relatives at risk: A randomized, double-masked, controlled trial. JO - Diabetes Care VL - 46 IS - 5 PY - 2023 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE: To examine whether iron intake and genetically determined iron overload interact in predisposing to the development of childhood islet autoimmunity (IA) and type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: In The Environmental Determinants of Diabetes in the Young (TEDDY) study, 7,770 genetically high-risk children were followed from birth until the development of IA and progression to T1D. Exposures included energy-adjusted iron intake in the first 3 years of life and a genetic risk score (GRS) for increased circulating iron. RESULTS: We found a U-shaped association between iron intake and risk of GAD antibody as the first autoantibody. In children with GRS ≥2 iron risk alleles, high iron intake was associated with an increased risk of IA, with insulin as first autoantibody (adjusted hazard ratio 1.71 [95% CI 1.14; 2.58]) compared with moderate iron intake. CONCLUSIONS: Iron intake may alter the risk of IA in children with high-risk HLA haplogenotypes. AU - Thorsen, S.U.* AU - Liu, X.* AU - Kataria, Y.* AU - Mandrup-Poulsen, T.* AU - Kaur, S.* AU - Uusitalo, U.* AU - Virtanen, S.M.* AU - Norris, J.M.* AU - Rewers, M.* AU - Hagopian, W.* AU - Yang, J.* AU - She, J.X.* AU - Akolkar, B.* AU - Rich, S.* AU - Aronsson, C.A.* AU - Lernmark, * AU - Ziegler, A.-G. AU - Toppari, J.* AU - Krischer, J.* AU - Parikh, H.M.* AU - Ellervik, C.* AU - Svensson, J.* C1 - 67560 C2 - 54071 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 1014-1018 TI - Interaction between dietary iron intake and genetically determined iron overload: Risk of islet autoimmunity and progression to Type 1 diabetes in the TEDDY study. JO - Diabetes Care VL - 46 IS - 5 PB - Amer Diabetes Assoc PY - 2023 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE: To study the interaction among HLA genotype, early probiotic exposure, and timing of complementary foods in relation to risk of islet autoimmunity (IA). RESEARCH DESIGN AND METHODS: The Environmental Determinants of Diabetes in the Young (TEDDY) study prospectively follows 8,676 children with increased genetic risk of type 1 diabetes. We used a Cox proportional hazards regression model adjusting for potential confounders to study early feeding and the risk of IA in a sample of 7,770 children. RESULTS: Any solid food introduced early (<6 months) was associated with increased risk of IA if the child had the HLA DR3/4 genotype and no probiotic exposure during the 1st year of life. Rice introduced at 4-5.9 months compared with later in the U.S. was associated with an increased risk of IA. CONCLUSIONS: Timing of solid food introduction, including rice, may be associated with IA in children with the HLA DR3/4 genotype not exposed to probiotics. The microbiome composition under these exposure combinations requires further study. AU - Uusitalo, U.* AU - Mramba, L.K.* AU - Aronsson, C.A.* AU - Vehik, K.* AU - Yang, J.* AU - Hummel, S. AU - Lernmark, * AU - Rewers, M.* AU - Hagopian, W.* AU - McIndoe, R.* AU - Toppari, J.* AU - Ziegler, A.G.* AU - Akolkar, B.* AU - Krischer, J.P.* AU - Virtanen, S.M.* AU - Norris, J.M.* AU - Germany clinical center (Ziegler, A.-G. AU - Gezginci, C. AU - Heublein, A. AU - Knopff, A. AU - Köger, M. AU - Koletzko, S. AU - Roth, R. AU - Scholz, M. AU - Stock, J. AU - Warncke, K. AU - Wendel, L. AU - Winkler, C.) AU - Schmidt, J. C1 - 67996 C2 - 54474 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 1839-1847 TI - HLA genotype and probiotics modify the association between timing of solid food introduction and islet autoimmunity in the TEDDY Study. JO - Diabetes Care VL - 46 IS - 10 PB - Amer Diabetes Assoc PY - 2023 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE Down syndrome (DS) is the most common form of chromosomal trisomy. Genetic factors in DS may increase the risk for diabetes. This study aimed to determine whether DS is associated with an increased incidence of diabetes and the rela- tionship with obesity across the life span compared with control patients. RESEARCH DESIGN AND METHODS This matched population–based cohort study analyzed UK Clinical Practice Research Datalink data from 1990 to 2020. RESULTS A total of 9,917 patients with DS and 38,266 control patients were analyzed. Dia- betes rates were higher in patients with DS (incidence rate ratio 3.67; 95% CI 2.43–5.55; P < 0.0001) and peaked at a younger age (median age at diagnosis 38 [interquartile range 28–49] years vs. 53 [43–61] years in control patients). Inci- dence rates (per 1,000 person-years) for type 1 diabetes mellitus were 0.44 (95% CI 0.31–0.61) in patients with DS vs. 0.13 (0.09–0.17) in control patients. Type 2 diabetes mellitus (T2DM) rates were higher in patients with DS versus control pa- tients in age-groups from 5 years up to 34 years. In patients with DS, peak mean BMI was higher and at a younger age (males 31.2 kg/m2 at age 31 years; females 32.1 kg/m2 at 43 years) versus control patients (males 29.5 kg/m2 at 54 years; females 29.2 kg/m2 at 51 years). Obesity was associated with an increased inci- dence of T2DM. CONCLUSIONS At younger ages, the incidence of diabetes in patients with DS is up to four times that of control patients. Peak mean BMI is higher and established earlier in DS, contributing to T2DM risk. Further investigation into the relationship between obe- sity and diabetes in DS is required to inform treatment and prevention measures. AU - Aslam. A.A.* AU - Baksh, R.A.* AU - Paper, S.E.* AU - Strydom, A.* AU - Gulliford, M.C.* AU - Chan, L.F.* AU - GO-DS21 Consortium (Beckers, J.) C1 - 66287 C2 - 52936 SP - 2892–2899 TI - Diabetes and obesity in down syndrome across the lifespan: A retrospective cohort study using U.K. electronic health records. JO - Diabetes Care VL - 45 IS - 12 PY - 2022 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE: To investigate whether socioeconomic deprivation and urbanization are associated with the frequency of diabetic ketoacidosis (DKA) at diagnosis of pediatric type 1 diabetes. RESEARCH DESIGN AND METHODS: Children and adolescents aged ≤18 years, living in Germany, with newly diagnosed type 1 diabetes documented between 2016 and 2019 in the Diabetes Prospective Follow-up Registry (DPV; Diabetes-Patienten-Verlaufsdokumentation), were assigned to a quintile of regional socioeconomic deprivation (German Index of Socioeconomic Deprivation) and to a degree of urbanization (Eurostat) by using their residence postal code. With multiple logistic regression models, we investigated whether the frequency of DKA at diagnosis was associated with socioeconomic deprivation or urbanization and whether associations differed by age-group, sex, or migration status. RESULTS: In 10,598 children and adolescents with newly diagnosed type 1 diabetes, the frequency of DKA was lowest in the least deprived regions (Q1: 20.6% [95% CI 19.0-22.4], and increased with growing socioeconomic deprivation to 26.9% [25.0-28.8] in the most deprived regions [Q5]; P for trend <0.001). In rural areas, the frequency of DKA at diagnosis was significantly higher than in towns and suburbs (intermediate areas) or in cities (27.6% [95% CI 26.0-29.3] vs. 22.7% [21.4-24.0], P < 0.001, or vs. 24.3% [22.9-25.7], P = 0.007, respectively). The results did not significantly differ by age-group, sex, or migration background or after additional adjustment for socioeconomic deprivation or urbanization. CONCLUSIONS: This study provides evidence that prevention of DKA at diagnosis by means of awareness campaigns and screening for presymptomatic type 1 diabetes should particularly target socioeconomically disadvantaged regions and rural areas. AU - Auzanneau, M.* AU - Rosenbauer, J.* AU - Warncke, K.* AU - Maier, W. AU - Kamrath, C.* AU - Hofmann, T.* AU - Wurm, M.* AU - Hammersen, J.* AU - Schröder, C.* AU - Hake, K.* AU - Holl, R.W.* C1 - 65548 C2 - 52317 SP - 1807-1813 TI - Frequency of ketoacidosis at diagnosis of pediatric type 1 diabetes associated with socioeconomic deprivation and Uubanization: Results from the German Multicenter DPV Registry. JO - Diabetes Care VL - 45 IS - 8 PY - 2022 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE: To investigate whether changes in circulating levels of pancreatic islet-related miRNA-375 (miR-375) are related to improved visceral and intrahepatic fat accumulation. RESEARCH DESIGN AND METHODS: This study included adults with abdominal obesity from an 18-month weight loss lifestyle intervention trial. Circulating miR-375-3p was measured at baseline and 18 months. MRI was performed (n = 139) to assess 18-month changes in abdominal and intrahepatic fat depots. RESULTS: Circulating miR-375-3p was related to fasting insulin and insulin resistance in participants with prediabetes. After the interventions, there was a significant increase of miR-375-3p (P < 0.001). Greater increase in miR-375-3p was associated with greater reductions of visceral (P = 0.024) and deep subcutaneous (P < 0.001) adipose tissues and intrahepatic fat content (P = 0.012). CONCLUSIONS: Increases in circulating miR-375-3p were associated with visceral and intrahepatic fat reduction. Changes in circulating pancreatic islet-related miR-375-3p may be linked to improved diabetogenic fat depots during weight loss lifestyle interventions. AU - Heianza, Y.* AU - Krohn, K.* AU - Yaskolka Meir, A.* AU - Wang, X.* AU - Ziesche, S.* AU - Ceglarek, U.* AU - Blüher, M. AU - Keller, M. AU - Kovacs, P.* AU - Shai, I.* AU - Qi, L.* C1 - 65469 C2 - 52311 SP - 1911-1913 TI - Changes in circulating miR-375-3p and improvements in visceral and hepatic fat contents in response to lifestyle interventions: The CENTRAL trial. JO - Diabetes Care VL - 45 IS - 8 PY - 2022 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE: The Environmental Determinants of Diabetes in the Young (TEDDY) study is uniquely capable of investigating age-specific differences associated with type 1 diabetes. Because age is a primary driver of heterogeneity in type 1 diabetes, we sought to characterize by age metabolic derangements prior to diagnosis and clinical features associated with diabetic ketoacidosis (DKA). RESEARCH DESIGN AND METHODS: The 379 TEDDY children who developed type 1 diabetes were grouped by age at onset (0-4, 5-9, and 10-14 years; n = 142, 151, and 86, respectively) with comparisons of autoantibody profiles, HLAs, family history of diabetes, presence of DKA, symptomatology at onset, and adherence to TEDDY protocol. Time-varying analysis compared those with oral glucose tolerance test data with TEDDY children who did not progress to diabetes. RESULTS: Increasing fasting glucose (hazard ratio [HR] 1.09 [95% CI 1.04-1.14]; P = 0.0003), stimulated glucose (HR 1.50 [1.42-1.59]; P < 0.0001), fasting insulin (HR 0.89 [0.83-0.95]; P = 0.0009), and glucose-to-insulin ratio (HR 1.29 [1.16-1.43]; P < 0.0001) were associated with risk of progression to type 1 diabetes. Younger children had fewer autoantibodies with more symptoms at diagnosis. Of 23 (6.1%) of 379 children with DKA at onset, only 1 (4.3%) of 23 had a first-degree relative (FDR) with type 1 diabetes compared with 102 (28.7%) of 356 FDR children without DKA (P = 0.008). Children with DKA were more likely to be nonadherent to study protocol (P = 0.047), with longer duration between their last TEDDY evaluation and diagnosis (median 10.2 vs. 2.0 months without DKA; P < 0.001). CONCLUSIONS: DKA at onset in TEDDY is uncommon, especially for FDRs. For those without familial risk, metabolic monitoring continues to provide a primary benefit of reduced DKA but requires regular follow-up. Clinical and laboratory features vary by age at onset, adding to the heterogeneity of type 1 diabetes. AU - Jacobsen, L.M.* AU - Vehik, K.* AU - Veijola, R.* AU - Warncke, K. AU - Toppari, J.* AU - Steck, A.K.* AU - Gesualdo, P.* AU - Akolkar, B.* AU - Lundgren, M.* AU - Hagopian, W.A.* AU - She, J.X.* AU - Rewers, M.* AU - Ziegler, A.G.* AU - Krischer, J.P.* AU - Larsson, H.E.* AU - Haller, M.J.* AU - TEDDY Study Group (Gezginci, C. AU - Heublein, A. AU - Hummel, S. AU - Knopff, A. AU - Koch, C. AU - Koletzko, S. AU - Roth, R. AU - Schmidt, J. AU - Scholz, M. AU - Stock, J. AU - Wendel, L. AU - Winkler, C.) C1 - 64129 C2 - 51808 SP - 624-633 TI - Heterogeneity of DKA incidence and age-specific clinical characteristics in children diagnosed with type 1 diabetes in the TEDDY Study. JO - Diabetes Care VL - 45 IS - 3 PY - 2022 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE: We sought to evaluate costs associated with public health screening for presymptomatic type 1 diabetes in 90,632 children as part of the Fr1da study in Bavaria and in forecasts for standard care. RESEARCH DESIGN AND METHODS: We report on resource use and direct costs for screening-related procedures in the Fr1da study coordination center and laboratory and in participating pediatric practices and local diabetes clinics. Data were obtained from Fr1da study documents, an online survey among pediatricians, and interviews and records of Fr1da staff members. Data were analyzed with tree models that mimic procedures during the screening process. Cost estimates are presented as they were observed in the Fr1da study and as they can be expected in standard care for various scenarios. RESULTS: The costs per child screened in the Fr1da study were €28.17 (95% CI 19.96; 39.63) and the costs per child diagnosed with presymptomatic type 1 diabetes were €9,117 (6,460; 12,827). Assuming a prevalence of presymptomatic type 1 diabetes of 0.31%, as in the Fr1da study, the estimated costs in standard care in Germany would be €21.73 (16.76; 28.19) per screened child and €7,035 (5,426; 9,124) per diagnosed child. Of the projected screening costs, €12.25 would be the costs in the medical practice, €9.34 for coordination and laboratory, and €0.14 for local diabetes clinics. CONCLUSIONS: This study provides information for the planning and implementation of screening tests for presymptomatic type 1 diabetes in the general public and for the analysis of the cost-effectiveness of targeted prevention strategies. AU - Karl, F. AU - Winkler, C. AU - Ziegler, A.-G. AU - Laxy, M. AU - Achenbach, P. C1 - 64372 C2 - 51917 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 837-844 TI - Costs of public health screening of children for presymptomatic type 1 diabetes in Bavaria, Germany. JO - Diabetes Care VL - 45 IS - 4 PB - Amer Diabetes Assoc PY - 2022 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE: To distinguish among predictors of seroconversion, progression to multiple autoantibodies and from multiple autoantibodies to type 1 diabetes in young children. RESEARCH DESIGN AND METHODS: Genetically high-risk newborns (n = 8,502) were followed for a median of 11.2 years (interquartile range 9.3-12.6); 835 (9.8%) developed islet autoantibodies and 283 (3.3%) were diagnosed with type 1 diabetes. Predictors were examined using Cox proportional hazards models. RESULTS: Predictors of seroconversion and progression differed, depending on the type of first appearing autoantibody. Male sex, Finnish residence, having a sibling with type 1 diabetes, the HLA DR4 allele, probiotic use before age 28 days, and single nucleotide polymorphism (SNP) rs689_A (INS) predicted seroconversion to IAA-first (having islet autoantibody to insulin as the first appearing autoantibody). Increased weight at 12 months and SNPs rs12708716_G (CLEC16A) and rs2292239_T (ERBB3) predicted GADA-first (autoantibody to GAD as the first appearing). For those having a father with type 1 diabetes, the SNPs rs2476601_A (PTPN22) and rs3184504_T (SH2B3) predicted both. Younger age at seroconversion predicted progression from single to multiple autoantibodies as well as progression to diabetes, except for those presenting with GADA-first. Family history of type 1 diabetes and the HLA DR4 allele predicted progression to multiple autoantibodies but not diabetes. Sex did not predict progression to multiple autoantibodies, but males progressed more slowly than females from multiple autoantibodies to diabetes. SKAP2 and MIR3681HG SNPs are newly reported to be significantly associated with progression from multiple autoantibodies to type 1 diabetes. CONCLUSIONS: Predictors of IAA-first versus GADA-first autoimmunity differ from each other and from the predictors of progression to diabetes. AU - Krischer, J.P.* AU - Liu, X.* AU - Lernmark, Å.* AU - Hagopian, W.A.* AU - Rewers, M.J.* AU - She, J.X.* AU - Toppari, J.* AU - Ziegler, A.-G. AU - Akolkar, B.* C1 - 66283 C2 - 52768 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 2271-2281 TI - Predictors of the initiation of islet autoimmunity and progression to multiple autoantibodies and clinical diabetes: The TEDDY study. JO - Diabetes Care VL - 45 IS - 10 PB - Amer Diabetes Assoc PY - 2022 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE: Insulin action in the human brain reduces food intake, improves whole-body insulin sensitivity, and modulates body fat mass and its distribution. Obesity and type 2 diabetes are often associated with brain insulin resistance, resulting in impaired brain-derived modulation of peripheral metabolism. So far, no pharmacological treatment for brain insulin resistance has been established. Since sodium-glucose cotransporter 2 (SGLT2) inhibitors lower glucose levels and modulate energy metabolism, we hypothesized that SGLT2 inhibition may be a pharmacological approach to reverse brain insulin resistance. RESEARCH DESIGN AND METHODS: In this randomized, double-blind, placebo-controlled clinical trial, 40 patients (mean ± SD; age 60 ± 9 years; BMI 31.5 ± 3.8 kg/m2) with prediabetes were randomized to receive 25 mg empagliflozin every day or placebo. Before and after 8 weeks of treatment, brain insulin sensitivity was assessed by functional MRI combined with intranasal administration of insulin to the brain. RESULTS: We identified a significant interaction between time and treatment in the hypothalamic response to insulin. Post hoc analyses revealed that only empagliflozin-treated patients experienced increased hypothalamic insulin responsiveness. Hypothalamic insulin action significantly mediated the empagliflozin-induced decrease in fasting glucose and liver fat. CONCLUSIONS: Our results corroborate insulin resistance of the hypothalamus in humans with prediabetes. Treatment with empagliflozin for 8 weeks was able to restore hypothalamic insulin sensitivity, a favorable response that could contribute to the beneficial effects of SGLT2 inhibitors. Our findings position SGLT2 inhibition as the first pharmacological approach to reverse brain insulin resistance, with potential benefits for adiposity and whole-body metabolism. AU - Kullmann, S. AU - Hummel, J. AU - Wagner, R. AU - Dannecker, C. AU - Vosseler, A. AU - Fritsche, L. AU - Veit, R. AU - Kantartzis, K. AU - Machann, J. AU - Birkenfeld, A.L. AU - Stefan, N. AU - Häring, H.-U. AU - Peter, A. AU - Preissl, H. AU - Fritsche, A. AU - Heni, M. C1 - 63435 C2 - 51433 SP - 398-406 TI - Empagliflozin improves insulin sensitivity of the hypothalamus in humans with prediabetes: A randomized, double-blind, placebo-controlled, phase 2 trial. JO - Diabetes Care VL - 45 IS - 2 PY - 2022 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE: Suboptimal nutrition in pregnancy is associated with worse offspring cardiometabolic health. DNA methylation may be an underlying mechanism. We meta-analyzed epigenome-wide association studies (EWAS) of maternal dietary glycemic index and load with cord blood DNA methylation. RESEARCH DESIGN AND METHODS: We calculated maternal glycemic index and load from food frequency questionnaires and ran EWAS on cord blood DNA methylation in 2,003 mother-offspring pairs from three cohorts. Analyses were additionally stratified by maternal BMI categories. We looked-up the findings in EWAS of maternal glycemic traits and BMI as well as in EWAS of birth weight and child BMI. We examined associations with gene expression in child blood in the online Human Early Life Exposome eQTM catalog and in 223 adipose tissue samples. RESULTS: Maternal glycemic index and load were associated with cord blood DNA methylation at 41 cytosine-phosphate-guanine sites (CpGs, P < 1.17 × 10-7), mostly in mothers with overweight/obesity. We did not observe overlap with CpGs associated with maternal glycemic traits, BMI, or child birth weight or BMI. Only DNA methylation at cg24458009 and cg23347399 was associated with expression of PCED1B and PCDHG, respectively, in child blood, and DNA methylation at cg27193519 was associated with expression of TFAP4, ZNF500, PPL, and ANKS3 in child subcutaneous adipose tissue. CONCLUSIONS: We observed multiple associations of maternal glycemic index and load during pregnancy with cord blood DNA methylation, mostly in mothers with overweight/obesity; some of these CpGs were associated with gene expression. Additional studies are required to further explore functionality, uncover causality, and study pathways to offspring health. AU - Küpers, L.K.* AU - Fernández-Barrés, S.* AU - Mancano, G.* AU - Johnson, L.* AU - Ott, R. AU - Vioque, J.* AU - Colombo, M.* AU - Landgraf, K.* AU - Tobi, E.W.* AU - Körner, A.* AU - Gaillard, R.* AU - de Vries, J.H.M.* AU - Jaddoe, V.W.V.* AU - Vrijheid, M.* AU - Sharp, G.C.* AU - Felix, J.F.* C1 - 65562 C2 - 52275 SP - 1822-1832 TI - Maternal dietary glycemic index and glycemic load in pregnancy and offspring cord blood DNA methylation. JO - Diabetes Care VL - 45 IS - 8 PY - 2022 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE: To use islet autoantibody titers to improve the estimation of future type 1 diabetes risk in children. RESEARCH DESIGN AND METHODS: Prospective cohort studies in Finland, Germany, Sweden, and the U.S. followed 24,662 children at increased genetic or familial risk to develop islet autoimmunity and diabetes. For 1,604 children with confirmed positivity, titers of autoantibodies against insulin (IAA), GAD antibodies (GADA), and insulinoma-associated antigen 2 (IA-2A) were harmonized for diabetes risk analyses. RESULTS: Survival analysis from time of confirmed positivity revealed markedly different 5-year diabetes risks associated with IAA (n = 909), GADA (n = 1076), and IA-2A (n = 714), when stratified by quartiles of titer, ranging from 19% (GADA 1st quartile) to 60% (IA-2A 4th quartile). The minimum titer associated with a maximum difference in 5-year risk differed for each autoantibody, corresponding to the 58.6th, 52.4th, and 10.2nd percentile of children specifically positive for each of IAA, GADA, and IA-2A, respectively. Using these autoantibody type-specific titer thresholds in the 1,481 children with all autoantibodies tested, the 5-year risk conferred by single (n = 954) and multiple (n = 527) autoantibodies could be stratified from 6 to 75% (P < 0.0001). The thresholds effectively identified children with a ≥50% 5-year risk when considering age-specific autoantibody screening (57-65% positive predictive value and 56-74% sensitivity for ages 1-5 years). Multivariable analysis confirmed the significance of associations between the three autoantibody titers and diabetes risk, informing a childhood risk surveillance strategy. CONCLUSIONS: This study defined islet autoantibody type-specific titer thresholds that significantly improved type 1 diabetes risk stratification in children. AU - Ng, K.* AU - Stavropoulos, H.* AU - Anand, V.* AU - Veijola, R.* AU - Toppari, J.* AU - Maziarz, M.* AU - Lundgren, M.* AU - Waugh, K.C.* AU - Frohnert, B.I.* AU - Martin, F.* AU - Hagopian, W.* AU - Achenbach, P. C1 - 63659 C2 - 51502 SP - 160-168 TI - Islet autoantibody type-specific titer thresholds improve stratification of risk of progression to type 1 diabetes in children. JO - Diabetes Care VL - 45 IS - 1 PY - 2022 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE: Finerenone reduced the risk of kidney and cardiovascular events in people with chronic kidney disease (CKD) and type 2 diabetes in the FIDELIO-DKD and FIGARO-DKD phase 3 studies. Effects of finerenone on outcomes in patients taking sodium-glucose cotransporter 2 inhibitors (SGLT2is) were evaluated in a prespecified pooled analysis of these studies. RESEARCH DESIGN AND METHODS: Patients with type 2 diabetes and urine albumin-to-creatinine ratio (UACR) ≥30 to ≤5,000 mg/g and estimated glomerular filtration rate (eGFR) ≥25 mL/min/1.73 m2 were randomly assigned to finerenone or placebo; SGLT2is were permitted at any time. Outcomes included cardiovascular composite (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) and kidney composite (kidney failure, sustained ≥57% eGFR decline, or renal death) end points, changes in UACR and eGFR, and safety outcomes. RESULTS: Among 13,026 patients, 877 (6.7%) received an SGLT2i at baseline and 1,113 (8.5%) initiated one during the trial. For the cardiovascular composite, the hazard ratios (HRs) were 0.87 (95% CI 0.79-0.96) without SGLT2i and 0.67 (95% CI 0.42-1.07) with SGLT2i. For the kidney composite, the HRs were 0.80 (95% CI 0.69-0.92) without SGLT2i and 0.42 (95% CI 0.16-1.08) with SGLT2i. Baseline SGLT2i use did not affect risk reduction for the cardiovascular or kidney composites with finerenone (Pinteraction = 0.46 and 0.29, respectively); neither did SGLT2i use concomitant with study treatment. CONCLUSIONS: Benefits of finerenone compared with placebo on cardiorenal outcomes in patients with CKD and type 2 diabetes were observed irrespective of SGLT2i use. AU - Rossing, P.* AU - Anker, S.D.* AU - Filippatos, G.* AU - Pitt, B.* AU - Ruilope, L.M.* AU - Birkenfeld, A.L. AU - McGill, J.B.* AU - Rosas, S.E.* AU - Joseph, A.* AU - Gebel, M.* AU - Roberts, L.* AU - Scheerer, M.F.* AU - Bakris, G.L.* AU - Agarwal, R.* C1 - 66012 C2 - 53053 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 2991–2998 TI - Finerenone in patients with chronic kidney disease and type 2 diabetes by sodium-glucose cotransporter 2 inhibitor treatment: The FIDELITY analysis. JO - Diabetes Care VL - 45 IS - 12 PB - Amer Diabetes Assoc PY - 2022 SN - 0149-5992 ER - TY - JOUR AU - Schlögl, H. AU - Stumvoll, M.* C1 - 64126 C2 - 51807 SP - 273-275 TI - The brains behind SGLT2 inhibition. JO - Diabetes Care VL - 45 IS - 2 PY - 2022 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE: Maternal glycemic dysregulation during pregnancy increases the risk of adverse health outcomes in her offspring, a risk thought to be linearly related to maternal hyperglycemia. It is hypothesized that changes in offspring DNA methylation (DNAm) underline these associations. RESEARCH DESIGN AND METHODS: To address this hypothesis, we conducted fixed-effects meta-analyses of epigenome-wide association study (EWAS) results from eight birth cohorts investigating relationships between cord blood DNAm and fetal exposure to maternal glucose (Nmaximum = 3,503), insulin (Nmaximum = 2,062), and area under the curve of glucose (AUCgluc) following oral glucose tolerance tests (Nmaximum = 1,505). We performed lookup analyses for identified cytosine-guanine dinucleotides (CpGs) in independent observational cohorts to examine associations between DNAm and cardiometabolic traits as well as tissue-specific gene expression. RESULTS: Greater maternal AUCgluc was associated with lower cord blood DNAm at neighboring CpGs cg26974062 (β [SE] = 0.013 [2.1 × 10-3], P value corrected for false discovery rate [PFDR] = 5.1 × 10-3) and cg02988288 (β [SE]-0.013 [2.3 × 10-3], PFDR = 0.031) in TXNIP. These associations were attenuated in women with GDM. Lower blood DNAm at these two CpGs near TXNIP was associated with multiple metabolic traits later in life, including type 2 diabetes. TXNIP DNAm in liver biopsies was associated with hepatic expression of TXNIP. We observed little evidence of associations between either maternal glucose or insulin and cord blood DNAm. CONCLUSIONS: Maternal hyperglycemia, as reflected by AUCgluc, was associated with lower cord blood DNAm at TXNIP. Associations between DNAm at these CpGs and metabolic traits in subsequent lookup analyses suggest that these may be candidate loci to investigate in future causal and mediation analyses. AU - Tobi, E.W.* AU - Juvinao-Quintero, D.L.* AU - Ronkainen, J.* AU - Ott, R. AU - Alfano, R.* AU - Canouil, M.* AU - Geurtsen, M.L.* AU - Khamis, A.* AU - Küpers, L.K.* AU - Lim, I.Y.* AU - Perron, P.* AU - Pesce, G.* AU - Tuhkanen, J.* AU - Starling, A.P.* AU - Andrew, T.* AU - Binder, E.* AU - Caiazzo, R.* AU - Chan, J.K.Y.* AU - Gaillard, R.* AU - Gluckman, P.D.* AU - Keikkala, E.* AU - Karnani, N.* AU - Mustaniemi, S.* AU - Nawrot, T.S.* AU - Pattou, F.* AU - Plusquin, M.* AU - Raverdy, V.* AU - Tan, K.H.* AU - Tzala, E.* AU - Räikkönen, K.* AU - Winkler, C. AU - Ziegler, A.-G. AU - Annesi-Maesano, I.* AU - Bouchard, L.* AU - Chong, Y.S.* AU - Dabelea, D.* AU - Felix, J.F.* AU - Heude, B.* AU - Jaddoe, V.W.V.* AU - Lahti, J.* AU - Reimann, B.* AU - Vääräsmäki, M.* AU - Bonnefond, A.* AU - Froguel, P.* AU - Hummel, S. AU - Kajantie, E.* AU - Jarvelin, M.R.* AU - Steegers-Theunissen, R.P.M.* AU - Howe, C.G.* AU - Hivert, M.F.* AU - Sebert, S.* C1 - 64257 C2 - 51932 SP - 614-623 TI - Maternal glycemic dysregulation during pregnancy and neonatal blood DNA methylation: Meta-analyses of epigenome-wide association studies. JO - Diabetes Care VL - 45 IS - 3 PY - 2022 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE: Biomarkers predicting risk of type 1 diabetes (stage 3) among children with islet autoantibodies are greatly needed to prevent diabetic ketoacidosis and facilitate prevention therapies. RESEARCH DESIGN AND METHODS: Children in the prospective The Environmental Determinants of Diabetes in the Young (TEDDY) study (n = 707) with confirmed diabetes-associated autoantibodies (GAD antibody, IA-2A, and/or insulin autoantibody) and two or more HbA1c measurements were followed to diabetes or median age 11.1 years. Once confirmed autoantibody positive, HbA1c was measured quarterly. Cox models and receiver operative characteristic curve analyses revealed the prognostic utility for risk of stage 3 on a relative HbA1c increase from the baseline visit or an oral glucose tolerance test (OGTT) 2-h plasma glucose (2-hPG). This HbA1c approach was then validated in the Type 1 Diabetes TrialNet Pathway to Prevention Study (TrialNet) (n = 1,190). RESULTS: A 10% relative HbA1c increase from baseline best marked the increased risk of stage 3 in TEDDY (74% sensitive; 88% specific). Significant predictors of risk for HbA1c change were age and HbA1c at the baseline test, genetic sex, maximum number of autoantibodies, and maximum rate of HbA1c increase by time of change. The multivariable model featuring a HbA1c ≥10% increase and these additional factors revealed increased risk of stage 3 in TEDDY (hazard ratio [HR] 12.74, 95% CI 8.7-18.6, P < 0.0001) and TrialNet (HR 5.09, 95% CI 3.3-7.9, P < 0.0001). Furthermore, the composite model using HbA1c ≥10% increase performed similarly to an OGTT 2-hPG composite model (TEDDY area under the curve [AUC] 0.88 and 0.85, respectively) and to the HbA1c model in TrialNet (AUC 0.82). CONCLUSIONS: An increase of ≥10% in HbA1c from baseline is as informative as OGTT 2-hPG in predicting risk of stage 3 in youth with genetic risk and diabetes-associated autoantibodies. AU - Vehik, K.* AU - Boulware, D.* AU - Killian, M.* AU - Rewers, M.* AU - McIndoe, R.A.* AU - Toppari, J.* AU - Lernmark, A.* AU - Akolkar, B.* AU - Ziegler, A.-G. AU - Rodriguez, H.* AU - Schatz, D.A.* AU - Krischer, J.P.* AU - Hagopian, W.* C1 - 66280 C2 - 52767 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 2342-2349 TI - Rising hemoglobin A1c in the nondiabetic range predicts progression of type 1 diabetes as well as oral glucose tolerance tests. JO - Diabetes Care VL - 45 IS - 10 PB - Amer Diabetes Assoc PY - 2022 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE: One-hour plasma glucose (1-h PG) during the oral glucose tolerance test (OGTT) is an accurate predictor of type 2 diabetes. We performed a meta-analysis to determine the optimum cutoff of 1-h PG for detection of type 2 diabetes using 2-h PG as the gold standard. RESEARCH DESIGN AND METHODS: We included 15 studies with 35,551 participants from multiple ethnic groups (53.8% Caucasian) and 2,705 newly detected cases of diabetes based on 2-h PG during OGTT. We excluded cases identified only by elevated fasting plasma glucose and/or HbA1c. We determined the optimal 1-h PG threshold and its accuracy at this cutoff for detection of diabetes (2-h PG ≥11.1 mmol/L) using a mixed linear effects regression model with different weights to sensitivity/specificity (2/3, 1/2, and 1/3). RESULTS: Three cutoffs of 1-h PG, at 10.6 mmol/L, 11.6 mmol/L, and 12.5 mmol/L, had sensitivities of 0.95, 0.92, and 0.87 and specificities of 0.86, 0.91, and 0.94 at weights 2/3, 1/2, and 1/3, respectively. The cutoff of 11.6 mmol/L (95% CI 10.6, 12.6) had a sensitivity of 0.92 (0.87, 0.95), specificity of 0.91 (0.88, 0.93), area under the curve 0.939 (95% confidence region for sensitivity at a given specificity: 0.904, 0.946), and a positive predictive value of 45%. CONCLUSIONS: The 1-h PG of ≥11.6 mmol/L during OGTT has a good sensitivity and specificity for detecting type 2 diabetes. Prescreening with a diabetes-specific risk calculator to identify high-risk individuals is suggested to decrease the proportion of false-positive cases. Studies including other ethnic groups and assessing complication risk are warranted. AU - Ahuja, V.* AU - Aronen, P.* AU - Pramodkumar, T.A.* AU - Looker, H.* AU - Chetrit, A.* AU - Bloigu, A.H.* AU - Juutilainen, A.* AU - Bianchi, C.* AU - La Sala, L.* AU - Anjana, R.M.* AU - Pradeepa, R.* AU - Venkatesan, U.* AU - Jebarani, S.* AU - Baskar, V.* AU - Fiorentino, T.V.* AU - Timpel, P.* AU - DeFronzo, R.A.* AU - Ceriello, A.* AU - Del Prato, S.* AU - Abdul-Ghani, M.* AU - Keinänen-Kiukaanniemi, S.* AU - Dankner, R.* AU - Bennett, P.H.* AU - Knowler, W.C.* AU - Schwarz, P.E. AU - Sesti, G.* AU - Oka, R.* AU - Mohan, V.* AU - Groop, L.* AU - Tuomilehto, J.* AU - Ripatti, S.* AU - Bergman, M.* AU - Tuomi, T.* C1 - 61704 C2 - 50404 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 1062-1069 TI - Accuracy of 1-hour plasma glucose during the oral glucose tolerance test in diagnosis of type 2 diabetes in adults: A meta-analysis. JO - Diabetes Care VL - 44 IS - 4 PB - Amer Diabetes Assoc PY - 2021 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE: To combine prospective cohort studies, by including HLA harmonization, and estimate risk of islet autoimmunity and progression to clinical diabetes. RESEARCH DESIGN AND METHODS: For prospective cohorts in Finland, Germany, Sweden, and the U.S., 24,662 children at increased genetic risk for development of islet autoantibodies and type 1 diabetes have been followed. Following harmonization, the outcomes were analyzed in 16,709 infants-toddlers enrolled by age 2.5 years. RESULTS: In the infant-toddler cohort, 1,413 (8.5%) developed at least one autoantibody confirmed at two or more consecutive visits (seroconversion), 865 (5%) developed multiple autoantibodies, and 655 (4%) progressed to diabetes. The 15-year cumulative incidence of diabetes varied in children with one, two, or three autoantibodies at seroconversion: 45% (95% CI 40-52), 85% (78-90), and 92% (85-97), respectively. Among those with a single autoantibody, status 2 years after seroconversion predicted diabetes risk: 12% (10-25) if reverting to autoantibody negative, 30% (20-40) if retaining a single autoantibody, and 82% (80-95) if developing multiple autoantibodies. HLA-DR-DQ affected the risk of confirmed seroconversion and progression to diabetes in children with stable single-autoantibody status. Their 15-year diabetes incidence for higher- versus lower-risk genotypes was 40% (28-50) vs. 12% (5-38). The rate of progression to diabetes was inversely related to age at development of multiple autoantibodies, ranging from 20% per year to 6% per year in children developing multipositivity in ≤2 years or >7.4 years, respectively. CONCLUSIONS: The number of islet autoantibodies at seroconversion reliably predicts 15-year type 1 diabetes risk. In children retaining a single autoantibody, HLA-DR-DQ genotypes can further refine risk of progression. AU - Anand, V.* AU - Li, Y.* AU - Liu, B.* AU - Ghalwash, M.* AU - Koski, E.* AU - Ng, K.* AU - Dunne, J.L.* AU - Jönsson, J.* AU - Winkler, C. AU - Knip, M.* AU - Toppari, J.* AU - Ilonen, J.* AU - Killian, M.B.* AU - Frohnert, B.I.* AU - Lundgren, M. AU - Ziegler, A.-G. AU - Hagopian, W.* AU - Veijola, R.* AU - Rewers, M.* C1 - 62469 C2 - 50823 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 2269-2276 TI - Islet autoimmunity and HLA markers of presymptomatic and clinical type 1 diabetes: Joint analyses of prospective cohort studies in Finland, Germany, Sweden, and the U.S. JO - Diabetes Care VL - 44 IS - 10 PB - Amer Diabetes Assoc PY - 2021 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE: We investigated the processes underlying glycemic deterioration in type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: A total of 732 recently diagnosed patients with T2D from the Innovative Medicines Initiative Diabetes Research on Patient Stratification (IMI DIRECT) study were extensively phenotyped over 3 years, including measures of insulin sensitivity (OGIS), β-cell glucose sensitivity (GS), and insulin clearance (CLIm) from mixed meal tests, liver enzymes, lipid profiles, and baseline regional fat from MRI. The associations between the longitudinal metabolic patterns and HbA1c deterioration, adjusted for changes in BMI and in diabetes medications, were assessed via stepwise multivariable linear and logistic regression. RESULTS: Faster HbA1c progression was independently associated with faster deterioration of OGIS and GS and increasing CLIm; visceral or liver fat, HDL-cholesterol, and triglycerides had further independent, though weaker, roles (R2 = 0.38). A subgroup of patients with a markedly higher progression rate (fast progressors) was clearly distinguishable considering these variables only (discrimination capacity from area under the receiver operating characteristic = 0.94). The proportion of fast progressors was reduced from 56% to 8-10% in subgroups in which only one trait among OGIS, GS, and CLIm was relatively stable (odds ratios 0.07-0.09). T2D polygenic risk score and baseline pancreatic fat, glucagon-like peptide 1, glucagon, diet, and physical activity did not show an independent role. CONCLUSIONS: Deteriorating insulin sensitivity and β-cell function, increasing insulin clearance, high visceral or liver fat, and worsening of the lipid profile are the crucial factors mediating glycemic deterioration of patients with T2D in the initial phase of the disease. Stabilization of a single trait among insulin sensitivity, β-cell function, and insulin clearance may be relevant to prevent progression. AU - Bizzotto, R.* AU - Jennison, C.* AU - Jones, A.G.* AU - Kurbasic, A.* AU - Tura, A.* AU - Kennedy, G.* AU - Bell, J.D.* AU - Thomas, E.L.* AU - Frost, G.* AU - Eriksen, R.* AU - Koivula, R.W.* AU - Brage, S.* AU - Kaye, J.* AU - Hattersley, A.T.* AU - Heggie, A.* AU - McEvoy, D.* AU - 't Hart, L.M.* AU - Beulens, J.W.* AU - Elders, P.* AU - Musholt, P.B.* AU - Ridderstråle, M.* AU - Hansen, T.H.* AU - Allin, K.H.* AU - Hansen, T.* AU - Vestergaard, H.* AU - Lundgaard, A.T.* AU - Thomsen, H.S.* 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 - Forgie, I.M.* AU - Giordano, G.N.* AU - Pavo, I.* AU - Ruetten, H.* AU - Dermitzakis, E.* AU - McCarthy, M.I.* AU - Pedersen, O.* AU - Schwenk, J.M.* AU - Adamski, J. AU - Franks, P.W.* AU - Walker, M.* AU - Pearson, E.R.* AU - Mari, A.* AU - IMI DIRECT Consortium (Adam, J. AU - Grallert, H. AU - Haid, M. AU - Sharma, S. AU - Thorand, B. AU - Troll, M.) C1 - 61173 C2 - 49657 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 511-518 TI - Processes underlying glycemic deterioration in type 2 diabetes: An IMI DIRECT Study. JO - Diabetes Care VL - 44 IS - 2 PB - Amer Diabetes Assoc PY - 2021 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE: In the LixiLan-G trial, switching to iGlarLixi, a once-daily titratable fixed-ratio combination of insulin glargine 100 units/mL and the glucagon-like peptide 1 receptor agonist (GLP-1 RA) lixisenatide, improved glucose control in type 2 diabetes uncontrolled with GLP-1 RAs over 26 weeks versus continuing prior GLP-1 RA. A prespecified, 26-week, single-arm extension of LixiLan-G aimed to determine the durability of iGlarLixi efficacy and safety over 52 weeks. RESEARCH DESIGN AND METHODS: Participants with type 2 diabetes uncontrolled by GLP-1 RAs (glycated hemoglobin [HbA1c] 7-9% [53-75 mmol/mol]) were initially randomized to switch to iGlarLixi or continue prior GLP-1 RA. Those randomized to iGlarLixi who completed the 26-week primary end point period could continue iGlarLixi open-label treatment over a 26-week extension to assess durability of efficacy and safety. RESULTS: Glycemic control achieved with iGlarLixi at week 26 (mean HbA1c 6.7% [50 mmol/mol]) was maintained at week 52 (mean HbA1c 6.7% [50 mmol/mol]; mean ± SD change from baseline at week 52: -1.0 ± 0.9% [11 ± 10 mmol/mol]). Proportions of participants reaching HbA1c <7% (53 mmol/mol) with iGlarLixi were similar at week 26 (62%) and 52 (64%), as were those reaching this target without documented symptomatic (<3.0 mmol/L) hypoglycemia (57% and 58%). Safety of iGlarLixi was similar at weeks 26 and 52, with low rates of documented symptomatic hypoglycemia and gastrointestinal events. CONCLUSIONS: The efficacy and safety of iGlarLixi at the end of the 26-week randomized treatment period was maintained over the 26-week extension period in the LixiLan-G trial. AU - Blonde, L.* AU - Rosenstock, J.* AU - Frias, J.* AU - Birkenfeld, A.L. AU - Niemoeller, E.* AU - Souhami, E.* AU - Ji, C.* AU - Del Prato, S.* AU - Aroda, V.R.* C1 - 61084 C2 - 49684 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 774-780 TI - Durable effects of iGlarLixi up to 52 weeks in type 2 diabetes: The LixiLan-G Extension Study. JO - Diabetes Care VL - 44 IS - 3 PB - Amer Diabetes Assoc PY - 2021 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE: Islet autoimmunity develops before clinical type 1 diabetes and includes multiple and single autoantibody phenotypes. The objective was to determine age-related risks of islet autoantibodies that reflect etiology and improve screening for presymptomatic type 1 diabetes. RESEARCH DESIGN AND METHODS: The Environmental Determinants of Diabetes in the Young study prospectively monitored 8,556 genetically at-risk children at 3- to 6-month intervals from birth for the development of islet autoantibodies and type 1 diabetes. The age-related change in the risk of developing islet autoantibodies was determined using landmark and regression models. RESULTS: The 5-year risk of developing multiple islet autoantibodies was 4.3% (95% CI 3.8-4.7) at 7.5 months of age and declined to 1.1% (95% CI 0.8-1.3) at a landmark age of 6.25 years (P < 0.0001). Risk decline was slight or absent in single insulin and GAD autoantibody phenotypes. The influence of sex, HLA, and other susceptibility genes on risk subsided with increasing age and was abrogated by age 6 years. Highest sensitivity and positive predictive value of multiple islet autoantibody phenotypes for type 1 diabetes was achieved by autoantibody screening at 2 years and again at 5-7 years of age. CONCLUSIONS: The risk of developing islet autoimmunity declines exponentially with age, and the influence of major genetic factors on this risk is limited to the first few years of life. AU - Bonifacio, E. AU - Weiß, A. AU - Winkler, C. AU - Hippich, M. AU - Rewers, M.J.* AU - Toppari, J.* AU - Lernmark, A.* AU - She, J.X.* AU - Hagopian, W.A.* AU - Krischer, J.P.* AU - Vehik, K.* AU - Schatz, D.A.* AU - Akolkar, B.* AU - Ziegler, A.-G. C1 - 61481 C2 - 50285 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 2260-2268 TI - An age-related exponential decline in the risk of multiple islet autoantibody seroconversion during childhood. JO - Diabetes Care VL - 44 IS - 10 PB - Amer Diabetes Assoc PY - 2021 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE: Gestational diabetes mellitus (GDM) is associated with an increased risk of obesity and insulin resistance in offspring later in life, which might be explained by epigenetic changes in response to maternal hyperglycemic exposure. RESEARCH DESIGN AND METHODS: We explored the association between GDM exposure and maternal blood and newborn cord blood methylation in 536 mother-offspring pairs from the prospective FinnGeDi cohort using Illumina MethylationEPIC 850K BeadChip arrays. We assessed two hypotheses. First, we tested for shared maternal and offspring epigenetic effects resulting from GDM exposure. Second, we tested whether GDM exposure and maternal methylation had an epigenetic effect on the offspring. RESULTS: We did not find any epigenetic marks (differentially methylated CpG probes) with shared and consistent effects between mothers and offspring. After including maternal methylation in the model, we identified a single significant (false discovery rate 1.38 × 10-2) CpG at the cg22790973 probe (TFCP2) associated with GDM. We identified seven additional FDR-significant interactions of maternal methylation and GDM status, with the strongest association at the same cg22790973 probe (TFCP2), as well as cg03456133, cg24440941 (H3C6), cg20002843 (LOC127841), cg19107264, and cg11493553 located within the UBE3C gene and cg17065901 in FAM13A, both susceptibility genes for type 2 diabetes and BMI, and cg23355087 within the DLGAP2 gene, known to be involved in insulin resistance during pregnancy. CONCLUSIONS: Our study reveals the potential complexity of the epigenetic transmission between mothers with GDM and their offspring, likely determined by not only GDM exposure but also other factors indicated by maternal epigenetic status, such as maternal metabolic history. AU - Canouil, M.* AU - Khamis, A.* AU - Keikkala, E.* AU - Hummel, S. AU - Lobbens, S.* AU - Bonnefond, A.* AU - Delahaye, F.* AU - Tzala, E.* AU - Mustaniemi, S.* AU - Vaarasmaki, M.* AU - Jarvelin, M.R.* AU - Sebert, S.* AU - Kajantie, E.* AU - Froguel, P.* AU - Andrew, T.* C1 - 62344 C2 - 50707 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 1992-1999 TI - Epigenome-wide association study reveals methylation loci associated with offspring gestational diabetes mellitus exposure and maternal methylome. JO - Diabetes Care VL - 44 IS - 9 PB - Amer Diabetes Assoc PY - 2021 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE: To estimate the health utility impact of diabetes-related complications in a large, longitudinal U.S. sample of people with type 2 diabetes. RESEARCH DESIGN AND METHODS: We combined Health Utilities Index Mark 3 data on patients with type 2 diabetes from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) and Look AHEAD (Action for Health in Diabetes) trials and their follow-on studies. Complications were classified as events if they occurred in the year preceding the utility measurement; otherwise, they were classified as a history of the complication. We estimated utility decrements associated with complications using a fixed-effects regression model. RESULTS: Our sample included 15,252 persons with an average follow-up of 8.2 years and a total of 128,873 person-visit observations. The largest, statistically significant (P < 0.05) health utility decrements were for stroke (event, -0.109; history, -0.051), amputation (event, -0.092; history, -0.150), congestive heart failure (event, -0.051; history, -0.041), dialysis (event, -0.039), estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 (event, -0.043; history, -0.025), angina (history, -0.028), and myocardial infarction (MI) (event, -0.028). There were smaller effects for laser photocoagulation and eGFR <60 mL/min/1.73 m2. Decrements for dialysis history, angina event, MI history, revascularization event, revascularization history, laser photocoagulation event, and hypoglycemia were not significant (P ≥ 0.05). CONCLUSIONS: With use of a large study sample and a longitudinal design, our estimated health utility scores are expected to be largely unbiased. Estimates can be used to describe the health utility impact of diabetes complications, improve cost-effectiveness models, and inform diabetes policies. AU - Neuwahl, S.J.* AU - Zhang, P.* AU - Chen, H.* AU - Shao, H.* AU - Laxy, M. AU - Anderson, A.M.* AU - Craven, T.E.* AU - Hoerger, T.J.* C1 - 60777 C2 - 49526 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 381-389 TI - Patient health utility equations for a type 2 diabetes model. JO - Diabetes Care VL - 44 IS - 2 PB - Amer Diabetes Assoc PY - 2021 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE: To assess the independent causal effect of BMI and type 2 diabetes (T2D) on socioeconomic outcomes by applying two-sample Mendelian randomization (MR) analysis. RESEARCH DESIGN AND METHODS: We performed univariable and multivariable two-sample MR to jointly assess the effect BMI and T2D on socioeconomic outcomes. We used overlapping genome-wide significant single nucleotide polymorphisms for BMI and T2D as instrumental variables. Their causal impact on household income and regional deprivation was assessed using summary-level data from the UK Biobank. RESULTS: In the univariable analysis, higher BMI was related to lower income (marginal effect of 1-SD increase in BMI [β = -0.092; 95% CI -0.138; -0.047]) and higher deprivation (β = 0.051; 95% CI 0.022; 0.079). In the multivariable MR, the effect of BMI controlling for diabetes was slightly lower for income and deprivation. Diabetes was not associated with these outcomes. CONCLUSIONS: High BMI, but not diabetes, shows a causal link with socioeconomic outcomes. AU - Pedron, S. AU - Kurz, C.F. AU - Schwettmann, L. AU - Laxy, M. C1 - 60947 C2 - 49675 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 850-852 TI - The effect of BMI and type 2 diabetes on socioeconomic status: A two-sample multivariable mendelian randomization study. JO - Diabetes Care VL - 44 IS - 3 PB - Amer Diabetes Assoc PY - 2021 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE: To estimate trends in total payment and patients' out-of-pocket (OOP) payments of noninsulin glucose-lowering drugs by class from 2005 to 2018. RESEARCH DESIGN AND METHODS: We analyzed data for 53 million prescriptions from adults aged >18 years with type 2 diabetes under fee-for-service plans from the 2005-2018 IBM MarketScan Commercial Databases. The total payment was measured as the amount that the pharmacy received, and the OOP payment was the sum of copay, coinsurance, and deductible paid by the beneficiaries. We applied a joinpoint regression to evaluate nonlinear trends in cost between 2005 and 2018. We further conducted a decomposition analysis to explore the drivers for total payment change. RESULTS: Total annual payments for older drug classes, including metformin, sulfonylurea, meglitinide, α-glucosidase inhibitors, and thiazolidinedione, have declined during 2005-2018, ranging from -$271 (-53.8%) (USD) for metformin to -$2,406 (-92.2%) for thiazolidinedione. OOP payments for these drug classes also reduced. In the same period, the total annual payments for the newer drug classes, including dipeptidyl peptidase-4 inhibitors, glucagon-like peptide 1 receptor agonists, and sodium-glucose cotransporter 2 inhibitors, have increased by $2,181 (88.4%), $3,721 (77.6%), and $1,374 (37.0%), respectively. OOP payment for these newer classes remained relatively unchanged. Our study findings indicate that switching toward the newer classes for noninsulin glucose-lowering drugs was the main driver that explained the total payment increase. CONCLUSIONS: Average annual payments and OOP payment for noninsulin glucose-lowering drugs have increased significantly from 2005 to 2018. The uptake of newer drug classes was the main driver. AU - Shao, H.* AU - Laxy, M. AU - Benoit, S.R.* AU - Cheng, Y.J.* AU - Gregg, E.W.* AU - Zhang, P.* C1 - 61323 C2 - 50152 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 925-934 TI - Trends in total and out-of-pocket payments for noninsulin glucose-lowering drugs among U.S. adults with large-employer private health insurance from 2005 to 2018. JO - Diabetes Care VL - 44 IS - 4 PB - Amer Diabetes Assoc PY - 2021 SN - 0149-5992 ER - TY - JOUR AU - Shao, H. AU - Zhang, P.* AU - Benoit, S.R.* AU - Imperatore, G.* AU - Cheng, Y.J.* AU - Gregg, E.W.* AU - Yang, S.* C1 - 62759 C2 - 51009 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - e1-e3 TI - Trends in total and out-of-pocket payments for insulin among privately insured U.S. adults with diabetes from 2005 to 2018. JO - Diabetes Care VL - 44 IS - 9 PB - Amer Diabetes Assoc PY - 2021 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE: Natriuretic peptide (NP) concentrations are increased in cardiovascular diseases (CVDs) but are associated with a lower diabetes risk. We investigated associations of N-terminal pro-B-type NP (NT-proBNP) and midregional proatrial NP (MR-proANP) with incident type 2 diabetes stratified by the presence of CVD. RESEARCH DESIGN AND METHODS: Based on the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) Consortium, we included 45,477 participants with NT-proBNP measurements (1,707 developed type 2 diabetes over 6.5 years of median follow-up; among these, 209 had CVD at baseline) and 11,537 participants with MR-proANP measurements (857 developed type 2 diabetes over 13.8 years of median follow-up; among these, 106 had CVD at baseline). The associations were estimated using multivariable Cox regression models. RESULTS: Both NPs were inversely associated with incident type 2 diabetes (hazard ratios [95% CI] per 1-SD increase of log NP: 0.84 [0.79; 0.89] for NT-proBNP and 0.77 [0.71; 0.83] for MR-proANP). The inverse association between NT-proBNP and type 2 diabetes was significant in individuals without CVD but not in individuals with CVD (0.81 [0.76; 0.86] vs. 1.04 [0.90; 1.19]; P multiplicative interaction = 0.001). There was no significant difference in the association of MR-proANP with type 2 diabetes between individuals without and with CVD (0.75 [0.69; 0.82] vs. 0.81 [0.66; 0.99]; P multiplicative interaction = 0.236). CONCLUSIONS: NT-proBNP and MR-proANP are inversely associated with incident type 2 diabetes. However, the inverse association of NT-proBNP seems to be modified by the presence of CVD. Further investigations are warranted to confirm our findings and to investigate the underlying mechanisms. AU - Sujana, C. AU - Salomaa, V.* AU - Kee, F.* AU - Costanzo, S.* AU - Söderberg, S.* AU - Jordan, J.* AU - Jousilahti, P.* AU - Neville, C.* AU - Iacoviello, L.* AU - Oskarsson, V.* AU - Westermann, D.* AU - Koenig, W.* AU - Kuulasmaa, K.* AU - Reinikainen, J.* AU - Blankenberg, S.* AU - Zeller, T.* AU - Herder, C. AU - Mansmann, U.* AU - Peters, A. AU - Thorand, B. C1 - 63055 C2 - 51253 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 2527-2535 TI - Natriuretic peptides and risk of type 2 diabetes: Results from the biomarkers for cardiovascular risk assessment in Europe (BiomarCaRE) consortium. JO - Diabetes Care VL - 44 IS - 11 PB - Amer Diabetes Assoc PY - 2021 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE: As diabetes technology use in youth increases worldwide, inequalities in access may exacerbate disparities in hemoglobin A1c (HbA1c). We hypothesized that an increasing gap in diabetes technology use by socioeconomic status (SES) would be associated with increased HbA1c disparities. RESEARCH DESIGN AND METHODS: Participants aged <18 years with diabetes duration ≥1 year in the Type 1 Diabetes Exchange (T1DX, U.S., n = 16,457) and Diabetes Prospective Follow-up (DPV, Germany, n = 39,836) registries were categorized into lowest (Q1) to highest (Q5) SES quintiles. Multiple regression analyses compared the relationship of SES quintiles with diabetes technology use and HbA1c from 2010-2012 to 2016-2018. RESULTS: HbA1c was higher in participants with lower SES (in 2010-2012 and 2016-2018, respectively: 8.0% and 7.8% in Q1 and 7.6% and 7.5% in Q5 for DPV; 9.0% and 9.3% in Q1 and 7.8% and 8.0% in Q5 for T1DX). For DPV, the association between SES and HbA1c did not change between the two time periods, whereas for T1DX, disparities in HbA1c by SES increased significantly (P < 0.001). After adjusting for technology use, results for DPV did not change, whereas the increase in T1DX was no longer significant. CONCLUSIONS: Although causal conclusions cannot be drawn, diabetes technology use is lowest and HbA1c is highest in those of the lowest SES quintile in the T1DX, and this difference for HbA1c broadened in the past decade. Associations of SES with technology use and HbA1c were weaker in the DPV registry. AU - Addala, A.* AU - Auzanneau, M.* AU - Miller, K.* AU - Maier, W. AU - Foster, N.* AU - Kapellen, T.* AU - Walker, A.* AU - Rosenbauer, J.* AU - Maahs, D.M.* AU - Holl, R.W.* C1 - 60672 C2 - 49583 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 133-140 TI - A decade of disparities in diabetes technology use and HbA1c in pediatric type 1 diabetes: A transatlantic comparison. JO - Diabetes Care VL - 44 IS - 1 PB - Amer Diabetes Assoc PY - 2020 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE Most individuals with type 2 diabetes also have obesity, and treatment with some diabetes medications, including insulin, can cause further weight gain. No approved chronic weight management medications have been prospectively investigated in individuals with overweight or obesity and insulin-treated type 2 diabetes. The primary objective of this study was to assess the effect of liraglutide 3.0 mg versus placebo on weight loss in this population. RESEARCH DESIGN AND METHODS Satiety and Clinical Adiposity-Liraglutide Evidence (SCALE) Insulin was a 56-week, randomized, double-blind, placebo-controlled, multinational, multicenter trial in individuals with overweight or obesity and type 2 diabetes treated with basal insulin and <= 2 oral antidiabetic drugs. RESULTS Individuals were randomized to liraglutide 3.0 mg (n = 198) or placebo (n = 198), combined with intensive behavioral therapy (IBT). At 56 weeks, mean weight change was -5.8% for liraglutide 3.0 mg versus -1.5% with placebo (estimated treatment difference -4.3% [95% CI -5.5; -3.2]; P < 0.0001). With liraglutide 3.0 mg, 51.8% of individuals achieved >= 5% weight loss versus 24.0% with placebo (odds ratio 3.41 [95% CI 2.19; 5.31]; P < 0.0001). Liraglutide 3.0 mg was associated with significantly greater reductions in mean HbA(1c) and mean daytime glucose values and less need for insulin versus placebo, despite a treat-to-glycemic-target protocol. More hypoglycemic events were observed with placebo than liraglutide 3.0 mg. No new safety or tolerability issues were observed. CONCLUSIONS In individuals with overweight or obesity and insulin-treated type 2 diabetes, liraglutide 3.0 mg as an adjunct to IBT was superior to placebo regarding weight loss and improved glycemic control despite lower doses of basal insulin and without increases in hypoglycemic events. AU - Garvey, W.T.* AU - Birkenfeld, A.L. AU - Dicker, D.* AU - Mingrone, G.* AU - Pedersen, S.D.* AU - Satylganova, A.* AU - Skovgaard, D.* AU - Sugimoto, D.* AU - Jensen, C.* AU - Mosenzon, O.* C1 - 58539 C2 - 48318 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 1085-1093 TI - Efficacy and Safety of Liraglutide 3.0 mg in Individuals With Overweight or Obesity and Type 2 Diabetes Treated With Basal Insulin: The SCALE Insulin Randomized Controlled Trial. JO - Diabetes Care VL - 43 IS - 5 PB - Amer Diabetes Assoc PY - 2020 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE To evaluate whether the sodium-glucose cotransporter 2 inhibitor empagliflozin (EMPA) reduces liver fat content (LFC) in recent-onset and metabolically well-controlled type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS Patients with T2D (n = 84) (HbA(1c) 6.6 +/- 0.5% [49 +/- 10 mmol/mol], known disease duration 39 +/- 27 months) were randomly assigned to 24 weeks of treatment with 25 mg daily EMPA or placebo. The primary end point was the difference of the change in LFC as measured with magnetic resonance methods from 0 (baseline) to 24 weeks between groups. Tissue-specific insulin sensitivity (secondary outcome) was assessed by two-step clamps using an isotope dilution technique. Exploratory analysis comprised circulating surrogate markers of insulin sensitivity and liver function. Statistical comparison was done by ANCOVA adjusted for respective baseline values, age, sex, and BMI. RESULTS EMPA treatment resulted in a placebo-corrected absolute change of -1.8% (95% CI -3.4, -0.2; P = 0.02) and relative change in LFC of -22% (-36, -7; P = 0.009) from baseline to end of treatment, corresponding to a 2.3-fold greater reduction. Weight loss occurred only with EMPA (placebo-corrected change -2.5 kg [-3.7, -1.4]; P < 0.001), while no placebo-corrected change in tissue-specific insulin sensitivity was observed. EMPA treatment also led to placebo-corrected changes in uric acid (-74 mol/L [-108, -42]; P < 0.001) and high-molecular-weight adiponectin (36% [16, 60]; P < 0.001) levels from 0 to 24 weeks. CONCLUSIONS EMPA effectively reduces hepatic fat in patients with T2D with excellent glycemic control and short known disease duration. Interestingly, EMPA also decreases circulating uric acid and raises adiponectin levels despite unchanged insulin sensitivity. EMPA could therefore contribute to the early treatment of nonalcoholic fatty liver disease in T2D. AU - Kahl, S.* AU - Gancheva, S.* AU - Straßburger, K.* AU - Herder, C.* AU - Machann, J. AU - Katsuyama, H.* AU - Kabisch, S.* AU - Henkel, E.* AU - Kopf, S.* AU - Lagerpusch, M.* AU - Kantartzis, K. AU - Kupriyanova, Y.* AU - Markgraf, D.F.* AU - Van Gemert, T.* AU - Knebel, B.* AU - Wolkersdorfer, M.F.* AU - Kuss, O.* AU - Hwang, J.H.* AU - Bornstein, S.R. AU - Kasperk, C.* AU - Stefan, N. AU - Pfeiffer, A.* AU - Birkenfeld, A.L.* AU - Roden, M.* C1 - 56949 C2 - 47378 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 298-305 TI - Empagliflozin effectively lowers liver fat content in well-controlled Type 2 Diabetes: A randomized, double-blind, phase 4, placebo-controlled trial. JO - Diabetes Care VL - 43 IS - 2 PB - Amer Diabetes Assoc PY - 2020 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE This study investigates two-phase growth patterns in early life and their association with development of islet autoimmunity (IA) and type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS The Environmental Determinants of Diabetes in the Young (TEDDY) study followed 7,522 genetically high-risk children in Sweden, Finland, Germany, and the U.S. from birth for a median of 9.0 years (interquartile range 5.7-10.6) with available growth data. Of these, 761 (10.1%) children developed IA and 290 (3.9%) children were diagnosed with T1D. Bayesian two-phase piecewise linear mixed models with a random change point were used to estimate children's individual growth trajectories. Cox proportional hazards models were used to assess the effects of associated growth parameters on the risks of IA and progression to T1D. RESULTS A higher rate of weight gain in infancy was associated with increased IA risk (hazard ratio [HR] 1.09 [95% CI 1.02, 1.17] per 1 kg/year). A height growth pattern with a lower rate in infancy (HR 0.79 [95% CI 0.70, 0.90] per 1 cm/year), higher rate in early childhood (HR 1.48 [95% CI 1.22, 1.79] per 1 cm/year), and younger age at the phase transition (HR 0.76 [95% CI 0.58, 0.99] per 1 month) was associated with increased risk of progression from IA to T1D. A higher rate of weight gain in early childhood was associated with increased risk of progression from IA to T1D (HR 2.57 [95% CI 1.34, 4.91] per 1 kg/year) in children with first-appearing GAD autoantibody only. CONCLUSIONS Growth patterns in early life better clarify how specific growth phases are associated with the development of T1D. AU - Liu, X.* AU - Vehik, K.* AU - Huang, Y.* AU - Larsson, H.E.* AU - Toppari, J.* AU - Ziegler, A.-G. AU - She, J.-X.* AU - Rewers, M.* AU - Hagopian, W.A.* AU - Akolkar, B.* AU - Krischer, J.P.* AU - Teddy Study Group* C1 - 57757 C2 - 48117 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 556-562 TI - Distinct growth phases in early life associated with the risk of type 1 diabetes: The TEDDY study. JO - Diabetes Care VL - 43 IS - 3 PB - Amer Diabetes Assoc PY - 2020 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE To investigate the role of epigenetics in statins' diabetogenic effect comparing DNA methylation (DNAm) between statin users and nonusers in an epigenome-wide association study in blood. RESEARCH DESIGN AND METHODS Five cohort studies' participants (n = 8,270) were classified as statin users when they were on statin therapy at the time of DNAm assessment with Illumina 450K or EPIC array or noncurrent users otherwise. Associations of DNAm with various outcomes like incident type 2 diabetes, plasma glucose, insulin, and insulin resistance (HOMA of insulin resistance [HOMA-IR]) as well as with gene expression were investigated. RESULTS Discovery (n = 6,820) and replication (n = 1,450) phases associated five DNAm sites with statin use: cg17901584 (1.12 x 10(-25) [DHCR24]), cg10177197 (3.94 x 10(-08) [DHCR24]), cg06500161 (2.67 x 10(-23) [ABCG1]), cg27243685 (6.01 x 10(-09) [ABCG1]), and cg05119988 (7.26 x 10(-12) [SC4MOL]). Two sites were associated with at least one glycemic trait or type 2 diabetes. Higher cg06500161 methylation was associated with higher fasting glucose, insulin, HOMA-IR, and type 2 diabetes (odds ratio 1.34 [95% CI 1.22, 1.47]). Mediation analyses suggested that ABCG1 methylation partially mediates the effect of statins on high insulin and HOMA-IR. Gene expression analyses showed that statin exposure and ABCG1 methylation were associated with ABCG1 downregulation, suggesting epigenetic regulation of ABCG1 expression. Further, outcomes insulin and HOMA-IR were significantly associated with ABCG1 expression. CONCLUSIONS This study sheds light on potential mechanisms linking statins with type 2 diabetes risk, providing evidence on DNAm partially mediating statins' effects on insulin traits. Further efforts shall disentangle the molecular mechanisms through which statins may induce DNAm changes, potentially leading to ABCG1 epigenetic regulation. AU - Ochoa-Rosales, C.* AU - Portilla-Fernandez, E.* AU - Nano, J. AU - Wilson, R. AU - Lehne, B.* AU - Mishra, P.P.* AU - Gao, X.* AU - Ghanbari, M.* AU - Rueda-Ochoa, O.L.* AU - Juvinao-Quintero, D.* AU - Loh, M.* AU - Zhang, W.* AU - Kooner, J.S.* AU - Grabe, H.J.* AU - Felix, S.B.* AU - Schöttker, B.* AU - Zhang, Y.* AU - Gieger, C. AU - Müller-Nurasyid, M. AU - Heier, M. AU - Peters, A. AU - Lehtimäki, T.* AU - Teumer, A.* AU - Brenner, H.* AU - Waldenberger, M. AU - Ikram, M.A.* AU - van Meurs, J.B.J.* AU - Franco, O.H.* AU - Voortman, T.* AU - Stricker, B.H.* AU - Muka, T.* C1 - 58647 C2 - 48196 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 875-884 TI - Epigenetic link between statin therapy and type 2 diabetes. JO - Diabetes Care VL - 43 IS - 4 PB - Amer Diabetes Assoc PY - 2020 SN - 0149-5992 ER - TY - JOUR AU - Soldo, J.* AU - Heni, M. AU - Königsrainer, A.* AU - Häring, H.-U. AU - Birkenfeld, A.L. AU - Peter, A. C1 - 59853 C2 - 49072 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - E134-E136 TI - Increased hepatic ACE2 expression in NAFL and diabetes-A risk for COVID-19 patients? JO - Diabetes Care VL - 43 IS - 10 PB - Amer Diabetes Assoc PY - 2020 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE The first-appearing b-cell autoantibody has been shown to influence risk of type 1 diabetes (T1D). Here, we assessed the risk of autoantibody spreading to the second-appearing autoantibody and further progression to clinical disease in The Environmental Determinants of Diabetes in the Young (TEDDY) study. RESEARCH DESIGN AND METHODS Eligible children with increased HLA-DR-DQ genetic risk for T1D were followed quarterly from age 3 months up to 15 years for development of a single first-appearing autoantibody (GAD antibody [GADA], insulin autoantibody [IAA], or insulinoma antigen-2 autoantibody [IA-2A]) and subsequent development of a single second-appearing autoantibody and progression to T1D. Autoantibody positivity was defined as positivity for a specific autoantibody at two consecutive visits confirmed in two laboratories. Zinc transporter 8 autoantibody (ZnT8A) was measured in children who developed another autoantibody. RESULTS There were 608 children who developed a single first-appearing autoantibody (IAA, n 5 282, or GADA, n 5 326) with a median follow-up of 12.5 years from birth. The risk of a second-appearing autoantibody was independent of GADA versus IAA as a first-appearing autoantibody (adjusted hazard ratio [HR] 1.12; 95% CI 0.88–1.42; P 5 0.36). Second-appearing GADA, IAA, IA-2A, or ZnT8A conferred an increased risk of T1D compared with children who remained positive for a single autoantibody, e.g., IAA or GADA second (adjusted HR 6.44; 95% CI 3.78–10.98), IA-2A second (adjusted HR 16.33; 95% CI 9.10–29.29; P <0.0001), or ZnT8A second (adjusted HR 5.35; 95% CI 2.61–10.95; P < 0.0001). In children who developed a distinct second autoantibody, IA-2A (adjusted HR 3.08; 95% CI 2.04–4.65; P < 0.0001) conferred a greater risk of progression to T1D as compared with GADA or IAA. Additionally, both a younger initial age at seroconversion and shorter time to the development of the second-appearing autoantibody increased the risk for T1D. CONCLUSIONS The hierarchical order of distinct autoantibody spreading was independent of the first-appearing autoantibody type and was age-dependent and augmented the risk of progression to T1D. AU - Vehik, K.* AU - Bonifacio, E. AU - Lernmark, A.* AU - Yu, L.* AU - Williams, A.* AU - Schatz, D.* AU - Rewers, M.* AU - She, J.X.* AU - Toppari, J.* AU - Hagopian, W.* AU - Akolkar, B.* AU - Ziegler, A.-G. AU - Krischer, J.P.* C1 - 59652 C2 - 48930 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 2066-2073 TI - Hierarchical order of distinct autoantibody spreading and progression to type 1 diabetes in the Teddy study. JO - Diabetes Care VL - 43 IS - 9 PB - Amer Diabetes Assoc PY - 2020 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVEGastrointestinal adverse effects occur in 20-30% of patients with metformin-treated type 2 diabetes, leading to premature discontinuation in 5-10% of the cases. Gastrointestinal intolerance may reflect localized high concentrations of metformin in the gut. We hypothesized that reduced transport of metformin via the plasma membrane monoamine transporter (PMAT) and organic cation transporter 1 (OCT1) could increase the risk of severe gastrointestinal adverse effects.RESEARCH DESIGN AND METHODSThe study included 286 severe metformin-intolerant and 1,128 metformin-tolerant individuals from the IMI DIRECT (Innovative Medicines Initiative: DIabetes REsearCh on patient straTification) consortium. We assessed the association of patient characteristics, concomitant medication, and the burden of mutations in the SLC29A4 and SLC22A1 genes on odds of intolerance.RESULTSWomen (P < 0.001) and older people (P < 0.001) were more likely to develop metformin intolerance. Concomitant use of transporter-inhibiting drugs increased the odds of intolerance (odds ratio [OR] 1.72, P < 0.001). In an adjusted logistic regression model, the G allele at rs3889348 (SLC29A4) was associated with gastrointestinal intolerance (OR 1.34, P = 0.005). rs3889348 is the top cis-expression quantitative trait locus for SLC29A4 in gut tissue where carriers of the G allele had reduced expression. Homozygous carriers of the G allele treated with transporter-inhibiting drugs had more than three times higher odds of intolerance compared with carriers of no G allele and not treated with inhibiting drugs (OR 3.23, P < 0.001). Use of a genetic risk score derived from rs3889348 and SLC22A1 variants found that the odds of intolerance were more than twice as high in individuals who carry three or more risk alleles compared with those carrying none (OR 2.15, P = 0.01).CONCLUSIONSThese results suggest that intestinal metformin transporters and concomitant medications play an important role in the gastrointestinal adverse effects of metformin. AU - Dawed, A.Y.* AU - Zhou, K.* AU - van Leeuwen, N.* AU - Mahajan, A.* AU - Robertson, N.* AU - Koivula, R.W.* AU - Elders, P.J.M.* AU - Rauh, S.P.* AU - Jones, A.G.* AU - Holl, R.W.* AU - Stingl, J.C.* AU - Franks, P.W.* AU - McCarthy, M.I.* AU - 't Hart, L.M.* AU - Pearson, E.R.* AU - DIRECT Consortium (Thorand, B. AU - Adamski, J. AU - Grallert, H. AU - Haid, M. AU - Sharma, S.) C1 - 56706 C2 - 47197 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 1027-1033 TI - Variation in the plasma membrane monoamine transporter (PMAT, encoded in SLC29A4) and organic cation transporter 1 (OCT1, encoded in SLC22A1) and gastrointestinal intolerance to metformin in type 2 diabetes: An IMI DIRECT study. JO - Diabetes Care VL - 42 IS - 6 PB - Amer Diabetes Assoc PY - 2019 SN - 0149-5992 ER - TY - JOUR AU - Hulman, A.* AU - Wagner, R. AU - Vistisen, D.* AU - Faerch, K.* AU - Balkau, B.* AU - Manco, M.* AU - Golay, A.* AU - Häring, H.-U. AU - Heni, M. AU - Fritsche, A. AU - Witte, D.R.* C1 - 55758 C2 - 46535 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - e56-e57 TI - Glucose measurements at various time points during the OGTT and their role in capturing glucose response patterns. JO - Diabetes Care VL - 42 IS - 4 PB - Amer Diabetes Assoc PY - 2019 SN - 0149-5992 ER - TY - JOUR AU - Kowall, B.* AU - Rathmann, W.* AU - Bongaerts, B.* AU - Kuss, O.* AU - Stang, A.* AU - Roden, M.* AU - Herder, C.* AU - Koenig, W.* AU - Huth, C. AU - Heier, M. AU - Thorand, B. AU - Ladwig, K.-H. AU - Holle, R. AU - Meisinger, C.* AU - Peters, A. C1 - 54979 C2 - 45989 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - E18-E20 TI - Incidence rates of type 2 diabetes in people with impaired fasting glucose (ADA vs. WHO Criteria) and impaired glucose tolerance: Results from an older population (KORA S4/F4/FF4 Study). JO - Diabetes Care VL - 42 IS - 2 PB - Amer Diabetes Assoc PY - 2019 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVEAssessment of the predictive power of The Environmental Determinants of Diabetes in the Young (TEDDY)-identified risk factors for islet autoimmunity (IA), the type of autoantibody appearing first, and type 1 diabetes (T1D).RESEARCH DESIGN AND METHODSA total of 7,777 children were followed from birth to a median of 9.1 years of age for the development of islet autoantibodies and progression to T1D. Time-dependent sensitivity, specificity, and receiver operating characteristic (ROC) curves were calculated to provide estimates of their individual and collective ability to predict IA and T1D.RESULTSHLA genotype (DR3/4 vs. others) was the best predictor for IA (Youden's index J = 0.117) and single nucleotide polymorphism rs2476601, in PTPN22, was the best predictor for insulin autoantibodies (IAA) appearing first (IAA-first) (J = 0.123). For GAD autoantibodies (GADA)-first, weight at 1 year was the best predictor (J = 0.114). In a multivariate model, the area under the ROC curve (AUC) was 0.678 (95% CI 0.655, 0.701), 0.707 (95% CI 0.676, 0.739), and 0.686 (95% CI 0.651, 0.722) for IA, IAA-first, and GADA-first, respectively, at 6 years. The AUC of the prediction model for T1D at 3 years after the appearance of multiple autoantibodies reached 0.706 (95% CI 0.649, 0.762).CONCLUSIONSPrediction modeling statistics are valuable tools, when applied in a time-until-event setting, to evaluate the ability of risk factors to discriminate between those who will and those who will not get disease. Although significantly associated with IA and T1D, the TEDDY risk factors individually contribute little to prediction. However, in combination, these factors increased IA and T1D prediction substantially. AU - Krischer, J.P.* AU - Liu, X.* AU - Vehik, K.* AU - Akolkar, B.* AU - Hagopian, W.A.* AU - Rewers, M.J.* AU - She, J.X.* AU - Toppari, J.* AU - Ziegler, A.-G. AU - Lernmark, A.* AU - The Teddy Study Group* C1 - 56280 C2 - 46913 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 1051-1060 TI - Predicting islet cell autoimmunity and type 1 diabetes: An 8-year TEDDY study progress report. JO - Diabetes Care VL - 42 IS - 6 PB - Amer Diabetes Assoc PY - 2019 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVETo investigate the associations between different anthropometric measurements and development of distal sensorimotor polyneuropathy (DSPN) considering interaction effects with prediabetes/diabetes and to evaluate subclinical inflammation as a potential mediator.RESEARCH DESIGN AND METHODSThis study was conducted among 513 participants from the Cooperative Health Research in the Region of Augsburg (KORA) F4/FF4 cohort (aged 62-81 years). Anthropometry was measured at baseline. Incident DSPN was defined by neuropathic impairments using the Michigan Neuropathy Screening Instrument at baseline and follow-up. Associations between anthropometric measurements and DSPN were estimated by multivariable logistic regression. Potential differences by diabetes status were assessed using interaction terms. Mediation analysis was conducted to determine the mediation effect of subclinical inflammation in these associations.RESULTSAfter a mean follow-up of 6.5 years, 127 cases with incident DSPN were detected. Both general and abdominal obesity were associated with development of DSPN. The odds ratios (95% CI) of DSPN were 3.06 (1.57; 5.97) for overweight, 3.47 (1.72; 7.00) for obesity (reference: normal BMI), and 1.22 (1.07; 1.38) for 5-cm differences in waist circumference, respectively. Interaction analyses did not indicate any differences by diabetes status. Two chemokines (C-C motif chemokine ligand 7 [CCL7] and C-X-C motif chemokine ligand 10 [CXCL10]) and one neuron-specific marker (Delta/Notch-like epidermal growth factor-related receptor [DNER]) were identified as potential mediators, which explained a proportion of the total effect up to 11% per biomarker.CONCLUSIONSGeneral and abdominal obesity were associated with incident DSPN among individuals with and without diabetes, and this association was partly mediated by inflammatory markers. However, further mechanisms and biomarkers should be investigated as additional mediators to explain the remainder of this association. AU - Schlesinger, S.* AU - Herder, C.* AU - Kannenberg, J.M.* AU - Huth, C. AU - Carstensen-Kirberg, M.* AU - Rathmann, W.* AU - Bönhof, G.J.* AU - Koenig, W.* AU - Heier, M. AU - Peters, A. AU - Meisinger, C. AU - Roden, M.* AU - Thorand, B. AU - Ziegler, D.* C1 - 54972 C2 - 46019 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 240-247 TI - General and abdominal obesity and incident distal sensorimotor polyneuropathy: Insights into inflammatory biomarkers as potential mediators in the KORA F4/FF4 cohort. JO - Diabetes Care VL - 42 IS - 2 PB - Amer Diabetes Assoc PY - 2019 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE Autoimmune diseases can be diagnosed early through the detection of autoantibodies. The aim of this study was to determine the risk of organ-specific autoimmunity in individuals with a family history of type 1 diabetes. RESEARCH DESIGN AND METHODS The study cohort included 2,441 first-degree relatives of patients with type 1 diabetes who were prospectively followed from birth to a maximum of 29.4 years (median 13.2 years). All were tested regularly for the development of autoantibodies associated with type 1 diabetes (islet), celiac disease (transglutaminase), or thyroid autoimmunity (thyroid peroxidase). The outcome was defined as an autoantibody-positive status on two consecutive samples. RESULTS In total, 394 relatives developed one (n = 353) or more (n = 41) of the three disease-associated autoantibodies during follow-up. The risk by age 20 years was 8.0% (95% CI 6.8-9.2%) for islet autoantibodies, 6.3% (5.1-7.5%) for transglutaminase autoantibodies, 10.7% (8.9-12.5%) for thyroid peroxidase autoantibodies, and 21.5% (19.5-23.5%) for any of these autoantibodies. Each of the three disease-associated autoantibodies was defined by distinct HLA, sex, genetic, and age profiles. The risk of developing any of these autoantibodies was 56.5% (40.8-72.2%) in relatives with HLA DR3/DR3 and 44.4% (36.6-52.2%) in relatives with HLA DR3/DR4-DQ8. CONCLUSIONS Relatives of patients with type 1 diabetes have a very high risk of organ-specific autoimmunity. Appropriate counseling and genetic and autoantibody testing for multiple autoimmune diseases may be warranted for relatives of patients with type 1 diabetes. AU - Winkler, C. AU - Jolink, M. AU - Knopff, A. AU - Kwarteng, N.-A. AU - Achenbach, P. AU - Bonifacio, E. AU - Ziegler, A.-G. C1 - 56359 C2 - 47032 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 1684-1691 TI - Age, HLA, and sex define a marked risk of organ-specific autoimmunity in first-degree relatives of patients with type 1 diabetes. JO - Diabetes Care VL - 42 IS - 9 PB - Amer Diabetes Assoc PY - 2019 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE: To study incident diabetic polyneuropathy (DPN) prospectively during the first 13 years after a screening-based diagnosis of type 2 diabetes and determine the associated risk factors for the development of DPN. RESEARCH DESIGN AND METHODS: We assessed DPN longitudinally in the Danish arm of the Anglo-Danish-Dutch study of Intensive Treatment of Diabetes in Primary Care (ADDITION) using the Michigan Neuropathy Screening Instrument questionnaire (MNSIQ), defining DPN with scores ≥4. Risk factors present at the diabetes diagnosis associated with the risk of incident DPN were estimated using Cox proportional hazard models adjusted for trial randomization group, sex, and age. RESULTS: Of the total cohort of 1,533 people, 1,445 completed the MNSIQ at baseline and 189 (13.1%) had DPN at baseline. The remaining 1,256 without DPN entered this study (median age 60.8 years [interquartile range 55.6; 65.6], 59% of whom were men). The cumulative incidence of DPN was 10% during 13 years of diabetes. Age (hazard ratio [HR] 1.03 [95% CI 1.00; 1.07]) (unit = 1 year), weight (HR 1.09 [95% CI 1.03; 1.16]) (unit = 5 kg), waist circumference (HR 1.14 [95% CI 1.05; 1.24]) (unit = 5 cm), BMI (HR 1.14 [95% CI 1.06; 1.23]) (unit = 2 kg/m2), log2 methylglyoxal (HR 1.45 [95% CI 1.12; 1.89]) (unit = doubling), HDL cholesterol (HR 0.82 [95% CI 0.69; 0.99]) (unit = 0.25 mmol/L), and LDL cholesterol (HR 0.92 [95% CI 0.86; 0.98]) (unit = 0.25 mmol/L) at baseline were significantly associated with the risk of incident DPN. CONCLUSIONS: This study provides further epidemiological evidence for obesity as a risk factor for DPN. Moreover, low HDL cholesterol levels and higher levels of methylglyoxal, a markerofdicarbonyl stress, are identifiedasrisk factors for the developmentofDPN. AU - Andersen, S.T.* AU - Witte, D.R.* AU - Dalsgaard, E.* AU - Andersen, H.* AU - Nawroth, P.P. AU - Fleming, T.* AU - Jensen, T.M.* AU - Finnerup, N.B.* AU - Jensen, T.S.* AU - Lauritzen, T.* AU - Feldman, E.L.* AU - Callaghan, B.C.* AU - Charles, M.* C1 - 53466 C2 - 44732 SP - 1068-1075 TI - Risk factors for incident diabetic polyneuropathy in a cohort with screen-detected type 2 diabetes followed for 13 years: Addition-Denmark. JO - Diabetes Care VL - 41 IS - 5 PY - 2018 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVEThis study analyzed whether area deprivation is associated with disparities in health care of pediatric type 1 diabetes in Germany.RESEARCH DESIGN AND METHODSWe selected patients <20 years of age with type 1 diabetes and German residence documented in the "diabetes patient follow-up" (Diabetes-Patienten-Verlaufsdokumentation [DPV]) registry for 2015/2016. Area deprivation was assessed by quintiles of the German Index of Multiple Deprivation (GIMD 2010) at the district level and was assigned to patients. To investigate associations between GIMD 2010 and indicators of diabetes care, we used multivariable regression models (linear, logistic, and Poisson) adjusting for sex, age, migration background, diabetes duration, and German federal state.RESULTSWe analyzed data from 29,284 patients. From the least to the most deprived quintile, use of continuous glucose monitoring systems (CGMS) decreased from 6.3 to 3.4% and use of long-acting insulin analogs from 80.8 to 64.3%, whereas use of rapid-acting insulin analogs increased from 74.7 to 79.0%; average HbA(1c) increased from 7.84 to 8.07% (62 to 65 mmol/mol), and the prevalence of overweight from 11.8 to 15.5%, but the rate of severe hypoglycemia decreased from 12.1 to 6.9 events/100 patient-years. Associations with other parameters showed a more complex pattern (use of continuous subcutaneous insulin infusion [CSII]) or were not significant.CONCLUSIONSArea deprivation was associated not only with key outcomes in pediatric type 1 diabetes but also with treatment modalities. Our results show, in particular, that the access to CGMS and CSII could be improved in the most deprived regions in Germany. AU - Auzanneau, M.* AU - Lanzinger, S.* AU - Bohn, B.* AU - Kroschwald, P.* AU - Kuhnle-Krahl, U.* AU - Holterhus, P.M.* AU - Placzek, K.* AU - Hamann, J.* AU - Bachran, R.* AU - Rosenbauer, J.* AU - Maier, W. C1 - 54535 C2 - 45570 CY - 1701 N Beauregard St, Alexandria, Va 22311-1717 Usa SP - 2517-2525 TI - Area deprivation and regional disparities in treatment and outcome quality of 29,284 pediatric patients with type 1 diabetes in Germany: A cross-sectional multicenter DPV analysis. JO - Diabetes Care VL - 41 IS - 12 PB - Amer Diabetes Assoc PY - 2018 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVEHuman obesity is associated with impaired central insulin signaling, and in very rare cases, severe obesity can be caused by congenital leptin deficiency. In such patients, leptin replacement results in substantial weight loss and improvement in peripheral metabolism.RESEARCH DESIGN AND METHODSIn a leptin-deficient patient, we investigated the impact of leptin substitution on central insulin action, as quantified by changes in neuronal activity after intranasal insulin application. This was assessed before and during the first year of metreleptin substitution.RESULTSAfter only 1 year, treatment with metreleptin reestablishes brain insulin sensitivity, particularly in the hypothalamus and, to a lesser degree, in the prefrontal cortex. Results are depicted in comparison with a control group. In our patient, brain activation changes were accompanied by substantial weight loss, reduced visceral adipose tissue, reduced intrahepatic lipid content, and improved whole-body insulin sensitivity.CONCLUSIONSLeptin replacement and weight loss improved homeostatic insulin action in the patient in question. AU - Frank-Podlech, S. AU - von Schnurbein, J.* AU - Veit, R. AU - Heni, M. AU - Machann, J. AU - Heinze, J.M. AU - Kullmann, S. AU - Manzoor, J.* AU - Mahmood, S.* AU - Häring, H.-U. AU - Preissl, H. AU - Wabitsch, M.* AU - Fritsche, A. C1 - 53362 C2 - 44707 CY - Alexandria SP - 907-910 TI - Leptin replacement reestablishes brain insulin action in the hypothalamus in congenital leptin deficiency. JO - Diabetes Care VL - 41 IS - 4 PB - Amer Diabetes Assoc PY - 2018 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE: The aim of this study is to provide reliable regression-based estimates of costs associated with different type 2 diabetes complications. RESEARCH DESIGN AND METHODS: We used nationwide statutory health insurance (SHI) data from 316,220 patients with type 2 diabetes. Costs for inpatient and outpatient care, pharmaceuticals, rehabilitation, and nonmedical aids and appliances were assessed in the years 2013-2015. Quarterly observations are available for each year. We estimated costs (in 2015 euro) for complications using a generalized estimating equations model with a normal distribution adjusted for age, sex, occurrence of different complications, and history of complications at baseline, 2012. Two- and threefold interactions were included in an extended model. RESULTS: The base case model estimated total costs in the quarter of event for the example of a 60-69-year-old man as follows: diabetic foot €1,293, amputation €14,284, retinopathy €671, blindness €2,933, nephropathy €3,353, end-stage renal disease (ESRD) €22,691, nonfatal stroke €9,769, fatal stroke €11,176, nonfatal myocardial infarction (MI)/cardiac arrest (CA) €8,035, fatal MI/CA €8,700, nonfatal ischemic heart disease (IHD) €6,548, fatal IHD €20,942, chronic heart failure €3,912, and angina pectoris €2,695. In the subsequent quarters, costs ranged from €681 for retinopathy to €6,130 for ESRD. CONCLUSIONS: Type 2 diabetes complications have a significant impact on total health care costs in the SHI system, not only in the quarter of event but also in subsequent years. Men and women from different age-groups differ in their costs for complications. Our comprehensive estimates may support the parametrization of diabetes models and help clinicians and policymakers to quantify the economic burden of diabetic complications in the context of new prevention and treatment programs. AU - Kähm, K. AU - Laxy, M. AU - Schneider, U.* AU - Rogowski, W.H.* AU - Lhachimi, S.K.* AU - Holle, R. C1 - 52895 C2 - 44241 SP - 971-978 TI - Health care costs associated with incident complications in patients with type 2 diabetes in Germany. JO - Diabetes Care VL - 41 IS - 5 PY - 2018 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE To examine duration of breastfeeding and timing of complementary foods and risk of islet autoimmunity (IA). RESEARCH DESIGN AND METHODS The Environmental Determinants of Diabetes in the Young (TEDDY) study prospectively follows 8,676 childrenwith increased genetic risk of type 1 diabetes (T1D) in the U.S., Finland, Germany, and Sweden. This study included 7,563 children with at least 9 months of follow-up. Blood samples were collected every 3 months from birth to evaluate IA, defined as persistent, confirmed positive antibodies to insulin (IAAs), GAD, or insulinoma antigen-2. We examined the associations between diet and the risk of IA using Cox regression models adjusted for country, T1D family history, HLA genotype, sex, and early probiotic exposure. Additionally, we investigated martingale residuals and log-rank statistics to determine cut points for ages of dietary exposures. RESULTS Later introduction of glutenwas associatedwith increased risk of any IA and IAA. The hazard ratios (HRs) for every 1-month delay in gluten introduction were 1.05 (95% CI 1.01, 1.10; P = 0.02) and 1.08 (95% CI 1.00, 1.16; P = 0.04), respectively. Martingale residual analysis suggested that the age at gluten introduction could be grouped as < 4, 4-9, and > 9 months. The risk of IA associated with introducing gluten before 4months of age was lower (HR 0.68; 95% CI 0.47, 0.99), and the risk of IA associated with introducing it later than the age of 9 months was higher (HR 1.57; 95% CI 1.07, 2.31) than introduction between 4 and 9 months of age. CONCLUSIONS The timing of gluten-containing cereals and IA should be studied further. AU - Uusitalo, U.* AU - Lee, H.S.* AU - Aronsson, C.A.* AU - Vehik, K.* AU - Yang, J.A.* AU - TEDDY Study Group (Hummel, S. AU - Ziegler, A.-G. AU - Teddy Study Group*) AU - Silvis, K.* AU - Lernmark, A.* AU - Rewers, M.* AU - Hagopian, W.* AU - She, J.X.* AU - Simell, O.* AU - Toppari, J.* AU - Akolkar, B.* AU - Krischer, J.* AU - Virtanen, S.M.* AU - Norris, J.M.* C1 - 52751 C2 - 44313 SP - 522-530 TI - Early infant diet and islet autoimmunity in the TEDDY Study. JO - Diabetes Care VL - 41 IS - 3 PY - 2018 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE: Experimental and epidemiological studies have implicated inflammatory processes in the pathogenesis of distal sensorimotor polyneuropathy (DSPN), but prospective studies are lacking. We hypothesized that biomarkers of inflammation predict the development and progression of DSPN in a population-based cohort. RESEARCH DESIGN AND METHODS: This study was based on participants aged 62-81 years from the Cooperative Health Research in the Region of Augsburg (KORA) F4/FF4 cohort, with a mean follow-up of 6.5 years. The predictive value of systemic levels of eight biomarkers of inflammation was assessed for incident DSPN in 133 incident case subjects and 397 individuals without incident DSPN, and for DSPN progression in 57 patients with prevalent DSPN at both time points. RESULTS: Higher hs-CRP, interleukin (IL)-6, tumor necrosis factor (TNF)-α, IL-1 receptor antagonist (IL-1RA), and soluble intercellular adhesion molecule (sICAM-1) and lower adiponectin levels were associated with incident DSPN in age- and sex-adjusted analysis; IL-18 and omentin were not. IL-6 (odds ratio 1.31 [95% CI 1.00-1.71]) and TNF-α (odds ratio 1.31 [95% CI 1.03-1.67]) remained associated with incident DSPN after adjusting for known DSPN risk factors. The addition of both cytokines to a clinical risk model improved model fit and reclassification. sICAM-1 and IL-1RA were positively associated with progression of DSPN. CONCLUSIONS: Systemic subclinical and vascular inflammation predicted both the onset and progression of DSPN over 6.5 years in an older general population. Thus modulation of inflammatory processes may be relevant to prevent and/or treat diabetic neuropathy. AU - Herder, C.* AU - Kannenberg, J.M.* AU - Huth, C. AU - Carstensen-Kirberg, M.* AU - Rathmann, W.* AU - Koenig, W.* AU - Heier, M. AU - Püttgen, S.* AU - Thorand, B. AU - Peters, A. AU - Roden, M.* AU - Meisinger, C. AU - Ziegler, D.* C1 - 50654 C2 - 42564 CY - Alexandria SP - 569-576 TI - Proinflammatory cytokines predict the incidence and progression of distal sensorimotor polyneuropathy: KORA F4/FF4 Study. JO - Diabetes Care VL - 40 IS - 4 PB - Amer Diabetes Assoc PY - 2017 SN - 0149-5992 ER - TY - JOUR AB - Studies on the introduction of infant formulas and its effect on the risk of islet autoimmunity and type 1 diabetes (T1D) have yielded inconsistent results. We investigated whether the introduction of formula based on hydrolyzed cow's milk as the first formula is associated with reduced islet autoimmunity risk in a large prospective cohort. RESEARCH DESIGN AND METHODS: The Environmental Determinants of Diabetes in the Young (TEDDY) study prospectively monitors 8,676 children at increased genetic risk for T1D. Autoantibodies to insulin, GAD65, and IA2 were measured regularly to define islet autoimmunity. Information on formula feeding was collected by questionnaires at 3 months of age. RESULTS: In survival analyses, after adjustment for family history with T1D, HLA genotype, sex, country, delivery mode, breast-feeding ≥3 months, and seasonality of birth, we observed no significant association with islet autoimmunity in infants who received extensively hydrolyzed compared with nonhydrolyzed cow's milk-based formula as the first formula during the first 3 months (adjusted hazard ratio 1.38 [95% CI 0.95; 2.01]), and a significantly increased risk for extensively hydrolyzed formula introduced during the first 7 days (adjusted hazard ratio 1.57 [1.04; 2.38]). Using a partially hydrolyzed or other formula as the first formula, or no formula, was not associated with islet autoimmunity risk. CONCLUSIONS: These results add to the existing evidence that islet autoimmunity risk is not reduced, and may be increased, by using hydrolyzed compared with nonhydrolyzed cow's milk-based infant formula as the first formula in infants at increased genetic risk for T1D. AU - TEDDY Study Group (Hummel, S. AU - Beyerlein, A. AU - Ziegler, A.-G.) AU - Tamura, R.* AU - Uusitalo, U.* AU - Aronsson, C.A.* AU - Yang, J.* AU - Riikonen, A.* AU - Lernmark, A.* AU - Rewers, M.J.* AU - Hagopian, W.A.* AU - She, J.-X.* AU - Simell, O.G.* AU - Toppari, J.* AU - Akolkar, B.* AU - Krischer, J.P.* AU - Virtanen, S.M.* AU - Norris, J.M.* C1 - 50515 C2 - 42305 CY - Alexandria SP - 398-404 TI - First infant formula type and risk of islet autoimmunity in the environmental determinants of diabetes in the young (TEDDY) study. JO - Diabetes Care VL - 40 IS - 2 PB - Amer Diabetes Assoc PY - 2017 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE To assess parent anxiety in response to genetic and islet autoantibody (IA) testing in children at increased genetic risk for type 1 diabetes followed from birth in The Environmental Determinants of Diabetes in the Young (TEDDY) study. RESEARCH DESIGN AND METHODS Parent anxiety about TEDDY children's risk was assessed with the State Anxiety Inventory (SAI). Parents completed the SAI when the child was 3, 6, and 15 months old and annually thereafter. Children were tested for IA every 3 months for 4 years and every 6 months thereafter. Parent SAI scores of 6,799 children followed with IA testing for at least 1 and up to 6 years were examined. RESULTS At study inception, parents showed high levels of anxiety in response to their child's increased genetic type 1 diabetes risk;mothersweremore anxious than fathers, and parents with diabetes in the family were more anxious than parents with no family history. In response to repeated IA-negative (IA2) test results, parent anxiety declined to normal levels. Anxiety increased in parents faced with an IA-positive (IA+) test result. Parents faced with two or more types of IA+ test results showed particularly high levels of anxiety (all P < 0.001). CONCLUSIONS Infant genetic screening for type 1 diabetes raises parent anxiety when the child is at increased risk, but anxiety dissipates over time in cases of repeated IA2 results. IA+ results heighten parent anxiety, and parents faced with two or more types of IA+ results may experience considerable anxiety for longer periods. AU - Johnson, S.B.* AU - Lynch, K.F.* AU - TEDDY Study Group (Roth, R.) AU - Schatz, D.* C1 - 51775 C2 - 43479 CY - Alexandria SP - 1167-1172 TI - My child is islet autoantibody positive: Impact on parental anxiety. JO - Diabetes Care VL - 40 IS - 9 PB - Amer Diabetes Assoc PY - 2017 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE The human vitamin E-binding glycoprotein afamin is primarily expressed in the liver and has been associated with prevalent and incident metabolic syndrome. These data were in line with observations in transgenic mice. We thus investigated whether afamin concentrations are associated with prediabetes, type 2 diabetes, and insulin resistance (IR). RESEARCH DESIGN AND METHODS Individual-level baseline (n = 20,136) and follow-up data (n = 14,017) of eight prospective cohort studies were investigated. Study-level data were combined using random-effects meta-analyses. Main outcomes were prevalent and incident type 2 diabetes, prediabetes, and IR. Discrimination and reclassification of participants was analyzed for incident type 2 diabetes. RESULTS Mean afamin concentrations between studies ranged from 61 to 73 mg/L. The eight studies included 1,398 prevalent and 585 incident cases of type 2 diabetes. Each increase of afamin by 10 mg/L was associated with prevalent type 2 diabetes (odds ratio [OR] 1.19 [95% CI 1.12-1.26], P= 5.96x10(-8)). Afamin was positively associated with IR assessed by HOMA-IR (beta 0.110 [95% CI 0.089-0.132], P = 1.37x10(-23)). Most importantly, afamin measured at baseline was an independent predictor for 585 incident cases of type 2 diabetes (OR 1.30 [95% CI 1.23-1.38], P = 3.53 x 10(-19)) and showed a significant and valuable gain in risk classification accuracy when added to this extended adjustment model. CONCLUSIONS This pooled analysis in > 20,000 individuals showed that afamin is strongly associated with IR, prevalence, and incidence of type 2 diabetes independent of major metabolic risk factors or parameters. Afamin might be a promising novel marker for the identification of individuals at high risk for the development of type 2 diabetes. AU - Kollerits, B.* AU - Lamina, C.* AU - Huth, C. AU - Marques-Vidal, P.* AU - Kiechl, S.* AU - Seppälä, I.* AU - Cooper, J.* AU - Hunt, S.C.* AU - Meisinger, C. AU - Herder, C.* AU - Kedenko, L.* AU - Willeit, J.* AU - Thorand, B. AU - Daehnhardt, D.* AU - Stöckl, D. AU - Willeit, K.* AU - Roden, M.* AU - Rathmann, W.* AU - Paulweber, B.* AU - Peters, A. AU - Kähönen, M.* AU - Lehtimäki, T.* AU - Raitakari, O.T.* AU - Humphries, S.E.* AU - Vollenweider, P.* AU - Dieplinger, H.* AU - Kronenberg, F.* C1 - 52037 C2 - 43683 CY - Alexandria SP - 1386-1393 TI - Plasma concentrations of afamin are associated with prevalent and incident type 2 diabetes: A pooled analysis in more than 20,000 individuals. JO - Diabetes Care VL - 40 IS - 10 PB - Amer Diabetes Assoc PY - 2017 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE We tested the associations between genetic background and selected environmental exposures with respect to islet autoantibodies and type 1 diabetes. RESEARCH DESIGN AND METHODS Infants with HLA-DR high-risk genotypes were prospectively followed for diabetesrelated autoantibodies. Single nucleotide polymorphisms (SNPs) came from the Illumina ImmunoChip and environmental exposure data were by parental report. Children were followed to age 6 years. RESULTS Insulin autoantibodies occurred earlier than GAD antibody (GADA) and then declined, while GADA incidence rose and remained constant (significant in HLA-DR4 but not in the DR3/3 children). The presence of SNPs rs2476601 (PTPN22) and rs2292239 (ERBB3) demonstrated increased risk of both autoantibodies to insulin (IAA) only and GADA only. SNP rs689 (INS) was protective of IAA only, but not of GADA only. The rs3757247 (BACH2) SNP demonstrated increased risk of GADA only. Male sex, father or sibling as the diabetic proband, introduction of probiotics under 28 days of age, and weight at age 12 monthswere associated with IAA only, but only father as the diabetic proband and weight at age 12 months were associated with GADA only. Mother as the diabetic proband was not a significant risk factor. CONCLUSIONS These results show clear differences in the initiation of autoimmunity according to genetic factors and environmental exposures that give rise to IAAorGADA as the first appearing indication of autoimmunity. AU - Krischer, J.P.* AU - Lynch, K.F.* AU - Lernmark, A.* AU - Hagopian, W.A.* AU - Rewers, M.J.* AU - She, J.X.* AU - Toppari, J.* AU - TEDDY Study Group (Ziegler, A.-G.) AU - Akolkar, B.* C1 - 51777 C2 - 43738 CY - Alexandria SP - 1194-1202 TI - Genetic and environmental interactions modify the risk of diabetes-related autoimmunity by 6 years of age: The TEDDY Study. JO - Diabetes Care VL - 40 IS - 9 PB - Amer Diabetes Assoc PY - 2017 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE: Obesity and type 2 diabetes mellitus (T2DM) are associated with altered food-related neuronal functions. Besides weight loss, substantial improvement of glucose metabolism in patients with T2DM can be achieved by bariatric surgery. We aimed to target the neuronal and behavioral correlates of improved glycemic control after bariatric surgery. RESEARCH DESIGN AND METHODS: Two patient groups with T2DM were recruited. The treatment group (n = 12) included patients after Roux-en-Y gastric bypass (RYGB) surgery and a control group of patients who did not undergo surgery (n = 12). The groups were matched for age and current BMI. HbA1c was matched by using the presurgical HbA1c of the RYGB group and the current HbA1c of the nonsurgical group. Neuronal activation during a food reward task was measured using functional MRI (fMRI). Behavioral data were assessed through questionnaires. RESULTS: RYGB improved HbA1c from 7.07 ± 0.50 to 5.70 ± 0.16% (P < 0.05) and BMI from 52.21 ± 1.90 to 35.71 ± 0.84 kg/m(2) (P < 0.001). Behavioral results showed lower wanting and liking scores as well as lower eating behavior-related pathologies for the patients after RYGB than for similar obese subjects without surgery but impaired glycemic control. The fMRI analysis showed higher activation for the nonsurgical group in areas associated with inhibition and reward as well as in the precuneus, a major connectivity hub in the brain. By contrast, patients after RYGB showed higher activation in the visual, motor, cognitive control, memory, and gustatory regions. CONCLUSIONS: In obese patients with diabetes, RYGB normalizes glycemic control and leads to food reward-related brain activation patterns that are different from obese patients with less-well-controlled T2DM and without bariatric surgery. The differences in food reward processing might be one factor in determining the outcome of bariatric surgery in patients with T2DM. AU - Frank, S.* AU - Heinze, J.M. AU - Fritsche, A. AU - Linder, K.* AU - von Feilitzsch, M.* AU - Königsrainer, A.* AU - Häring, H.-U. AU - Veit, R. AU - Preissl, H. C1 - 48806 C2 - 41414 CY - Alexandria SP - 1311-1317 TI - Neuronal food reward activity in patients with type 2 diabetes with improved glycemic control after bariatric surgery. JO - Diabetes Care VL - 39 IS - 8 PB - Amer Diabetes Assoc PY - 2016 SN - 0149-5992 ER - TY - JOUR AU - Jordan, J.* AU - El-Armouche, A.* AU - Hanefeld, M.* AU - Bornstein, S.R. AU - Birkenfeld, A.L. C1 - 50278 C2 - 42113 CY - Alexandria SP - E224-E225 TI - CV Protection in the EMPA-REG OUTCOME Trial: A "Thrifty Substrate" Hypothesis. Diabetes Care 2016;39:1108-1114. JO - Diabetes Care VL - 39 IS - 12 PB - Amer Diabetes Assoc PY - 2016 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE: β-Cell autoantibodies are a feature of the preclinical phase of type 1 diabetes. Here, we asked how frequently they revert in a cohort of children at risk for type 1 diabetes and whether reversion has any effect on type 1 diabetes risk. RESEARCH DESIGN AND METHODS: Children were up to 10 years of age and screened more than once for insulin autoantibody, GAD antibody, and insulinoma antigen-2 antibodies. Persistent autoantibody was defined as an autoantibody present on two or more consecutive visits and confirmed in two reference laboratories. Reversion was defined as two or more consecutive negative visits after persistence. Time-dependent Cox regression was used to examine how reversion modified the risk of development of multiple autoantibodies and type 1 diabetes. RESULTS: Reversion was relatively frequent for autoantibodies to GAD65 (19%) and insulin (29%), but was largely restricted to children who had single autoantibodies (24%) and rare in children who had developed multiple autoantibodies (<1%). Most (85%) reversion of single autoantibodies occurred within 2 years of seroconversion. Reversion was associated with HLA genotype, age, and decreasing titer. Children who reverted from single autoantibodies to autoantibody negative had, from birth, a risk for type 1 diabetes of 0.14 per 100 person-years; children who never developed autoantibodies, 0.06 per 100 person-years; and, children who remained single-autoantibody positive, 1.8 per 100 person-years. CONCLUSIONS: Type 1 diabetes risk remained high in children who had developed multiple β-cell autoantibodies even when individual autoantibodies reverted. We suggest that monitoring children with single autoantibodies for at least 1 year after seroconversion is beneficial for stratification of type 1 diabetes risk. AU - Vehik, K.* AU - Lynch, K.F.* AU - Schatz, D.A.* AU - Akolkar, B.* AU - Hagopian, W. AU - Rewers, M.* AU - She, J.X.* AU - Simell, O.* AU - Toppari, J.* AU - Ziegler, A.-G. AU - Lernmark, A.* AU - Bonifacio, E.* AU - Krischer, J.P.* AU - TEDDY Study Group (Beyerlein, A. AU - Hummel, M. AU - Hummel, S. AU - Janz, N. AU - Knopff, A. AU - Peplow, C. AU - Roth, R. AU - Scholz, M. AU - Stock, J. AU - Strauss, E. AU - Warncke, K. AU - Wendel, L. AU - Winkler, C.) C1 - 48835 C2 - 41440 CY - Alexandria SP - 1535-1542 TI - Reversion of β-cell autoimmunity changes risk of type 1 diabetes: TEDDY study. JO - Diabetes Care VL - 39 IS - 9 PB - Amer Diabetes Assoc PY - 2016 SN - 0149-5992 ER - TY - JOUR AB - Clinical type 1 diabetes is preceded by an asymptomatic phase that can be identified by serum islet autoantibodies. This perspective proposes that there is now sufficient evidence to allow a broader use of islet autoantibodies as biomarkers to diagnose type 1 diabetes that is already at an asymptomatic stage, so that attempts to prevent clinical hyperglycemia become a feature of disease management. Prediction would first, therefore, shift toward the use of genetic and other biomarkers to determine the likelihood that islet autoimmunity will develop in an infant, and second, toward metabolic assessment to stage and biomarkers to determine the rate of progression to hyperglycemia in children in whom islet autoimmunity is diagnosed. A case is presented for future comprehensive risk assessment that commences at birth and includes attempts to predict, stage, and prevent initiation and progression of the disease process at multiple stages. The biomarkers required achieving this level of sophistication and dissemination are discussed. AU - Bonifacio, E. C1 - 44913 C2 - 37138 SP - 989-996 TI - Predicting type 1 diabetes using biomarkers. JO - Diabetes Care VL - 38 IS - 6 PY - 2015 SN - 0149-5992 ER - TY - JOUR AU - Brandmaier, S. AU - Xu, T. AU - Illig, T.* AU - Suhre, K. AU - Adamski, J. AU - Wang-Sattler, R. C1 - 47421 C2 - 39317 SP - e216-e217 TI - Response to Comment on Xu et al. Effects of metformin on metabolite profiles and LDL cholesterol in patients with type 2 diabetes. Diabetes Care 2015;38:1858-1867. JO - Diabetes Care VL - 38 IS - 12 PY - 2015 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE: Inflammatory processes have been implicated in the pathogenesis of painful neuropathy in rodents, but the relationship between inflammatory biomarkers and painful distal sensorimotor polyneuropathy (DSPN) has not been assessed in population-based studies. Therefore, we investigated whether circulating levels of seven pro- and anti-inflammatory immune mediators were associated with painful DSPN in older individuals in a large population-based study. RESEARCH DESIGN AND METHODS: The study population consisted of individuals with painless (n = 337) and painful DSPN (n = 54) from a source population (n = 1,047) of men and women aged 61-82 years who participated in the German KORA F4 survey (2006-2008). We measured circulating levels of seven immune mediators and assessed their associations with the presence of painful DSPN using multiple logistic regression models. RESULTS: After adjustment for age and sex, we found positive associations between serum concentrations of the cytokine interleukin (IL)-6 and the soluble intercellular adhesion molecule (sICAM)-1 and painful DSPN (P = 0.004 and P = 0.005, respectively), whereas no associations were observed for C-reactive protein, IL-18, tumor necrosis factor-α, adiponectin, and IL-1 receptor antagonist (IL-1RA, P = 0.07-0.38). Associations between IL-6 and sICAM-1 and painful DSPN remained significant after additional adjustment for waist circumference, height, hypertension, cholesterol, smoking, alcohol intake, physical activity, history of myocardial infarction and/or stroke, presence of other neurological conditions, and use of nonsteroidal anti-inflammatory drugs (P = 0.005 and P = 0.016, respectively). CONCLUSIONS: Painful DSPN is linked to systemic subclinical and vascular inflammation in the older population independent of anthropometric, lifestyle, and metabolic confounders. AU - Herder, C.* AU - Bongaerts, B.W.* AU - Rathmann, W.* AU - Heier, M. AU - Kowall, B.* AU - Koenig, W.* AU - Thorand, B. AU - Roden, M.* AU - Meisinger, C. AU - Ziegler, D.* C1 - 32559 C2 - 35145 SP - 91-96 TI - Differential association between biomarkers of subclinical inflammation and painful polyneuropathy: Results from the KORA F4 study. JO - Diabetes Care VL - 38 IS - 1 PY - 2015 SN - 0149-5992 ER - TY - JOUR AB - Insights from prospective, longitudinal studies of individuals at risk for developing type 1 diabetes have demonstrated that the disease is a continuum that progresses sequentially at variable but predictable rates through distinct identifiable stages prior to the onset of symptoms. Stage 1 is defined as the presence of β-cell autoimmunity as evidenced by the presence of two or more islet autoantibodies with normoglycemia and is presymptomatic, stage 2 as the presence of β-cell autoimmunity with dysglycemia and is presymptomatic, and stage 3 as onset of symptomatic disease. Adoption of this staging classification provides a standardized taxonomy for type 1 diabetes and will aid the development of therapies and the design of clinical trials to prevent symptomatic disease, promote precision medicine, and provide a framework for an optimized benefit/risk ratio that will impact regulatory approval, reimbursement, and adoption of interventions in the early stages of type 1 diabetes to prevent symptomatic disease. AU - Insel, R.A.* AU - Dunne, J.L.* AU - Atkinson, M.A.* AU - Chiang, J.L.* AU - Dabelea, D.* AU - Gottlieb, P.A.* AU - Greenbaum, C.J.* AU - Herold, K.C.* AU - Krischer, J.P.* AU - Lernmark, A.* AU - Ratner, R.E.* AU - Rewers, M.J.* AU - Schatz, D.A.* AU - Skyler, J.S.* AU - Sosenko, J.M.* AU - Ziegler, A.-G. C1 - 46962 C2 - 39091 SP - 1964-1974 TI - Staging presymptomatic type 1 diabetes: A scientific statement of JDRF, the Endocrine Society, and the American Diabetes Association. JO - Diabetes Care VL - 38 IS - 10 PY - 2015 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE: Gut microbiome dysbiosis is associated with numerous diseases, including type 1 diabetes. This pilot study determines how geographical location affects the microbiome of infants at high risk for type 1 diabetes in a population of homogenous HLA class II genotypes. RESEARCH DESIGN AND METHODS: High-throughput 16S rRNA sequencing was performed on stool samples collected from 90 high-risk, nonautoimmune infants participating in The Environmental Determinants of Diabetes in the Young (TEDDY) study in the U.S., Germany, Sweden, and Finland. RESULTS: Study site-specific patterns of gut colonization share characteristics across continents. Finland and Colorado have a significantly lower bacterial diversity, while Sweden and Washington state are dominated by Bifidobacterium in early life. Bacterial community diversity over time is significantly different by geographical location. CONCLUSIONS: The microbiome of high-risk infants is associated with geographical location. Future studies aiming to identify the microbiome disease phenotype need to carefully consider the geographical origin of subjects. AU - Kemppainen, K.M.* AU - Ardissone, A.N.* AU - Davis-Richardson, A.G.* AU - Fagen, J.R.* AU - Gano, K.A.* AU - León-Novelo, L.G.* AU - Vehik, K.* AU - Casella, G.* AU - Simell, O.* AU - Ziegler, A.-G. AU - Rewers, M.J.* AU - Lernmark, A.* AU - Hagopian, W.* AU - She, J.X.* AU - Krischer, J.P.* AU - Akolkar, B.* AU - Schatz, D.A.* AU - Atkinson, M.A.* AU - Triplett, E.W.* 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 - 43041 C2 - 35958 CY - Alexandria SP - 329-332 TI - Early childhood gut microbiomes show strong geographic differences among subjects at high risk for type 1 diabetes. JO - Diabetes Care VL - 38 IS - 2 PB - Amer Diabetes Assoc PY - 2015 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE: Impaired brain insulin action has been linked to obesity, type 2 diabetes, and neurodegenerative diseases. To date, the central nervous effects of insulin in obese humans still remain ill-defined, and no study thus far has evaluated the specific brain areas affected by insulin resistance. RESEARCH DESIGN AND METHODS: In 25 healthy lean and 23 overweight/obese participants, we performed magnetic resonance imaging to measure cerebral blood flow (CBF) before and 15 and 30 min after application of intranasal insulin or placebo. Additionally, participants explicitly rated pictures of high-caloric savory and sweet food 60 min after the spray for wanting and liking. RESULTS: In response to insulin compared with placebo, we found a significant CBF decrease in the hypothalamus in both lean and overweight/obese participants. The magnitude of this response correlated with visceral adipose tissue independent of other fat compartments. Furthermore, we observed a differential response in the lean compared with the overweight/obese group in the prefrontal cortex, resulting in an insulin-induced CBF reduction in lean participants only. This prefrontal cortex response significantly correlated with peripheral insulin sensitivity and eating behavior measures as disinhibition and food craving. Behaviorally, we were able to observe a significant reduction for the wanting of sweet foods after insulin application in lean men only. CONCLUSIONS: Brain insulin action was selectively impaired in the prefrontal cortex in overweight and obese adults and in the hypothalamus in participants with high visceral adipose tissue, potentially promoting an altered homeostatic set point and reduced inhibitory control contributing to overeating behavior. AU - Kullmann, S. AU - Heni, M. AU - Veit, R. AU - Scheffler, K.* AU - Machann, J. AU - Häring, H.-U. AU - Fritsche, A. AU - Preissl, H. C1 - 43922 C2 - 36637 SP - 1044-1050 TI - Selective insulin resistance in homeostatic and cognitive control brain areas in overweight and obese adults. JO - Diabetes Care VL - 38 IS - 6 PY - 2015 SN - 0149-5992 ER - TY - JOUR AU - Shariful Islam, S.M.* AU - Niessen, L.W.* AU - Ferrari, U. AU - Ali, L.* AU - Seissler, J. AU - Lechner, A. C1 - 46416 C2 - 37549 CY - Alexandria SP - e112-e113 TI - Effects of mobile phone SMS to improve glycemic control among patients with type 2 diabetes in Bangladesh: A prospective, parallel-group, randomized controlled trial. JO - Diabetes Care VL - 38 IS - 8 PB - Amer Diabetes Assoc PY - 2015 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE: While it is known that there is progression to diabetes in <10 years in 70% of children with two or more islet autoantibodies, predictors of the progression to diabetes are only partially defined. RESEARCH DESIGN AND METHODS: The Environmental Determinants of Diabetes in the Young (TEDDY) study has observed 8,503 children who were at increased genetic risk for autoimmune diabetes. Insulin autoantibodies (IAAs), GAD65 autoantibodies (GADAs), and insulinoma-associated protein 2 autoantibodies (IA-2As) were measured every 3 months until 4 years of age and every 6 months thereafter; if results were positive, the autoantibodies were measured every 3 months. RESULTS: Life table analysis revealed that the cumulative incidence of diabetes by 5 years since the appearance of the first autoantibody differed significantly by the number of positive autoantibodies (47%, 36%, and 11%, respectively, in those with three autoantibodies, two autoantibodies, and one autoantibody, P < 0.001). In time-varying survival models adjusted for first-degree relative status, number of autoantibodies, age at first persistent confirmed autoantibodies, and HLA genotypes, higher mean IAA and IA-2A levels were associated with an increased risk of type 1 diabetes in children who were persistently autoantibody positive (IAAs: hazard ratio [HR] 8.1 [95% CI 4.6-14.2]; IA-2A: HR 7.4 [95% CI 4.3-12.6]; P < 0.0001]. The mean GADA level did not significantly affect the risk of diabetes. CONCLUSIONS: In the TEDDY study, children who have progressed to diabetes usually expressed two or more autoantibodies. Higher IAA and IA-2A levels, but not GADA levels, increased the risk of diabetes in those children who were persistently autoantibody positive. AU - Steck, A.K.* AU - Vehik, K.* AU - Bonifacio, E.* AU - Lernmark, A.* AU - Ziegler, A.-G. AU - Hagopian, W.A.* AU - She, J.* AU - Simell, O.* AU - Akolkar, B.* AU - Krischer, J.* AU - Schatz, D.* AU - Rewers, M.J.* 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 - 43262 C2 - 36371 CY - Alexandria SP - 808-813 TI - Predictors of progression from the appearance of islet autoantibodies to early childhood diabetes: The Environmental Determinants of Diabetes in the Young (TEDDY). JO - Diabetes Care VL - 38 IS - 5 PB - Amer Diabetes Assoc PY - 2015 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE Metformin is used as a first-line oral treatment for type 2 diabetes (T2D). However, the underlying mechanism is not fully understood. Here, we aimed to comprehensively investigate the pleiotropic effects of metformin. RESEARCH DESIGN AND METHODS We analyzed both metabolomic and genomic data of the population-based KORA cohort. To evaluate the effect of metformin treatment on metabolite concentrations, we quantified 131 metabolites in fasting serum samples and used multivariable linear regression models in three independent cross-sectional studies (n = 151 patients with T2D treated with metformin [mt-T2D]). Additionally, we used linear mixed-effect models to study the longitudinal KORA samples (n = 912) and performed mediation analyses to investigate the effects of metformin intake on blood lipid profiles. We combined genotyping data with the identified metformin-associated metabolites in KORA individuals (n = 1,809) and explored the underlying pathways. RESULTS We found significantly lower (P < 5.0E-06) concentrations of three metabolites (acyl-alkyl phosphatidylcholines [PCs]) when comparing mt-T2D with four control groups who were not using glucose-lowering oral medication. These findings were controlled for conventional risk factors of T2D and replicated in two independent studies. Furthermore, we observed that the levels of these metabolites decreased significantly in patients after they started metformin treatment during 7 years’ follow-up. The reduction of these metabolites was also associated with a lowered blood level of LDL cholesterol (LDL-C). Variations of these three metabolites were significantly associated with 17 genes (including FADS1 and FADS2) and controlled by AMPK, a metformin target. CONCLUSIONS Our results indicate that metformin intake activates AMPK and consequently suppresses FADS, which leads to reduced levels of the three acyl-alkyl PCs and LDL-C. Our findings suggest potential beneficial effects of metformin in the prevention of cardiovascular disease.   AU - Xu, T. AU - Brandmaier, S. AU - Messias, A.C. AU - Herder, C.* AU - Draisma, H.H.* AU - Demirkan, A.* AU - Yu, Z. AU - Ried, J.S. AU - Haller, T.* AU - Heier, M. AU - Campillos, M. AU - Fobo, G. AU - Stark, R.G. AU - Holzapfel, C.* AU - Adam, J. AU - Chi, S. AU - Rotter, M. AU - Panni, T. AU - Quante, A.S. AU - He, Y.* AU - Prehn, C. AU - Römisch-Margl, W. AU - Kastenmüller, G. AU - Willemsen, G.* AU - Pool, R.* AU - Kasa, K.* AU - van Dijk, K.W.* AU - Hankemeier, T.* AU - Meisinger, C. AU - Thorand, B. AU - Ruepp, A. AU - Hrabě de Angelis, M. AU - Li, Y.* AU - Wichmann, H.-E. AU - Stratmann, B.* AU - Strauch, K. AU - Metspalu, A.* AU - Gieger, C. AU - Suhre, K. AU - Adamski, J. AU - Illig, T. AU - Rathmann, W.* AU - Roden, M.* AU - Peters, A. AU - van Duijn, C.M.* AU - Boomsma, D.I.* AU - Meitinger, T. AU - Wang-Sattler, R. C1 - 46520 C2 - 37624 SP - 1858-1867 TI - Effects of metformin on metabolite profiles and LDL cholesterol in patients with type 2 diabetes. JO - Diabetes Care VL - 38 IS - 10 PY - 2015 SN - 0149-5992 ER - TY - JOUR AU - Beyerlein, A. AU - Chmiel, R. AU - Hummel, S. AU - Winkler, C. AU - Bonifacio, E.* AU - Ziegler, A.-G. C1 - 32001 C2 - 34927 CY - Alexandria SP - e194-e195 TI - Timing of gluten introduction and islet autoimmunity in young children: Updated results from the BABYDIET study. JO - Diabetes Care VL - 37 IS - 9 PB - Amer Diabetes Assoc PY - 2014 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE Patients with latent autoimmune diabetes in adults (LADA) express autoantibodies against the 65-kDa isoform of GAD antibody (GADA). Intervention with recombinant human GAD65 formulated with aluminium hydroxide (GAD-alum) given twice subcutaneously to LADA patients at intervals of 4 weeks was safe and did not compromise β-cell function in a Phase II clinical trial. GADA affinity has been shown to predict progression to type 1 diabetes. Here, we asked whether GADA affinity was affected by the GAD65 antigen-specific vaccination and/or associated with β-cell function in participants of this trial. RESEARCH DESIGN AND METHODS GADA affinity was measured in sera of 46 LADA patients obtained prior to the 1st week and 20 weeks after the second injection with GAD-alum or placebo using competitive binding experiments with [125I]-labeled and unlabeled human GAD65. RESULTS At baseline, GADA affinities ranged from 1.9 × 107 to 5.0 × 1012 L/mol (median 2.8 × 1010 L/mol) and were correlated with GADA titers (r = 0.47; P = 0.0009), fasting (r = −0.37; P = 0.01) and stimulated (r = −0.40; P = 0.006) C-peptide concentrations, and HbA1c (r = 0.39; P = 0.007). No significant changes in affinity were observed from baseline to week 24. Patients with GADA affinities in the lower first quartile (<4 × 109 L/mol) had better preserved fasting C-peptide concentrations at baseline than those with higher affinities (mean 1.02 vs. 0.66 nmol/L; P = 0.004) and retained higher concentrations over 30 months of follow-up (mean 1.26 vs. 0.62 nmol/L; P = 0.01). CONCLUSIONS Intervention with GAD-alum in LADA patients had no effect on GADA affinity. Our data suggest that patients with low GADA affinity have a prolonged preservation of residual β-cell function. AU - Krause, S. AU - Landherr, U.* AU - Agardh, C.-D.* AU - Hausmann, S. AU - Link, K.* AU - Hansen, J.M.* AU - Lynch, K.F.* AU - Powell, M.* AU - Furmaniak, J.* AU - Rees-Smith, B.* AU - Bonifacio, E.* AU - Ziegler, A.-G. AU - Lernmark, A.* AU - Achenbach, P. C1 - 30757 C2 - 33835 CY - Alexandria SP - 1675-1680 TI - GAD autoantibody affinity in adult patients with latent autoimmune diabetes, the study participants of a GAD65 vaccination trial. JO - Diabetes Care VL - 37 IS - 6 PB - Amer Diabetes Assoc PY - 2014 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVELittle is known about the impact of diabetes self-management behavior (SMB) on long-term outcomes. We aimed to examine the association among patient-reported SMB, intermediate clinical outcomes, and mortality in patients with type 2 diabetes.RESEARCH DESIGN AND METHODSData were collected from 340 patients with type 2 diabetes of the KORA-A study (1997/1998) who were recruited from two previous population-based surveys (n = 161) and a myocardial infarction registry (n = 179) in southern Germany. Based on previous methodological work, a high level of SMB was defined as being compliant with at least four of six different self-care dimensions, comprising physical exercise, foot care, blood glucose self-monitoring, weight monitoring, having a diet plan, and keeping a diabetes diary. The vital status of the participants was observed until 2009. Multivariable linear, logistic, and Cox regression models were applied to assess the association with intermediate clinical outcomes at baseline and to predict mortality over the follow-up period, adjusted for sociodemographic, behavioral, and disease-related factors.RESULTSIn the cross-sectional perspective, a high level of SMB was weakly associated with a lower glycated hemoglobin A1c level (-0.44% [-4.8 mmol/mol] [95% CI -0.88-0.00]), but not with low-density lipoprotein cholesterol, systolic blood pressure, or the presence of microalbuminuria, peripheral arterial disease, or polyneuropathy. During a mean follow-up time of 11.6 years, 189 patients died. SMB was a preventive factor for all-cause (hazard ratio 0.61 [95% CI 0.40-0.91]) and cardiovascular mortality (0.65 [95% CI 0.41-1.03]).CONCLUSIONSAlthough measuring SMB is difficult and the used operationalization might be limited, our results give some indication that a high level of SMB is associated with prolonged life expectancy in patients with type 2 diabetes and highlight the potential impact of the patients' active contribution on the long-term trajectory of the disease. We assume that the used proxy for SMB is associated with unmeasured, but important, dimensions of health behavior. AU - Laxy, M. AU - Mielck, A. AU - Hunger, M. AU - Schunk, M. AU - Meisinger, C. AU - Rückert, I.-M. AU - Rathmann, W.* AU - Holle, R. C1 - 30919 C2 - 34020 CY - Alexandria SP - 1604-1612 TI - The association between patient-reported self-management behavior, intermediate clinical outcomes, and mortality in patients with type 2 diabetes: Results from the KORA-A study. JO - Diabetes Care VL - 37 IS - 6 PB - Amer Diabetes Assoc PY - 2014 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVEMothers of children at risk for type 1 diabetes report engaging in preventive behaviors. The purpose of this study is to further document these actions in an international, longitudinal sample and examine variables that predict whether mothers engage in these behaviors.RESEARCH DESIGN AND METHODSThis study examined an international sample (from Finland, Germany, Sweden, and the U.S.) from the naturalistic, longitudinal The Environmental Determinants of Diabetes in the Young (TEDDY) study, which tracked children genetically at risk for type 1 diabetes from birth to age 15 years. Mothers of 7,613 infants aged 6 months and 6,503 infants aged 15 months completed questionnaires assessing psychosocial factors and actions intended to prevent diabetes.RESULTSMany mothers (29.9% at 6 months and 42.8% at 15 months) reported engaging in a behavior intended to prevent type 1 diabetes, with the largest percentages (20.9-29.2%) reporting making changes to their child's diet (e.g., reducing the consumption of sweets and carbohydrates). Factors related to engaging in preventive behaviors include older maternal age; higher maternal education; minority status; having only one child; having a first-degree relative with type 1 diabetes; being from a country other than Sweden; having an accurate perception of the child's increased risk for developing diabetes; having postpartum depression, maternal anxiety, and worry about the risk of diabetes; and believing that diabetes can be prevented.CONCLUSIONSThe findings of this study suggest that many mothers engage in actions to prevent diabetes and highlight the importance of tracking these behaviors to ensure the validity of naturalistic observational studies. AU - Smith, L.B.* AU - Lynch, K.F.* AU - Baxter, J.* AU - Lernmark, B.* AU - Roth, R.* AU - Simell, T.* AU - Johnson, S.B.* AU - TEDDY Study Group (Ziegler, A.-G. AU - Beyerlein, A. AU - Henneberger, L. AU - Hummel, M. AU - Hummel, S. AU - Knopff, A. AU - Krause, S. AU - Peplow, C. AU - Pflüger, M. AU - Roth, R. AU - Schenkel, J. AU - Stock, J. AU - Strauss, E. AU - Warncke, K. AU - Winkler, C.) C1 - 44224 C2 - 39399 CY - Alexandria SP - 325-331 TI - Factors associated with maternal-reported actions to prevent type 1 diabetes in the first year of the TEDDY study. JO - Diabetes Care VL - 37 IS - 2 PB - Amer Diabetes Assoc PY - 2014 SN - 0149-5992 ER - TY - JOUR AU - Stefan, N. AU - Peter, A. AU - Häring, H.-U. C1 - 42806 C2 - 35353 SP - e278-279 TI - Comment on Hedderson et al. Prepregnancy SHBG concentrations and risk for subsequently developing gestational diabetes mellitus. Diabetes Care 2014;37:1296-1303. JO - Diabetes Care VL - 37 IS - 12 PY - 2014 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE Distal sensorimotor polyneuropathy (DSPN) is a severe complication of type 2 diabetes. This study aimed to assess the prevalence of unawareness of DSPN in prediabetes and diabetes in a sample of the older population of Augsburg, Germany. RESEARCH DESIGN AND METHODS Glucose tolerance status was determined in 61- to 82-year-old participants of the population-based KORA F4 Study (2006-2008) (n = 1,100). Clinical DSPN was defined as the presence of bilaterally impaired foot-vibration perception and/or bilaterally impaired foot-pressure sensation. DSPN case subjects were considered unaware of their condition when answering "no" to the question, "Has a physician ever told you that you are suffering from nerve damage, neuropathy, polyneuropathy, or diabetic foot?" RESULTS Clinical DSPN was prevalent in 154 (14%) participants, 140 of whom were unaware of their disorder. At a prevalence of 23.9% (95% CI 12.6-38.8), participants with combined impaired fasting glucose and impaired glucose tolerance had the highest prevalence of DSPN. Of these, 10 of 11 (91%) were unaware of having clinical DSPN. Participants with known diabetes had an equally high prevalence of DSPN [22.0% (16.2-28.9)], with 30 of the 39 (77%) DSPN case subjects unaware of having the disorder. Among subjects with known diabetes who reported to have had their feet examined by a physician, 18 of 25 (72%) clinical DSPN case subjects emerged unaware of having DSPN. CONCLUSIONS Our findings showed a high prevalence of unawareness of having clinical DSPN among the prediabetic and diabetic groups and an insufficient frequency of professional foot examinations, suggesting inadequate attention to diabetic foot prevention practice. AU - Bongaerts, B.W.* AU - Rathmann, W.* AU - Heier, M. AU - Kowall, B.* AU - Herder, C.* AU - Stöckl, D. AU - Meisinger, C. AU - Ziegler, D.* C1 - 24380 C2 - 31531 SP - 1141-1146 TI - Older subjects with diabetes and prediabetes are frequently unaware of having distal sensorimotor polyneuropathy: The KORA F4 study. JO - Diabetes Care VL - 36 IS - 5 PB - Amer. Diabetes Assoc. PY - 2013 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE Inflammatory processes have been implicated in the pathogenesis of diabetic distal sensorimotor polyneuropathy (DSPN), but their possible relationship has not been assessed at the population level. RESEARCH DESIGN AND METHODS We determined serum concentrations of mediators of subclinical inflammation among 1,047 participants 61-82 years of age from the population-based Cooperative Health Research in the Region of Augsburg (KORA) F4 study (Germany). Logistic and linear regression models were fitted to assess associations between immune mediators (log-transformed) and the presence of clinical DSPN (dichotomous variable) or Michigan Neuropathy Screening Instrument (MNSI) examination score (continuous variable), respectively. RESULTS Serum concentrations of the anti-inflammatory interleukin (IL)-1 receptor antagonist (IL-1RA) were positively associated with the presence of DSPN and higher MNSI scores in age-adjusted and sex-adjusted analyses, whereas IL-6, IL-18, and soluble intercellular adhesion molecule-1 were positively associated with only MNSI scores. No associations were observed for adiponectin, C-reactive protein, or tumor necrosis factor-α. Associations for IL-1RA and IL-6 with the MNSI score remained statistically significant after additional adjustment for waist circumference, height, hypertension, cholesterol, smoking, alcohol intake, physical activity, history of myocardial infarction or stroke, presence of neurological conditions, and use of nonsteroidal anti-inflammatory drugs. CONCLUSIONS We conclude that DSPN is linked to proinflammatory and anti-inflammatory, possibly compensatory, processes in the older general population. Future studies should clarify the temporal sequence and causality of these associations. AU - Herder, C.* AU - Bongaerts, B.W.* AU - Rathmann, W.* AU - Heier, M. AU - Kowall, B.* AU - Koenig, W.* AU - Thorand, B. AU - Roden, M.* AU - Meisinger, C. AU - Ziegler, D.* C1 - 28384 C2 - 33346 SP - 3663-3870 TI - Association of subclinical inflammation with polyneuropathy in the older population: KORA F4 study. JO - Diabetes Care VL - 36 IS - 11 PB - Amer. Diabetes Assoc. PY - 2013 SN - 0149-5992 ER - TY - JOUR AU - Icks, A.* AU - Claessen, H.* AU - Strassburger, K.* AU - Tepel, M.* AU - Waldeyer, R.* AU - Chernyak, N.* AU - Albers, B.* AU - Baechle, C.* AU - Rathmann, W.* AU - Meisinger, C. AU - Thorand, B. AU - Hunger, M. AU - Schunk, M. AU - Stark, R.G. AU - Rückert, I.-M. AU - Peters, A. AU - Huth, C. AU - Stöckl, D. AU - Giani, G.* AU - Holle, R. C1 - 23926 C2 - 31303 SP - 53-54 TI - Drug costs in prediabetes and undetected diabetes compared with diagnosed diabetes and normal glucose tolerance: Results from the population-based KORA survey in Germany. JO - Diabetes Care VL - 36 IS - 4 PB - Amer. Diabetes Assoc. PY - 2013 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVENonalcoholic fatty liver (NAFL) is thought to contribute to insulin resistance and its metabolic complications. However, some individuals with NAFL remain insulin sensitive. Mechanisms involved in the susceptibility to develop insulin resistance in humans with NAFL are largely unknown. We investigated circulating markers and mechanisms of a metabolically benign and malignant NAFL by applying a metabolomic approach.RESEARCH DESIGN AND METHODSA total of 265 metabolites were analyzed before and after a 9-month lifestyle intervention in plasma from 20 insulin-sensitive and 20 insulin-resistant subjects with NAFL. The relevant plasma metabolites were then tested for relationships with insulin sensitivity in 17 subjects without NAFL and in plasma from 29 subjects with liver tissue samples.RESULTSThe best separation of the insulin-sensitive from the insulin-resistant NAFL group was achieved by a metabolite pattern including the branched-chain amino acids leucine and isoleucine, ornithine, the acylcarnitines C3:0-, C16:0-, and C18:0-carnitine, and lysophosphatidylcholine (lyso-PC) C16:0 (area under the ROC curve, 0.77 [P = 0.00023] at baseline and 0.80 [P = 0.000019] at follow-up). Among the individual metabolites, predominantly higher levels of lyso-PC C16:0, both at baseline (P = 0.0039) and at follow-up (P = 0.001), were found in the insulin-sensitive compared with the insulin-resistant subjects. In the non-NAFL groups, no differences in lyso-PC C16:0 levels were found between the insulin-sensitive and insulin-resistant subjects, and these relationships were replicated in plasma from subjects with liver tissue samples.CONCLUSIONSFrom a plasma metabolomic pattern, particularly lyso-PCs are able to separate metabolically benign from malignant NAFL in humans and may highlight important pathways in the pathogenesis of fatty liver-induced insulin resistance. AU - Lehmann, R.* AU - Franken, H.* AU - Dammeier, S.* AU - Rosenbaum, L.* AU - Kantartzis, K.* AU - Peter, A.* AU - Tell, A.* AU - Adam, P.* AU - Li, J.* AU - Xu, G.* AU - Königsrainer, A.* AU - Machann, J.* AU - Schick, F.* AU - Hrabě de Angelis, M. AU - Schwab, M.* AU - Staiger, H.* AU - Schleicher, E.* AU - Gastaldelli, A.* AU - Fritsche, A.* AU - Häring, H.-U.* AU - Stefan, N.* C1 - 23628 C2 - 31221 SP - 2331-2338 TI - Circulating lysophosphatidylcholines are markers of a metabolically benign nonalcoholic fatty liver. JO - Diabetes Care VL - 36 IS - 8 PB - American Diabetes Assoc. PY - 2013 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE We sought to investigate whether elevated levels of acute-phase serum amyloid A (A-SAA) protein precede the onset of type 2 diabetes independently of other risk factors, including parameters of glucose metabolism. RESEARCH DESIGN AND METHODS Within the population-based Cooperative Health Research in the Region of Augsburg (KORA) S4 study, we measured A-SAA concentrations in 836 initially nondiabetic subjects (55-74 years of age) without clinically overt inflammation who participated in a 7-year follow-up examination including an oral glucose tolerance test. RESULTS A-SAA concentrations were significantly associated with incident type 2 diabetes (odds ratio [OR] for a one-SD increase of A-SAA adjusted for age and sex = 1.28 [95% CI 1.08-1.53], P = 0.005), particularly in younger subjects (P value for interaction = 0.047). The association attenuated when adjusting for parameters of glucose metabolism (fasting glucose, fasting insulin, HbA1c, and 2-h glucose; OR 1.16 [0.95-1.42], P = 0.15). Similar analyses for high-sensitive C-reactive protein (hs-CRP) yielded the following ORs: 1.39 (1.10-1.68, P = 0.0006) and 1.13 (0.88-1.45, P = 0.34), respectively. In contrast, A-SAA concentrations were significantly associated with 2-h glucose levels at follow-up even after adjustment for parameters of glucose metabolism (P = 0.008, n = 803). CONCLUSIONS Our findings indicate similarly strong prospective associations with type 2 diabetes for A-SAA and hs-CRP and suggest a potential causal link via postchallenge hyperglycemia. AU - Marzi, C. AU - Huth, C. AU - Herder, C.* AU - Baumert, J.J. AU - Thorand, B. AU - Rathmann, W.* AU - Meisinger, C. AU - Wichmann, H.-E. AU - Roden, M.* AU - Peters, A. AU - Grallert, H. AU - Koenig, W.* AU - Illig, T. C1 - 24834 C2 - 31699 SP - 1321-1326 TI - Acute-phase serum amyloid A protein and its implication in the development of type 2 diabetes in the KORA S4/F4 study. JO - Diabetes Care VL - 36 IS - 5 PB - Amer. Diabetes Assoc. PY - 2013 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE-To assess the prevalence of distal sensorimotor polyneuropathy (DSPN) in an older population and to examine its relationship with prediabetes. RESEARCH DESIGN AND METHODS-Glucose tolerance status was determined in 61- to 82-year-old participants (n = 1,100) of the population-based Cooperative Health Research in the Region of Augsburg (KORA) F4 Survey (2006-2008). Clinical DSPN was defined as bilaterally impaired foot-vibration perception and/or foot-pressure sensation. RESULTS-Prevalence of clinical DSPN was similar in subjects with known diabetes (22.0%) and subjects with combined impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) (23.9%). Among prediabetic subgroups, IFG-IGT, but not isolated-IFG and -IGT, was associated with a higher risk of clinical DSPN, compared with normal glucose tolerance. A J-shaped association was observed between clinical DSPN and quartiles of 2-h postchallenge glucose, but not with fasting glucose and HbA(1c) levels. CONCLUSIONS-Subjects with IFG-IGT and known diabetes had a similar prevalence of clinical DSPN. Elevated 2-h postload glucose levels appeared important for disease risk. AU - Bongaerts, B.W.C.* AU - Rathmann, W.* AU - Kowall, B.* AU - Herder, C.* AU - Stöckl, D. AU - Meisinger, C. AU - Ziegler, D.* C1 - 8556 C2 - 30283 SP - 1891-1893 TI - Postchallenge hyperglycemia is positively associated with diabetic polyneuropathy: The KORA F4 study. JO - Diabetes Care VL - 35 IS - 9 PB - Amer. Diabetes Assoc. PY - 2012 SN - 0149-5992 ER - TY - JOUR AB - To test if knowledge of type 2 diabetes genetic variants improves disease prediction. We tested 40 single nucleotide polymorphisms (SNPs) associated with diabetes in 3,471 Framingham Offspring Study subjects followed over 34 years using pooled logistic regression models stratified by age (<50 years, diabetes cases = 144; or ≥50 years, diabetes cases = 302). Models included clinical risk factors and a 40-SNP weighted genetic risk score. We tested 40 single nucleotide polymorphisms (SNPs) associated with diabetes in 3,471 Framingham Offspring Study subjects followed over 34 years using pooled logistic regression models stratified by age (<50 years, diabetes cases = 144; or ≥50 years, diabetes cases = 302). Models included clinical risk factors and a 40-SNP weighted genetic risk score. Knowledge of common genetic variation appropriately reclassifies younger people for type 2 diabetes risk beyond clinical risk factors but not older people. AU - de Miguel-Yanes, J.M.* AU - Shrader, P.* AU - Pencina, M.J.* AU - Fox, C.S.* AU - Manning, A.K.* AU - Grant, R.W.* AU - Dupuis, J.* AU - Florez, J.C* AU - D'Agostino, R.B, Sr.* AU - Cupples, L.A.* AU - Meigs, J.B* AU - MAGIC Investigators (Grallert, H. AU - Meisinger, C. AU - Gieger, C. AU - Thorand, B. AU - Wichmann, H.-E. AU - Illig, T.) 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.) C1 - 4691 C2 - 28472 CY - Alexandria, USA SP - 121-125 TI - Genetic risk reclassification for type 2 diabetes by age below or above 50 years using 40 type 2 diabetes risk single nucleotide polymorphisms. JO - Diabetes Care VL - 34 IS - 1 PB - Amer. Diabetes Assoc. PY - 2011 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE: To determine whether delaying the introduction of gluten in infants with a genetic risk of islet autoimmunity is feasible, safe, and may reduce the risk of type 1 diabetes-associated islet autoimmunity. RESEARCH DESIGN AND METHODS: A total of 150 infants with a first-degree family history of type 1 diabetes and a risk HLA genotype were randomly assigned to a first gluten exposure at age 6 months (control group) or 12 months (late-exposure group) and were followed 3 monthly until the age of 3 years and yearly thereafter for safety (for growth and autoantibodies to transglutaminase C [TGCAs]), islet autoantibodies to insulin, GAD, insulinoma-associated protein 2, and type 1 diabetes. RESULTS: Adherence to the dietary-intervention protocol was reported from 70% of families. During the first 3 years, weight and height were similar in children in the control and late-exposure groups, as was the probability of developing TGCAs (14 vs. 4%; P = 0.1). Eleven children in the control group and 13 children in the late-exposure group developed islet autoantibodies (3-year risk: 12 vs. 13%; P = 0.6). Seven children developed diabetes, including four in the late-exposure group. No significant differences were observed when children were analyzed as per protocol on the basis of the reported first gluten exposure of the children. CONCLUSIONS: Delaying gluten exposure until the age of 12 months is safe but does not substantially reduce the risk for islet autoimmunity in genetically at-risk children. AU - Hummel, S. AU - Pflüger, M. AU - Hummel, M. AU - Bonifacio, E.* AU - Ziegler, A.-G. C1 - 5274 C2 - 28646 SP - 1301-1305 TI - Primary dietary intervention study to reduce the risk of islet autoimmunity in children at increased risk for type 1 diabetes: The BABYDIET study. JO - Diabetes Care VL - 34 IS - 6 PB - Amer Diabetes Assoc PY - 2011 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE: We examined the association between retinol-binding protein 4 (RBP4), a novel adipokine, and prediabetes (isolated impaired fasting glucose [i-IFG], isolated impaired glucose tolerance [i-IGT], and combined IFG and IGT) in men and women aged 32-81 years. RESEARCH DESIGN AND METHODS: The analysis was based on 2,614 participants without previously diagnosed diabetes and those with newly diagnosed diabetes of the Cooperative Health Research in the Region of Augsburg (KORA) F4 Study, conducted from 2006 to 2008 in southern Germany. Plasma RBP4 was analyzed by immunonephelometry. RESULTS: In logistic regression analysis, RBP4 levels in the fourth quartile versus the first quartile were significantly associated with prediabetes (i-IGT, i-IFG, and IFG/IGT; reference normal glucose tolerance) independent of known metabolic risk factors and lifestyle variables (odds ratio 1.63 [95% CI 1.17-2.27] after multivariable adjustment). Stratification by sex showed generally similar results. CONCLUSIONS: RBP4 levels were associated with prediabetes in individuals from the general population. Prospective studies investigating the impact of RBP4 on the development of glucose intolerance are needed. AU - Meisinger, C. AU - Rückert, I.-M. AU - Rathmann, W.* AU - Döring, A. AU - Thorand, B. AU - Huth, C. AU - Kowall, B.* AU - Koenig, W.* C1 - 5260 C2 - 28732 SP - 1648-1650 TI - Retinol-binding protein 4 is associated with prediabetes in adults from the general population: The Cooperative Health Research in the Region of Augsburg (KORA) F4 Study. JO - Diabetes Care VL - 34 IS - 7 PB - Amer Diabetes Assoc PY - 2011 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE: Autoantibodies to IA-2β (IA-2βA) are important risk markers of type 1 diabetes. We report the first Diabetes Antibody Standardization Program (DASP) evaluation of IA-2βA assays. RESEARCH DESIGN AND METHODS: Thirteen laboratories from nine countries received coded sera from 50 patients with newly diagnosed type 1 diabetes and 100 healthy blood donors. IA-2βA results were analyzed using receiver operating characteristic (ROC) curves. Concordance of antibody levels was compared using counts per minute (cpm), local and standard curve-derived common units. RESULTS: Median laboratory-assigned sensitivity was 47% (interquartile range [IQR] 45-51), specificity 98% (IQR 95-99), adjusted sensitivity at 95% specificity 50% (IQR 49-53), and area under the ROC curve 0.70 (IQR 0.69-0.73). Use of common IA-2βA units improved concordance between assays compared with local units and cpm (P < 0.0001). CONCLUSIONS: IA-2βA assays in multiple laboratories worldwide achieved good concordance and high specificity for type 1 diabetes. IA-2βA are suitable for inclusion in autoantibody testing for risk assessment in prediabetes AU - Schlosser, M.* AU - Mueller, P.W.* AU - Achenbach, P. AU - Lampasona, V.* AU - Bingley, P.J* AU - Participating Laboratories* C1 - 6876 C2 - 29379 CY - Alexandria SP - 2410-2412 TI - Diabetes antibody standardization program: First evaluation of assays for autoantibodies to IA-2β. JO - Diabetes Care VL - 34 IS - 11 PY - 2011 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE To assess the association between serum 25-hydroxyvitamin D (25-OHD) and incident type 2 diabetes and to determine whether the association is mediated by subclinical inflammation. RESEARCH DESIGN AND METHODS Using a case-cohort design, baseline levels of 25-OHD were measured in 416 case subjects with incident type 2 diabetes and 1,267 noncase subjects selected from a source population of 7,936 middle-aged participants in the population-based Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA)/Cooperative Health Research in the Region of Augsburg (KORA) study. RESULTS A significant inverse association was observed between serum 25-OHD and incident type 2 diabetes after adjustment for diabetes risk factors and season. The hazard ratio (HR) and 95% CI comparing tertile extremes was 0.63 (0.44-0.90) (P(trend) = 0.010). Further adjustment for C-reactive protein, interleukin-6, soluble intercellular adhesion molecule-1, and interferon-γ-inducible protein-10 attenuated this association by 16% (HR 0.73 [0.50-1.05], P = 0.090). CONCLUSIONS Vitamin D status is inversely related to type 2 diabetes risk and our data suggest that this association may be partially mediated by subclinical inflammation. AU - Thorand, B. AU - Zierer, A. AU - Huth, C. AU - Linseisen, J. AU - Meisinger, C. AU - Roden, M.* AU - Peters, A. AU - Koenig, W.* AU - Herder, C.* C1 - 6520 C2 - 28903 SP - 2320-2322 TI - Effect of serum 25-hydroxyvitamin D on risk for type 2 diabetes may be partially mediated by subclinical inflammation: Results from the MONICA/KORA Augsburg study. JO - Diabetes Care VL - 34 IS - 10 PB - American Diabetes Assoc. PY - 2011 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE: Gestational diabetes mellitus (GDM) is associated with high birth weight in the offspring. This may lead to overweight and insulin resistance during childhood. The aim of the study was to assess the impact of GDM on overweight risk and insulin resistance in offspring. RESEARCH DESIGN AND METHODS: BMI measurements were collected at age 2, 8, and 11 years from 232 offspring of mothers with GDM (OGDM) and compared with those from 757 offspring of mothers with type 1 diabetes (OT1D) and 431 offspring of nondiabetic mothers (ONDM) born between 1989 and 2000. Insulin resistance (homeostasis model assessment of insulin resistance [HOMA-IR]) was determined at age 8 and 11 years in 751 children (74 OGDM). Overweight was defined as BMI percentile >or=90; insulin resistance was defined by HOMA-IR. RESULTS: Overweight prevalence was increased in OGDM compared with OT1D and to ONDM throughout childhood (age 11 years 31.1, 15.8, and 15.5%; P = 0.005). Maternal obesity was an important predictor of overweight risk in children (age 11 years odds ratio 7.0 [95% CI 1.8-27.7]; P = 0.006); birth size and maternal smoking during pregnancy were inconsistently associated with and treatment of GDM during pregnancy did not affect overweight risk. HOMA-IR was increased in OGDM compared with offspring of ONDM mothers (P = 0.01, adjusted for sex and age) and was associated with the child's BMI (P = 0.004). CONCLUSIONS: Overweight and insulin resistance in children is increased in OGDM compared with OT1D or ONDM. The finding that overweight risk is associated mainly with maternal obesity suggests that familial predisposition contributes to childhood growth in these offspring. AU - Boerschmann, H.* AU - Pflüger, M. AU - Henneberger, L. AU - Ziegler, A.-G. AU - Hummel, S. C1 - 4393 C2 - 28066 SP - 1845-1849 TI - Prevalence and predictors of overweight and insulin resistance in offspring of mothers with gestational diabetes mellitus. JO - Diabetes Care VL - 33 IS - 8 PB - American Diabetes Assoc. PY - 2010 SN - 0149-5992 ER - TY - JOUR AB - The purpose of this study is to determine the optimal duration and intensity of exercise for elderly people for the prevention of the metabolic syndrome. RESEARCH DESIGN AND METHODS - The population-based Cooperative Research in the Region of Augsburg (KORA) S4 Survey with 1,653 participants aged 55-74 years was used to investigate the relationship between the metabolic syndrome and physical activity. RESULTS - Fifty-seven percent of men and 48% of women showed clinical symptoms of the metabolic syndrome. Leisure activities were common (>80% walked >30 min/day). Sports activities performed regularly for : <= 1 h per week reduced file odds of having the metabolic (odds ratio 0.70 [95% CI 0.49-1.02] for men and 0.74 [0.53-1.04] for women), and sports activities >2 h per week were even more effective (0.62 [0.42-0.92] for men and 0.59 [039-0.89] for women). In contrast, activities such as walking and cycling did not have an additional influence. CONCLUSIONS - Intense physical activity by the elderly should be promoted in addition to leisure physical activity for the prevention of the metabolic syndrome. AU - Hahn, V. AU - Halle, M.* AU - Schmidt-Trucksäss, A.* AU - Rathmann, W.* AU - Meisinger, C. AU - Mielck, A. C1 - 560 C2 - 26125 SP - 511-513 TI - Physical activity and the metabolic syndrome in elderly German men and women: Results from the population-based KORA survey. JO - Diabetes Care VL - 32 IS - 3 PB - Amer Diabetes Assoc PY - 2009 SN - 0149-5992 ER - TY - JOUR AB - Subclinical inflammation leads to insulin resistance and beta-cell dysfunction. This study aimed to assess whether levels of circulating transforming growth factor-beta1 (TGF-beta1)-a central, mainly immunosuppressive, and anti-inflammatory cytokine-were associated with incident type 2 diabetes. RESEARCH DESIGN AND METHODS: We measured serum levels of TGF-beta1 from 460 individuals with and 1,474 individuals without incident type 2 diabetes in a prospective case-cohort study within the population-based MONICA (MONItoring of Trends and Determinants in CArdiovascular Disease)/KORA (Cooperative Health Research in the Region of Augsburg) cohort. RESULTS: Elevated TGF-beta1 concentrations were associated with higher, not lower, risk for type 2 diabetes (age-, sex-, and survey-adjusted hazard ratios [95% CI] for increasing TGF-beta1 tertiles: 1.0, 1.08 [0.83-1.42], and 1.41 [1.08-1.83]; P(for) (trend) = 0.012). Adjustment for BMI and metabolic and lifestyle factors had virtually no impact on the effect size. CONCLUSIONS: Elevated serum concentrations of the cytokine TGF-beta1 indicate an increased risk for type 2 diabetes. TGF-beta1 may be upregulated to counterbalance metabolic and immunological disturbances preceding type 2 diabetes. AU - Herder, C.* AU - Zierer, A. AU - Koenig, W.* AU - Roden, M.* AU - Meisinger, C. AU - Thorand, B. C1 - 81 C2 - 26912 SP - 1921-1923 TI - Transforming growth factor-β1 and incident type 2 diabetes: Results from the MONICA/KORA case-cohort study, 1984-2002. JO - Diabetes Care VL - 32 IS - 10 PB - American Diabetes Assoc. PY - 2009 SN - 0149-5992 ER - TY - JOUR AB - Subclinical inflammation represents a risk factor of type 2 diabetes and several diabetes complications, but data on diabetic neuropathies are scarce. Therefore, we investigated whether circulating concentrations of acute-phase proteins, cytokines, and chemokines differ among diabetic patients with or without diabetic polyneuropathy. RESEARCH DESIGN AND METHODS - We measured 10 markers of subclinical inflammation in 227 type 2 diabetic patients with diabetic polyneuropathy who participated in the population-based MONICA/KORA Survey F3 (2004-2005; Augsburg, Germany). Diabetic polyneuropathy was diagnosed using the Michigan Neuropathy Screening Instrument (MNSI). RESULTS - After adjustment for multiple confounders, high levels of C-reactive protein and interleukin (IL)-6 were most consistently associated with diabetic polyneuropathy, high MNSI score, and specific neuropathic deficits, whereas some inverse associations were seen for IL-18. CONCLUSIONS - This study shows that subclinical inflammation is associated with diabetic polyneuropathy and neuropathic impairments. This association appears rather specific because only certain immune mediators and impairments are involved. AU - Herder, C.* AU - Lankisch, M.* AU - Ziegler, D.* AU - Rathmann, W.* AU - Koenig, W.* AU - Illig, T. AU - Döring, A. AU - Thorand, B. AU - Holle, R. AU - Giani, G.* AU - Martin, S.* AU - Meisinger, C. C1 - 1656 C2 - 26206 SP - 680-682 TI - Subclinical inflammation and diabetic polyneuropathy. JO - Diabetes Care VL - 32 IS - 4 PB - Amer Diabetes Assoc PY - 2009 SN - 0149-5992 ER - TY - JOUR AB - High serum uric acid levels lead to gout and have been reported to be associated with an increased risk of hypertension, obesity, metabolic syndrome, type 2 diabetes, and cardiovascular disease. Recently, the putative fructose transporter SLC2A9 was reported to influence uric acid levels. The aim of the present study was to examine the association of four single nucleotide polymorphisms within this gene with uric acid levels and to determine whether this association is modified by obesity. RESEARCH DESIGN AND METHODS: Four single nucleotide polymorphisms within SLC2A9 (rs6855911, rs7442295, rs6449213, and rs12510549) were genotyped in the population-based prospective Bruneck Study (n = 800) and in a case-control study from Utah including 1,038 subjects recruited for severe obesity and 831 control subjects. RESULTS: We observed highly significant associations between all four polymorphisms and uric acid levels in all study groups. Each copy of the minor allele decreased age- and sex-adjusted uric acid levels by 0.30-0.35 mg/dl on average, which translates to a relative decrease of 5-6% with P values ranging from 10(-9) to 10(-11) in the combined analysis. An extended adjustment for BMI, creatinine, gout medication, and alcohol intake improved P values to a range of 10(-14) to 10(-20). The association was more pronounced in women and the population-based Bruneck Study and was significantly modified by BMI, with stronger effect sizes in individuals with high BMI. CONCLUSIONS: Genetic variants within SLC2A9 have significant effects on uric acid levels and are modified by sex and BMI. AU - Brandstatter, A.* AU - Kiechl, S.* AU - Kollerits, B.* AU - Hunt, S.C.* AU - Heid, I.M. AU - Coassin, S.* AU - Willeit, J.* AU - Adams, T.D.* AU - Illig, T. AU - Hopkins, P.N.* AU - Kronenberg, F.* C1 - 3534 C2 - 25569 SP - 1662-1667 TI - Sex-specific association of the putative fructose transporter SLC2A9 variants with uric acid levels is modified by BMI. JO - Diabetes Care VL - 31 IS - 8 PB - Amer. Diabetes Assoc. PY - 2008 SN - 0149-5992 ER - TY - JOUR AB - It is controversial whether there is a glycemic threshold above which polyneuropathy develops and which are the most important factors associated with polyneuropathy in the general population. The aim of this study was to determine the prevalence and risk factors of polyneuropathy in subjects with diabetes, impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or normal glucose tolerance (NGT). RESEARCH DESIGN AND METHODS: Subjects with diabetes (n = 195) and control subjects matched for age and sex (n = 198) from the population-based MONICA (Monitoring Trends and Determinants on Cardiovascular Diseases)/KORA (Cooperative Research in the Region of Augsburg) Augsburg Surveys 1989/1990 (S2) and 1994/1995 (S3) aged 25-74 years were contacted again and assessed in 1997/1998 by the Michigan Neuropathy Screening Instrument using a score cut point >2. An oral glucose tolerance test was performed in the control subjects. RESULTS: Among the control subjects, 46 (23.2%) had IGT, 71 (35.9%) had IFG, and 81 had NGT. The prevalence of polyneuropathy was 28.0% in the diabetic subjects, 13.0% in those with IGT, 11.3% in those with IFG, and 7.4% in those with NGT (P AU - Ziegler, D.* AU - Rathmann, W.* AU - Dickhaus, T.* AU - Mielck, A. AU - KORA Study Group (Meisinger, C. AU - Wichmann, H.-E. AU - Holle, R. AU - John, J. AU - Illig, T. AU - Peters, A.) C1 - 1410 C2 - 25269 SP - 464-469 TI - Prevalence of polyneuropathy in pre-diabetes and diabetes is associated with abdominal obesity and macroangiopathy: The MONICA/KORA Augsburg Surveys S2 and S3. JO - Diabetes Care VL - 31 IS - 3 PB - Amer. Diabetes Assoc. PY - 2008 SN - 0149-5992 ER - TY - JOUR AB - To evaluate whether reduced heart rate variability (HRV), prolonged corrected QT (QTc) interval, or increased QT dispersion (QTD) are predictors of mortality in the general diabetic and nondiabetic population. RESEARCH DESIGN AND METHODS: Nondiabetic (n = 1,560) and diabetic (n = 160) subjects aged 55-74 years were assessed to determine whether reduced HRV, prolonged QTc interval, and increased QTD may predict all-cause mortality. Lowest quartiles for the maximum-minimum R-R interval difference (max-min, as measured at baseline from a 20-s standard 12-lead resting electrocardiogram without controlling for depth and rate of respiration), QTc >440 ms and QTD >60 ms, were used as cutpoints. RESULTS: During a 9-year follow-up, 10.5% of the nondiabetic and 30.6% of the diabetic population deceased. In the nondiabetic individuals, multivariate Cox proportional hazard models adjusted for cardiovascular risk factors and demographic variables showed that prolonged QTc interval (hazard ratio 2.02 [95% CI 1.29-3.17]; P = 0.002) but not low max-min (0.93 [0.65-1.34]; P = 0.700), and increased QTD (0.98 [0.60-1.60]; P = 0.939) were associated with increased mortality. In the diabetic subjects, prolonged QTc was also a predictor of mortality (3.00 [1.34-6.71]; P = 0.007), while a trend for an increased risk was noted in those with low max-min (1.74 [0.95-3.18]; P = 0.075), whereas increased QTD did not predict mortality (0.42 [0.06-3.16]; P = 0.402). CONCLUSIONS: Prolonged QTc interval, but not increased QTD, is an independent predictor of a twofold and threefold increased risk of mortality in the nondiabetic and diabetic elderly general population, respectively. Low HRV during spontaneous breathing tends to be associated with excess mortality in the diabetic but not nondiabetic population. AU - Ziegler, D.* AU - Zentai, C.P.* AU - Perz, S. AU - Rathmann, W.* AU - Haastert, B.* AU - Döring, A. AU - Meisinger, C. AU - KORA Study Group (Meisinger, C. AU - Wichmann, H.-E. AU - Holle, R. AU - John, J. AU - Illig, T. AU - Peters, A.) C1 - 2936 C2 - 25237 SP - 556-561 TI - Prediction of mortality using measures of cardiac autonomic dysfunction in the diabetic and nondiabetic population: The MONICA/KORA Augsburg Cohort Study. JO - Diabetes Care VL - 31 IS - 3 PB - Amer. Diabetes Assoc. PY - 2008 SN - 0149-5992 ER - TY - JOUR AB - Obesity and hypertension are regarded as the most important determinants of left ventricular mass in the community. Little is known about sex-specific influences of obesity, hypertension, and other risk factors on left ventricular mass in pre-diabetic or diabetic subjects. RESEARCH DESIGN AND METHODS: We examined how body composition, blood pressure, and other factors are related to left ventricular structure in elderly subjects (mean age 62 years, 88% of women postmenopausal) with pre-diabetes (impaired fasting glucose or impaired glucose tolerance; n = 112) and diabetes with (n = 181) and without (n = 213) overt cardiovascular disease (CVD). RESULTS: Neither microalbuminuria nor physical activity was significantly associated with left ventricular mass. In pre-diabetic as well as diabetic subjects with CVD, mainly BMI and fat mass, particularly in women, were correlated with left ventricular mass. In the diabetic group without overt CVD, fat mass was only slightly correlated with left ventricular mass. In the latter group waist-to-hip-ratio, and, only in men, systolic blood pressure, glucose, and A1C were moderately correlated with left ventricular mass. Multiregression analysis over all groups again revealed fat mass as the main determinant of left ventricular mass in women. In women but not men obesity was associated with a significantly increased prevalence of concentric left ventricular hypertrophy. CONCLUSIONS: In pre-diabetic and diabetic elderly subjects fat mass is the major determinant of left ventricular mass in women but not in men. These results may partly explain sex differences in CVD mortality in obese elderly diabetic subjects and underscore the need for activities focused on weight reduction. AU - Kuch, B.* AU - von Scheidt, W.* AU - Peter, W.* AU - Döring, A. AU - Piehlmeier, W.* AU - Landgraf, R.* AU - Meisinger, C. C1 - 2940 C2 - 24620 SP - 946-952 TI - Sex-specific determinants of left ventricular mass in pre-diabetic and type 2 diabetic subjects: The Augsburg Diabetes Family Study. JO - Diabetes Care VL - 30 IS - 4 PB - Amer. Diabetes Assoc. PY - 2007 SN - 0149-5992 ER - TY - JOUR AB - Although sex differences have been reported for associations between obesity and inflammation, the question of whether there is an effect modification by sex in the association between inflammation and type 2 diabetes has not been investigated in detail. Therefore, the aim of this study was to compare associations of markers of inflammation with type 2 diabetes risk between men and women. RESEARCH DESIGN AND METHODS: Following a case-cohort design, cases of incident type 2 diabetes were identified from 7,936 subjects aged 35-74 years at baseline who participated in the population-based Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA)/Cooperative Research in the Region of Augsburg (KORA) studies conducted between 1984 and 2002. Concentrations of C-reactive protein (CRP) and interleukin (IL)-6 were measured in 527 cases of incident type 2 diabetes (305 men and 222 women) and 1,698 noncases (889 men and 809 women). RESULTS: After adjustment for age and survey and lifestyle factors including smoking, alcohol intake, and physical activity, elevated concentrations of CRP showed a considerably stronger association with risk of type 2 diabetes in women (hazard ratio comparing tertile extremes 7.60 [95% CI 4.43-13.04]) than in men (1.84 [1.27-2.67]). The P value for the sex interaction was <0.001. Further adjustment for metabolic risk factors considerably attenuated these associations, and they became nonsignificant in men but remained significant in women. IL-6 was also more strongly associated with type 2 diabetes in women, but there was no significant sex interaction. CONCLUSIONS: Our data suggest that inflammatory processes may be of particular importance in the pathogenesis of type 2 diabetes in women. AU - Thorand, B. AU - Baumert, J.J. AU - Kolb, H.-J. AU - Meisinger, C. AU - Chambless, L.* AU - Koenig, W.* AU - Herder, C.* C1 - 3826 C2 - 24607 SP - 854-860 TI - Sex differences in the prediction of type 2 diabetes by inflammatory markers: Results from the MONICA/KORA Augsburg case-cohort study, 1984-2002. JO - Diabetes Care VL - 30 IS - 4 PB - Amer. Diabetes Assoc. PY - 2007 SN - 0149-5992 ER - TY - JOUR AU - Herder, C.* AU - Kolb, H.* AU - König, W.* AU - Haastert, B.* AU - Müller-Scholze, S.* AU - Rathmann, W.* AU - Holle, R. AU - Thorand, B. AU - Wichmann, H.-E. C1 - 3165 C2 - 23696 SP - 368-371 TI - Association of systemic concentrations of macrophage migration inhibitory factor with impaired glucose tolerance and type 2 diabetes. JO - Diabetes Care VL - 29 PY - 2006 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE - Previous studies have yielded conflicting results on the association of adiponectin levels and inflammation. Low systemic concentrations of adiponectin, as well as elevated levels of immune mediators, represent risk factors for the development of type 2 diabetes and coronary artery disease. The major aim of this cross-sectional study was to investigate the interdependence of hypoadiponectinemia and low-grade systemic inflammation. RESEARCH DESIGN AND METHODS - The study sample consisted of 606 participants aged 55-74 years (244 with normal glucose tolerance, 242 with impaired glucose tolerance, and 120 with newly diagnosed type 2 diabetes) of the population-based KORA S4 (Cooperative Health Research in the Region of Augsburg Survey 4; 1999-2001). Systemic concentrations of adiponectin and a wide range of anthropometric, metabolic, and inflammatory variables were available for analyses. The association of adiponectin with 15 immunological markers, including leukocyte count, acute-phase proteins, cytokines, cytokine receptors, and chemokines, was assessed using univariable and multivariable models. RESULTS - No evidence for a significant correlation between adiponectin and all immunological parameters except eotaxin could be found after multivariable adjustments, whereas multiple strong correlations with obesity and metabolic factors were present. CONCLUSIONS - From these data, we conclude that hypoadiponectinemia and a proinflammatory state are largely independent from each other. © 2006 by the American Diabetes Association. AU - Herder, C.* AU - Hauner, H.* AU - Haastert, B.* AU - Röhrig, K.* AU - König, W.* AU - Kolb, H.* AU - Müller-Scholze, S.* AU - Thorand, B. AU - Holle, R. AU - Rathmann, W.* C1 - 4826 C2 - 23844 SP - 1626-1631 TI - Hypoadiponectinemia and proinflammatory state: Two sides of the same coin? JO - Diabetes Care VL - 29 IS - 7 PY - 2006 SN - 0149-5992 ER - TY - JOUR AU - Herder, C.* AU - Baumert, J.J. AU - Kolb, H.* AU - Koenig, W.* AU - Martin, S.* AU - Thorand, B. C1 - 5584 C2 - 23788 SP - 174-175 TI - Circulating levels of interleukin-18 independent of body fat and fat-free mass: Results from the MONICA/KORA study. JO - Diabetes Care VL - 29 PY - 2006 SN - 0149-5992 ER - TY - JOUR AU - Kollerits, B.* AU - Auinger, M.* AU - Reisig, V. AU - Kästenbauer, T.* AU - Lingenhel, A.* AU - Irsigler, K.* AU - Prager, R.* AU - Kronenberg, F.* C1 - 1121 C2 - 23706 SP - 1661-1663 TI - Lipoprotein(a) as a predictor of cardiovascular disease in a prospectively followed cohort of patients with type 1 diabetes. JO - Diabetes Care VL - 29 PY - 2006 SN - 0149-5992 ER - TY - JOUR AU - Rathmann, W. AU - Haastert, B.* AU - Icks, A.* AU - Giani, G.* AU - Holle, R. AU - König, W.* AU - Löwel, H. AU - Meisinger, C. C1 - 2851 C2 - 23705 SP - S. 461 TI - Prevalence of the metabolic syndrome in the elderly population according to IDF, WHO and NCEP definitions and associations with C-reactive protein. The KORA Survey 2000. JO - Diabetes Care VL - 29 PY - 2006 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE — To compare the cost-effectiveness of different type 2 diabetes screening strat- egies using population-based data (KORA Survey; Augsburg, Germany; subjects aged 55–74 years), including participation data. RESEARCH DESIGN AND METHODS — The decision analytic model, which had a time horizon of 1 year, used the following screening strategies: fasting glucose testing, the oral glucose tolerance test (OGTT) following fasting glucose testing in impaired fasting glucose (IFG) (fasting glucose  OGTT), OGTT only, and OGTT if HbA 1c was  5.6% (HbA 1c  OGTT), all with or without first-step preselection ( p ). The main outcome measures were costs (in Euros), true-positive type 2 diabetic cases, incremental cost-effectiveness ratios (ICERs), third-party payers, and societal perspectives. RESULTS — After dominated strategies were excluded, the OGTT and HbA 1c  OGTT from the perspective of the statutory health insurance remained, as did fasting glucose  OGTT and HbA 1c  OGTT from the societal perspective. OGTTs ( € 4.90 per patient) yielded the lowest costs from the perspective of the statutory health insurance and fasting glucose  OGTT ( € 10.85) from the societal perspective. HbA 1c  OGTT was the most expensive ( € 21.44 and € 31.77) but also the most effective (54% detected cases). ICERs, compared with the next less effective strategies, were € 771 from the statutory health insurance and € 831 from the societal perspective. In the Monte Carlo analysis, dominance relations remained unchanged in 100 and 68% (statutory health insurance and societal perspective, respectively) of simulated populations. CONCLUSIONS — The most effective screening strategy was HbA 1c combined with OGTT because of high participation. However, costs were lower when screening with fasting glucose tests combined with OGTT or OGTT alone. The decision regarding which is the most favorable strategy depends on whether the goal is to identify a high number of cases or to incur lower costs at reasonable effectiveness. AU - Icks, A.* AU - Haastert, B.* AU - Gandjour, A.* AU - John, J.* AU - Löwel, H. AU - Holle, R. AU - Giani, G.* AU - Rathmann, W.* C1 - 5528 C2 - 23353 SP - 2120-2128 TI - Cost-effectiveness analysis of different screening procedures for type 2 diabetes. JO - Diabetes Care VL - 27 IS - 9 PY - 2005 SN - 0149-5992 ER - TY - JOUR AU - Meisinger, C. AU - Heier, M. AU - Döring, A. AU - Thorand, B. AU - Löwel, H. C1 - 1869 C2 - 23105 SP - 2985-2987 TI - Prevalence of known diabetes and antidiabetic therapy between 1984/1985 and 1999/2001 in Southern Germany. JO - Diabetes Care VL - 27 IS - 12 PY - 2005 SN - 0149-5992 ER - TY - JOUR AB - OBJECTIVE: The importance of screening for diabetic retinopathy has been established, but the best method for screening has not yet been determined. We report on a trial of assessment of digital photographs by telemedicine compared with standard retinal photographs of the same fields and clinical examination by ophthalmologists. RESEARCH DESIGN AND METHODS: A total of 129 diabetic inpatients were screened for diabetic retinopathy by slit-lamp biomicroscopy performed by an ophthalmologist and by two-field 50 degrees non-stereo digital fundus photographs assessed by six screening centers that received the images by electronic mail. Conventional 35-mm transparencies of the same fields as the digital photographs were assessed by a retinal specialist and served as the reference method for detection of diabetic retinopathy. Slit-lamp biomicroscopy was the reference method for the detection of macular edema. RESULTS: The prevalence of any form of diabetic retinopathy was 30% (n = 35); of sight-threatening retinopathy including macular edema, the prevalence was 6% (n = 7). The assessment of digital images by the six screening centers resulted in a median sensitivity of 85% and a median specificity of 90% for the detection of moderate nonproliferative or sight-threatening diabetic retinopathy. Clinically significant macular edema (n = 4) was correctly identified in 15 of the 24 grading reports. An additional seven reports referred the patients for further investigation because of concurrent diabetic retinopathy. CONCLUSIONS: Telescreening for diabetic retinopathy by an assessment of two-field 50 degrees non-stereo digital images is a valid screening method. Although detection of clinically significant macular edema using biomicroscopy is superior to digital or standard non-stereo photographs, only few patients with sight-threatening diabetic retinopathy are missed. AU - Liesenfeld, B.* AU - Kohner, E.* AU - Piehlmeier, W. AU - Kluthe, S. AU - Aldington, S.* AU - Porta, M.* AU - Bek, T.* AU - Obermaier, M.* AU - Mayer, H.* AU - Mann, G. AU - Holle, R. AU - Hepp, K.-D.* C1 - 21490 C2 - 19611 SP - 345-348 TI - A telemedical approach to the screening of diabetic retinopathy: Digital fundus photography. JO - Diabetes Care VL - 23 IS - 3 PY - 2000 SN - 0149-5992 ER -