Decline In Beta-cell Function Research Articles

Circulating MicroRNAs as Predictors of Beta Cell Function in Youth-Onset Type 2 Diabetes: The TODAY study.

In the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study, an intervention trial followed by an observational phase, half the participants reached the primary outcome (HbA1c ≥ 8% for at least 6 months) within 4 years which was associated with a decrease in C-peptide oral disposition index (oDI). We aimed to identify circulating miRNA species associated with decline in beta cell function. Following a preliminary survey of select participants using nCounter Human v3 miRNA Panel (NanoString Technologies), polymerase chain reaction analyses were carried out for 17 miRNAs from 365 participants from samples at baseline, 24, 60, 96, and 120 months. Using a backward selection approach, four baseline miRNA log2 fold changes independently predicted treatment failure; however, baseline HbA1c was higher in those with treatment failure. Three baseline miRNA log2 fold changes remained significant predictors of this C-peptide oDI decline ≥20% (p < 0.05). Increased levels of miRNA-155 (OR:1.2, 95%CI:1.1-1.4) and miRNA-130b (OR:1.3, 95%CI: 1.0-1.7) were associated with oDI decline, while decreased levels of miRNA-126 (OR:0.6, 95%CI: 0.4-0.8) were associated with oDI decline. miRNA-122 was negatively correlated with C-peptide oDI at baseline and 24-months (R = 0.22, p < 0.01 and R = 0.19, p < 0.01, respectively), and positively correlated with proinsulin, at baseline, 24-, and 60- months (R = 0.26, p < 0.01, R = 0.26, p < 0.01, R = 0.18, p < 0.01, respectively). The miRNA species associated with beta cell function are associated with alterations in cellular metabolism and apoptosis, suggesting that differences in baseline abundance may serve as circulating markers of beta cell dysfunction and provide potential mechanistic insights into the aggressive nature of youth-onset type 2 diabetes.

Deteriorating beta cell function is the dominant determinant of progression from normal glucose tolerance to prediabetes/diabetes in young women following pregnancy.

Excess adiposity, insulin resistance and beta cell dysfunction each contribute to the development of prediabetes (impaired glucose tolerance and/or impaired fasting glucose)/diabetes but their comparative impact in relation to one another remains uncertain. We thus ranked their contributions to incident dysglycaemia over the first 5 years postpartum in women reflecting the full spectrum of gestational glucose tolerance (spanning normoglycaemia to gestational diabetes) and hence a range of future diabetic risk. In this study, 302 women with normal glucose tolerance (NGT) on OGTT at 3 months postpartum underwent repeat OGTT at 1 year, 3 years and 5 years, enabling serial assessment of glucose tolerance, insulin sensitivity/resistance (Matsuda index, HOMA-IR) and beta cell function (insulin secretion-sensitivity index-2 [ISSI-2], insulinogenic index [IGI]/HOMA-IR). Determinants of prediabetes/diabetes were ranked by change in concordance index (CCI) of Cox proportional hazard regression models. Over 5 years of follow-up, 89 women progressed from NGT to prediabetes/diabetes (progressors). At 3 months postpartum, though all women were normoglycaemic, future progressors had higher fasting glucose (p=0.03) and 2 h glucose (p<0.0001) than non-progressors, coupled with higher BMI (p=0.001), greater insulin resistance (both Matsuda index and HOMA-IR, p≤0.02) and poorer beta cell function (both ISSI-2 and IGI/HOMA-IR, p≤0.006). Unlike their peers, progressors exhibited deteriorating beta cell function from 1 year to 5 years (both p<0.0001). On regression analyses, the dominant determinants of progression to prediabetes/diabetes were time-varying ISSI-2 (change in CCI 25.2%) and IGI/HOMA-IR (13.0%), in contrast to time-varying Matsuda index (2.9%) and HOMA-IR (0.5%). Neither time-varying BMI nor waist were significant predictors after adjustment for beta cell function and insulin sensitivity/resistance. Declining beta cell function is the dominant determinant of incident prediabetes/diabetes in young women following pregnancy.

Targeted serum proteomics of longitudinal samples from newly diagnosed youth with type 1 diabetes distinguishes markers of disease and C-peptide trajectory

Aims/hypothesisThere is a growing need for markers that could help indicate the decline in beta cell function and recognise the need and efficacy of intervention in type 1 diabetes. Measurements of suitably selected serum markers could potentially provide a non-invasive and easily applicable solution to this challenge. Accordingly, we evaluated a broad panel of proteins previously associated with type 1 diabetes in serum from newly diagnosed individuals during the first year from diagnosis. To uncover associations with beta cell function, comparisons were made between these targeted proteomics measurements and changes in fasting C-peptide levels. To further distinguish proteins linked with the disease status, comparisons were made with measurements of the protein targets in age- and sex-matched autoantibody-negative unaffected family members (UFMs).MethodsSelected reaction monitoring (SRM) mass spectrometry analyses of serum, targeting 85 type 1 diabetes-associated proteins, were made. Sera from individuals diagnosed under 18 years (n=86) were drawn within 6 weeks of diagnosis and at 3, 6 and 12 months afterwards (288 samples in total). The SRM data were compared with fasting C-peptide/glucose data, which was interpreted as a measure of beta cell function. The protein data were further compared with cross-sectional SRM measurements from UFMs (n=194).ResultsEleven proteins had statistically significant associations with fasting C-peptide/glucose. Of these, apolipoprotein L1 and glutathione peroxidase 3 (GPX3) displayed the strongest positive and inverse associations, respectively. Changes in GPX3 levels during the first year after diagnosis indicated future fasting C-peptide/glucose levels. In addition, differences in the levels of 13 proteins were observed between the individuals with type 1 diabetes and the matched UFMs. These included GPX3, transthyretin, prothrombin, apolipoprotein C1 and members of the IGF family.Conclusions/interpretationThe association of several targeted proteins with fasting C-peptide/glucose levels in the first year after diagnosis suggests their connection with the underlying changes accompanying alterations in beta cell function in type 1 diabetes. Moreover, the direction of change in GPX3 during the first year was indicative of subsequent fasting C-peptide/glucose levels, and supports further investigation of this and other serum protein measurements in future studies of beta cell function in type 1 diabetes.Graphical

72-OR: Higher Genetic Risk for Type 2 Diabetes Is Associated with Faster Decline of Beta-Cell Function

Objective: Polygenic risk score (PRS) for type 2 diabetes (T2D) has been reported to be associated with beta cell function, but whether it is also associated with the longitudinal change of beta cell function is largely unknown. We aimed to evaluate the association of PRS and the trajectory of beta cell function in a community based prospective cohort. Method: We analyzed 6,323 participants without T2D at baseline from Ansan-Ansung cohort with 75-g 2-hour oral glucose tolerance tests taken biennially for 14 years. Disposition index (DI), derived from insulinogenic index at 60 minutes and Matsuda index, was used as a marker for beta cell function. PRS was calculated using 1.2 million variants from trans-ancestry T2D genome-wide association study using Bayesian regression (PRS-CSx). Participants were stratified into low (1st quintile), intermediate (2nd to 4th quintiles) and high genetic risk (5th quintile). Lifestyle was categorized as unfavorable, intermediate and favorable lifestyle according to Life’s Essential 8. Linear mixed model was applied. Result: During a median follow-up of 13 years, 379 (30.6%), 875 (23.0%) and 171 (13.4%) participants developed T2D in high, intermediate and low genetic risk group, respectively. Participants in high genetic risk group, compared to low genetic risk group, had a 33% lower DI at baseline (53 [95% CI 50, 56] vs 79 [74, 84]; P = 7.9×10-15), and a 1.7-fold faster rate of decline in log2(DI) per year (-0.035 [-0.028, -0.042] vs -0.020 [-0.013, -0.027]; P = 0.0026). Notably, we found significant interaction between the rate of decline in DI and T2D PRS (P = 8.5×10-5). Healthy lifestyle was associated with decreased rate of decline in DI across all genetic risk group. Conclusion: Having a high genetic risk for T2D was associated with not only a lower DI at baseline, but also a faster rate of decline in DI. Genetic information could be used to identify those at risk for rapid decline of beta cell function and emphasize lifestyle modification. Disclosure H.Lee: None. J.Choi: None. H.Son: None. K.Park: None. N.H.Cho: None. S.Kwak: None. Funding Ministry of Health &amp; Welfare, Republic of Korea

376-OR: Chronic Pancreatitis Does Not Induce Specific Alterations in Beta-Cell Function

Chronic pancreatitis (CP) is the most frequent cause of diabetes due to pancreatic diseases, known as type 3c diabetes mellitus (T3cDM). Although the specific alterations of T3cDM are not completely understood, individuals with T3cDM are considered affected by pancreatic endocrine insufficiency and often treated with insulin. To investigate the functional alterations of T3cDM, we evaluated differences in beta-cell function in patients with and without CP, classified according to their glucose tolerance (NGT, IGT, DM). We recruited 50 patients with CP and 96 individuals without CP (NCP). All participants underwent OGTT, hyperglycemic clamp (HC), hyperinsulinemic euglycemic clamp and mixed meal test (MMT) with measurement of GLP-1 and glucagon. Basal insulin secretion rate (ISR), total ISR, rate secretion and β-cell glucose sensitivity (RS and GS) were estimated by mathematical models from OGTT, MMT and HC. Comparing individuals classified into NGT, IGT or DM based on OGTT-derived glucose tolerance, we did not find any difference in beta-cell function derived by OGTT and MMT within the same category (e.g.: NGT-CP vs. NGT-NCP). GLP-1 and glucagon secretion during MMT was not significantly different between CP vs. NCP. Of note, we found that insulin secretion after arginine stimulus in HC, an indirect measure of beta-cell mass, was reduced only in DM-CP vs. DM-NCP (ARG CP 397 (132; 662) pmol/l vs NCP 795 (604; 1134) pmol/l; p= 0.023). No difference was found in insulin sensitivity evaluated as glucose uptake during euglycemic clamp. At equivalent levels of glucose tolerance, patients with CP had similar beta-cell function, GLP-1 and glucagon secretion to individuals without CP. People with T3cDM have less beta-cell mass than patients with DM without CP, but analogous residual beta-cell function, so they could benefit from other therapies apart from insulin. Future studies are warranted to investigate differences in beta-cell function decline between type 2 diabetes mellitus and T3cDM. Disclosure G.Ciccarelli: None. G.Di giuseppe: None. F.Cinti: None. A.Mari: Consultant; Eli Lilly and Company. T.Mezza: None. A.Giaccari: Speaker's Bureau; Abbott, AstraZeneca, Boehringer-Ingelheim, Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Novo Nordisk, Sanofi.

Progression from prediabetes to type 2 diabetes mellitus in adolescents: a real world experience.

Obesity in pediatric patients is strongly associated with increased vascular and metabolic risk. Prediabetes is present in up to 1 in 5 adolescents, aged 12-18 years-old, though is thought to remit spontaneously in a significant portion. Pediatric patients with type 2 diabetes mellitus (T2D) have a more rapid decline of beta-cell function and progression to treatment failure than adult T2D patients. Thus, there is a strong interest in better understanding the natural history of prediabetes in these youth. We aimed to evaluate the real-world rate of progression of prediabetes to T2D in adolescent patients. This is a retrospective study of 9,275 adolescent subjects aged 12-21 years-old with at least 3 years of de-identified commercial claims data and a new diagnosis of prediabetes during the observation period. Enrollees with a T2D diagnosis and/or diabetes medication use in the 1 year prior to prediabetes diagnosis or a T2D diagnosis in the 1 month following prediabetes diagnosis were excluded. Enrollees with diagnoses of type 1 diabetes (T1D) or polycystic ovarian syndrome over the 3 years were also excluded. Progression to T2D was defined by claims data of two T2D diagnoses at least 7 days apart, HbA1c ≥ 6.5%, and/or prescription of insulin without known T1D. Enrollees were followed for 2 years after prediabetes diagnosis. Overall, 232 subjects (2.5%) progressed from prediabetes to T2D. There were no differences found in T2D progression based on sex or age. Progression to T2D occurred at a median of 302 days after prediabetes diagnosis (IQR 123 to 518 days). This study was limited by the lack of laboratory/anthropometric data in administrative claims, as well as the exclusion of 23,825 enrollees for lack of continuous commercial claims data over 3 years. In the largest sample to date on adolescent prediabetes, we found a 2.5% progression of prediabetes to T2D over a median duration of about one year.

Characterizing T cell responses to enzymatically modified beta cell neo-epitopes.

Previous studies verify the formation of enzymatically post-translationally modified (PTM) self-peptides and their preferred recognition by T cells in subjects with type 1 diabetes (T1D). However, questions remain about the relative prevalence of T cells that recognize PTM self-peptides derived from different antigens, their functional phenotypes, and whether their presence correlates with a specific disease endotype. To address this question, we identified a cohort of subjects with T1D who had diverse levels of residual beta cell function. Using previously developed HLA class II tetramer reagents, we enumerated T cells that recognize PTM GAD epitopes in the context of DRB1*04:01 or PTM IA2 epitopes in the context of DQB1*03:02 (DQ8). Consistent with prior studies, we observed higher overall frequencies and a greater proportion of memory T cells in subjects with T1D than in HLA matched controls. There were significantly higher numbers of GAD specific T cells than IA2 specific T cells in subjects with T1D. T cells specific for both groups of epitopes could be expanded from the peripheral blood of subjects with established T1D and at-risk subjects. Expanded neo-epitope specific T cells primarily produced interferon gamma in both groups, but a greater proportion of T cells were interferon gamma positive in subjects with T1D, including some poly-functional cells that also produced IL-4. Based on direct surface phenotyping, neo-epitope specific T cells exhibited diverse combinations of chemokine receptors. However, the largest proportion had markers associated with a Th1-like phenotype. Notably, DQ8 restricted responses to PTM IA2 were over-represented in subjects with lower residual beta cell function. Neo-epitope specific T cells were present in at-risk subjects, and those with multiple autoantibodies have higher interferon gamma to IL-4 ratios than those with single autoantibodies, suggesting a shift in polarization during progression. These results reinforce the relevance of PTM neo-epitopes in human disease and suggest that distinct responses to neo-antigens promote a more rapid decline in beta cell function.

Insulin in practice for people with type 2 diabetes mellitus

The use of insulin in type 1 diabetes mellitus is life-saving owing to the absolute insulin deficiency resulting from autoimmune destruction of the beta cells in the pancreas​[1]​. Type 2 diabetes mellitus (T2DM) is characterised as a progressive disease owing to a combination of the development of insulin resistance and continuing decline of beta cell function​[2]​. […]

Brief history of the UK Prospective Diabetes Study

The UK Prospective Diabetes Study (UKPDS) epidemiological findings confirmed that T2DM is not a “mild” disease, with roughly 50% of patients having clinically evident complica- tions at diagnosis, emphasising the need for its early detection and treatment. Hyperglycaemia was identified as an independent coronary heart disease risk factor, with progressive hyperglycaemia shown to be a major pathophysiological feature of T2DM, driven by declining beta-cell function. People with T2DM and hypertension were found to be at double jeopardy for any diabetes endpoint, and worsening kidney function was shown to increase the risk of death substantially. The UKPDS 20-year trial results were the first to demon- strate that diabetic complications are not inevitable but can be prevented by more intensive blood glucose control and by metformin therapy, changing T2DM management guide- lines worldwide. The UKPDS also showed that tighter blood pressure control prevents diabetic complications; the benefits of the glucose and blood pressure interventions are additive. The UKPDS 10-year post-trial monitoring study was the first to identify the T2DM glycaemic and metformin legacy effects, with early more intensive therapy having continuing benefits long after the trial terminated. The trial demon- strated the need to achieve good glycaemic control as early as possible to minimise the risk of future complications.

Higher risk of severe hypoglycemia in children and adolescents with a rapid loss of C-peptide during the first 6 years after type 1 diabetes diagnosis

IntroductionThe progression to insulin deficiency in type 1 diabetes is heterogenous. This study aimed to identify early characteristics associated with rapid or slow decline of beta-cell function and how it...

OZ101, an oligofructose prebiotic, may prolong sulphonylurea efficcy in patients with type 2 diabetes: a pilot study: OZ101 and sulphonylurea-mediated glycaemic control

Aims: The sulphonylurea class of anti-diabetes drugs lose efficacy over time due to progressive beta-cell failure. Their long-term use may exacerbate gut microbial dysbiosis as they are derivatives of sulphonamide antibiotics. We conducted a pilot study to test the hypothesis that OZ101, administered as adjunctive prebiotic therapy, improves beta-cell function and glycaemic control in sulphonylurea-treated patients. Materials and Methods: Subjects with type 2 diabetes on sulphonylurea monotherapy (n=30) were randomized in a 24-week parallel dose range-finding study to either continue receiving their usual sulphonylurea-only treatment or add a thrice-daily regimen of 13.5 or 27 g/d doses of OZ101. HOMA-B, glycaemic parameters after 12 hours fasting, and glucose area under the curve (AUC; over 240 minutes) after intake of a pre-defined calorie milkshake were collected at baseline and 24 weeks. Results: Over 24-weeks, control subjects on sulphonylurea-only showed a decline in beta-cell function (35.54% decrease in HOMA-B from baseline, p = 0.01), whereas subjects taking sulphonylurea+13.5 g/d OZ101 improved (22.9% increase in HOMA-B from baseline, p = 0.031). There was a 0.95% (10mmol/mol) difference in HbA1c (p = 0.047) and 607 mmol/l*240min AUC (p = 0.039) in favour of the sulphonylurea +13.5g/d OZ101 compared with control group. HbA1c and AUC were not altered in subjects treated with sulphonylurea+27 g/d OZ101 compared with the control group. Microbiome profiling suggested reciprocal relationships in beneficial versus detrimental bacteria between control and treatment groups. Conclusions: Adjunctive intake of 13.5g/d OZ101 in patients on sulphonylurea therapy was safe, well-tolerated and associated with improved beta-cell function and stabilization of glycaemic control over 24 weeks. Absence of similar response for the 27 g/d OZ101 group may relate to changes in gut microbiome profiles. Future studies will determine the mechanistic link between OZ101 therapy, changes in gut microbiome, and metabolic responses.

342-OR: Low Incretin Effect Is Associated with Longitudinal Decline of Beta-Cell Function and Insulin Sensitivity in Obese Youth

Background: We assessed the longitudinal trajectory of beta-cell function with respect to baseline incretin effect in youth with obesity. Methods: At baseline and two years, youth with obesity and 2-h glucose ≥ 120mg/dL underwent a 3-hour OGTT and isoglycemic intravenous glucose infusion (to quantify the incretin effect) . Participants were stratified into three tertiles based on the baseline incretin effect. The oral minimal model quantified beta cell function (oDI) and insulin sensitivity (SI) . Results: Thirty participants completed the assessments [follow-up: age 18.6±2.4y, 19F; BMI 38.6±7.4 kg/m2, NGT/IGT/T2D 12/17/1]. At 2 years, 2-h glucose improved in the high incretin group (p=0.047) , but was stable in the middle- and low- incretin groups (panel G) . At 2 years, the baseline high-incretin group exhibited a lower 60-min glucose (p=0.026) than the low-incretin group, with similar 120-min glucose (p=0.696) , despite the low-incretin cohort’s relative increase in early insulin secretion (panel D, F) . The low-incretin tertile also exhibited a reduced β cell function (oDI) at follow-up (panel I) (p=0.044) mainly due to lower insulin sensitivity (panel H) (p=0.013) . Conclusion: Low incretin effect is associated with a longitudinal decline of beta cell function and decreased insulin sensitivity, despite greater first-phase insulin secretion. Disclosure A.Galderisi: None. J.O.Lat: None. S.Samuels: None. B.Pierpont: None. M.A.Van name: Research Support; Provention Bio, Inc. N.Santoro: None. S.Caprio: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases/NIH/DHHS (16-004945)

INNODIA Master Protocol for the evaluation of investigational medicinal products in children, adolescents and adults with newly diagnosed type 1 diabetes

BackgroundThe INNODIA consortium has established a pan-European infrastructure using validated centres to prospectively evaluate clinical data from individuals with newly diagnosed type 1 diabetes combined with centralised collection of clinical samples to determine rates of decline in beta-cell function and identify novel biomarkers, which could be used for future stratification of phase 2 clinical trials.MethodsIn this context, we have developed a Master Protocol, based on the “backbone” of the INNODIA natural history study, which we believe could improve the delivery of phase 2 studies exploring the use of single or combinations of Investigational Medicinal Products (IMPs), designed to prevent or reverse declines in beta-cell function in individuals with newly diagnosed type 1 diabetes. Although many IMPs have demonstrated potential efficacy in phase 2 studies, few subsequent phase 3 studies have confirmed these benefits. Currently, phase 2 drug development for this indication is limited by poor evaluation of drug dosage and lack of mechanistic data to understand variable responses to the IMPs. Identification of biomarkers which might permit more robust stratification of participants at baseline has been slow.DiscussionThe Master Protocol provides (1) standardised assessment of efficacy and safety, (2) comparable collection of mechanistic data, (3) the opportunity to include adaptive designs and the use of shared control groups in the evaluation of combination therapies, and (4) benefits of greater understanding of endpoint variation to ensure more robust sample size calculations and future baseline stratification using existing and novel biomarkers.

Severe hyperglycemia in an insulin-deficient patient with type 2 diabetes responding well to oral antidiabetic therapy

Type 2 diabetes mellitus (T2DM) is a chronic, progressive disease characterized by a steady decline in beta-cell function and insulin resistance. As a result, most patients with T2DM may require treatment with insulin after 15–20 years of diagnosis. Various pathophysiological defects were identified leading to hyperglycemia, including reduced insulin secretion due to beta-cell failure. They reduced beta-cell mass and a defect in insulin secretion, which leads to a relative insulin deficiency in these patients requiring insulin treatment. Most international guidelines recommend starting insulin treatment in patients with poor glucose control, mainly if the glycated hemoglobin (HbA1c) is above 9% with the presence of symptoms, especially in relatively newly diagnosed patients with T2DM. We present a 45-year-old patient with T2DM of 5 years duration who attended our center with severe hyperglycemia with evidence of insulin deficiency both clinically and biochemically, who responded well to oral antidiabetic agents achieving adequate glycemic control.

IL-1beta promotes the age-associated decline of beta cell function

SummaryAging is the prime risk factor for the development of type 2 diabetes. We investigated the role of the interleukin-1 (IL-1) system on insulin secretion in aged mice. During aging, expression of the protective IL-1 receptor antagonist decreased in islets, whereas IL-1beta gene expression increased specifically in the CD45 + islet immune cell fraction. One-year-old mice with a whole-body knockout of IL-1beta had higher insulin secretion in vivo and in isolated islets, along with enhanced proliferation marker Ki67 and elevated size and number of islets. Myeloid cell-specific IL-1beta knockout preserved glucose-stimulated insulin secretion during aging, whereas it declined in control mice. Isolated islets from aged myeloIL-1beta ko mice secreted more insulin along with increased expression of Ins2, Kir6.2, and of the cell-cycle gene E2f1. IL-1beta treatment of isolated islets reduced E2f1, Ins2, and Kir6.2 expression in beta cells. We conclude that IL-1beta contributes the age-associated decline of beta cell function.

149-LB: Fasting Blood Glucose (FBG) and Cardiovascular Disease (CVD) Risk in Hispanic Youth with Obesity

Introduction: Youth of minority race-ethnicity have higher prevalence of obesity and are at increase in risk for comorbidities. Elevated FBG within the normal range has been related to a decline in beta cell function. The relationship of FBG to CVD risk in youth is not clear. We investigated the relationship between FBG and CVD risk factors in a cohort of Hispanic youth with overweight (OW) and obesity (OB).Methods: 372 (186 males) pubertal, nondiabetic adolescents; mean age (SD) 13.9±2.5 years; 26% OW and 74% OB. They underwent measurement of anthropometrics, blood pressure (BP); body composition; fasting glucose, insulin, CRP, ALT, AST, triglycerides (TG), total, LDL and HDL-cholesterol. The homeostasis model assessment of insulin resistance (HOMA-IR) and TG to HDL ratio were calculated. Subjects were compared across tertiles of FBG (general linear model adjusting for sex).Results: The three FBG tertiles didn’t differ with respect to age, Tanner stage, %body fat, truncal fat, or liver transaminases. Measures of insulin resistance (IR), inflammation, dyslipidemia and BP increased across tertiles of FBG (Table 1).Conclusion: Elevated FBG in the nondiabetic range is associated with greater degree of IR, inflammation and adverse CVD risk profile, independent of total body or truncal fat or evidence of fatty liver disease. This data suggest that higher FBG identifies obese Hispanic youth at high risk for CVD.View largeDownload slideView largeDownload slide DisclosureR. S. Shawar: None. M. R. Puyau: None. F. Bacha: None.

1162-P: Proinsulin as a Biomarker for Beta-Cell Function in a Diverse Cohort

Declining beta-cell function is a key component in the development of type 2 diabetes (T2D). Early in disease progression, first-phase insulin secretion deteriorates, precipitating impaired glucose tolerance. Markers for early beta-cell decline could assist in identifying individuals at risk for disease progression, particularly among demographic groups at elevated risk for T2D. This study was designed to test the hypothesis that proinsulin concentrations would be inversely associated with first-phase beta-cell function, as reflected in the Disposition Index (DI), in a diverse cohort of young individuals without T2D. Participants were 117 men and women of African-American and European-American descent aged 19-45 years with normal glucose tolerance. An oral-glucose tolerance test (OGTT) was used to measure proinsulin concentrations and assess beta-cell function. Mathematical modeling was used to estimate insulin sensitivity (Si) and indices of beta-cell function specific to basal, first-phase, second-phase, and total insulin secretion (PhiB, PhiD, PhiS, PhiTot, respectively). First-phase DI (DId) was calculated as Si x PhiD and second-phase DI (DIs) as Si x PhiS. Proinsulin concentrations were normalized for C-peptide. Fasting and 2-h proinsulin concentrations were inversely associated with DId (r=-0.21, p=0.02 and r=-0.22, p=0.01, respectively). Neither fasting nor 2-h proinsulin concentrations were significantly associated with DIs. African-Americans, who as a group have an elevated prevalence of T2D, had 25% higher concentrations of fasting proinsulin and 18% higher concentrations of 2-h proinsulin compared to EA (p=0.001 and p=0.01, respectively). Proinsulin may be a practical biomarker for first-phase beta-cell function that could assist in identification of individuals at risk for T2D who would benefit from interventions to prevent deterioration of glucose metabolism. Disclosure C. Couch: None. B. Gower: Advisory Panel; Self; Abbott. F. Piccinini: Employee; Self; Medtronic. Funding National Institute of Diabetes and Digestive and Kidney Diseases (R01DK096388); Nutrition Obesity Research Center (P30DK056336); Diabetes Research Center (P30DK079626); National Heart, Lung, and Blood Institute (T32HL105349)

16-OR: Endocrine Manifestations of Pediatric HNF1B-MODY (MODY 5)

Objective: Mutations in hepatocyte nuclear factor 1B (HNF1B), are often identified based on a history of renal disease and diabetes mellitus, but other endocrine manifestations including dyslipidemia and hyperparathyroidism have not been well-defined in the literature. Given HNF1B-MODY is rare, there have been few case series defining the disease spectrum. This study analyzes the clinical characteristics of HNF1B-related endocrine disorders in 9 pediatric patients identified at a single pediatric tertiary care center. Methods: Data was collected through the Atypical Diabetes Registry and Biorepository at the Children’s Hospital of Philadelphia. Results: Of the 9 pediatric patients with HNF1B mutations or deletions, 7/9 (78%) have diabetes mellitus, 8/9 (89%) have renal disease, 8/9 (89%) have dyslipidemia, and 5/9 (55%) have hyperparathyroidism. Over half (55%) initially presented with diabetes mellitus, while the remaining 45% were diagnosed either based on family history or a genetic workup secondary to renal disease. No patients presented with diabetic ketoacidosis and only two presented with ketosis. Of the 4/9 with previously identified HNF1B-mutations, two have subsequently developed diabetes mellitus. Lipid profiles demonstrated: 7/9 with total cholesterol &amp;gt;170 mg/dL, 8/9 with triglycerides &amp;gt;100 mg/dL, 3/9 with LDL &amp;gt; 110 mg/dL and 3/9 with HDL &amp;lt; 40 mg/dL. In regards to calcium homeostasis, 55% have an elevated PTH (&amp;gt;65 pg/mL) with high-normal calcium levels. Autism spectrum disorder was diagnosed in 3/9 patients (2 with 17q12 deletion and 1 with HNF1B mutation). Conclusion: This study represents one of the largest series of pediatric patients with HNF1B-MODY at a single center. The majority of patients have had progressively declining beta-cell function resulting in diabetes mellitus. Nearly all had elevated lipids with hypertriglyceridemia predominating. Over half of the patients had elevated PTH levels preceding the decline in renal function concerning for primary hyperparathyroidism. Disclosure M. E. Craven: None. V. Bamba: None. A. C. Calabria: None. S. E. Pinney: None.

Genetic and environmental factors regulate the type 1 diabetes gene CTSH via differential DNA methylation

Cathepsin H (CTSH) is a type 1 diabetes (T1D) risk gene; large-scale genetic and epidemiological studies found that T1D genetic risk correlates with high CTSH expression, rapid decline of beta-cell function, and early onset T1D. Counterintuitively, transcriptional downregulation of CTSH by proinflammatory cytokines has been shown to promote beta-cell apoptosis. Here, we potentially explain these observed contrasting effects, describing a new mechanism where proinflammatory cytokines and T1D genetic risk variants regulate CTSH transcription via differential DNA methylation. We show that, in human islets, CTSH downregulation by the proinflammatory cytokine cocktail interleukin 1β + tumor necrosis factor α + interferon γ was coupled with DNA hypermethylation in an open chromatin region in CTSH intron 1. A luciferase assay in human embryonic kidney 293 cells revealed that methylation of three key cytosine–phosphate–guanine dinucleotide (CpG) residues in intron 1 was responsible for the reduction of promoter activity. We further found that cytokine-induced intron 1 hypermethylation is caused by lowered Tet1/3 activities, suggesting that attenuated active demethylation lowered CTSH transcription. Importantly, individuals who carry the T1D risk variant showed lower methylation variability at the intron 1 CpG residues, presumably making them less sensitive to cytokines, whereas individuals who carry the protective variant showed higher methylation variability, presumably making them more sensitive to cytokines and implying differential responses to environment between the two patient populations. These findings suggest that genetic and environmental influences on a T1D locus are mediated by differential variability and mean of DNA methylation.

Insulin resistance and type 2 diabetes in children

Type 2 diabetes (T2D) is an emerging health risk in obese children and adolescents. Both environmental (lack of physical activity, excess nutritional intake, sedentary lifestyle) and genetic factors contribute to this global epidemic. The growing prevalence of T2D in youth is also associated with a consistently increased incidence of metabolic and cardiovascular complications. Insulin resistance (IR), i.e., whole-body decreased glucose uptake in response to physiological insulin levels, determines impaired glucose homeostasis and it is recognized as cardinal trigger of T2D and cardiovascular disease in both adults and children. In particular, IR and beta-cell dysfunction lead to the persistent hyperglycemia which characterizes T2D. Indeed, both pathological states influence each other and presumably play a crucial, synergistic role in the pathogenesis of T2D, although the precise mechanisms are not completely understood. However, beta-cell dysfunction and IR induce impaired glucose metabolism, thus leading to the progression to T2D. Therefore, understanding the mechanisms correlated with the decline of beta-cell function and IR is crucial in order to control, prevent, and treat T2D in youth. This review focuses on the current knowledge regarding IR and T2D in children and adolescents and showcases interesting opportunities and stimulating challenges for the development of new preventative approaches and therapeutic strategies for young patients with T2D.