Corrected Insulin Response Research Articles

Increased Genetic Risk for β-Cell Failure Is Associated With β-Cell Function Decline in People With Prediabetes.

Partitioned polygenic scores (pPS) have been developed to capture pathophysiologic processes underlying type 2 diabetes (T2D). We investigated the influence of T2D pPS on diabetes-related traits and T2D incidence in the Diabetes Prevention Program. We generated five T2D pPS (β-cell, proinsulin, liver/lipid, obesity, lipodystrophy) in 2,647 participants randomized to intensive lifestyle, metformin or placebo arms. Associations were tested using general linear models and Cox regression adjusted for age, sex, and principal components. Sensitivity analyses included adjustment for BMI. Higher β-cell pPS was associated with lower insulinogenic index and corrected insulin response at one year follow-up adjusted for baseline measures (effect per pPS standard deviation (SD) -0.04, P=9.6 x 10-7; -8.45 uU/mg, P=5.6 x 10-6, respectively) and with increased diabetes incidence adjusted for BMI at nominal significance (HR 1.10 per SD, P=0.035). The liver/lipid pPS was associated with reduced one-year baseline-adjusted triglyceride levels (effect per SD -4.37, P=0.001). There was no significant interaction between T2D pPS and randomized groups. The remaining pPS were associated with baseline measures only. We conclude that despite interventions for diabetes prevention, participants with a high genetic burden of the β-cell cluster pPS had worsening in measures of β-cell function.

Can we Predict Incipient Diabetes Mellitus in Patients with Transfusion Dependent β-Thalassemia (β-TDT) Referred with a History of Prediabetes?

Prediabetes and diabetes mellitus (DM) are complications in adult patients with transfusion-dependent β-thalassemia (β-TDT), with their incidence increasing with age. This retrospective observational study describes the glycemic trajectories and evaluates predictive indices of β-cell function and insulin sensitivity/resistance in β-TDT patients with prediabetes, both in a steady state and during 3-h oral glucose tolerance test (OGTT), in order to identify patients at high risk for incipient diabetes. The study was mainly conducted at the Pediatric and Adolescent Outpatient Clinic, Quisisana Hospital, Ferrara (Italy), in collaboration with thalassemia referring centers across Italy. The study included 11 β-TDT (aged 15.11-31.10 years) with prediabetes. Methods: The ADA criteria for the diagnosis of glucose dysregulation were adopted. Investigations included evaluating plasma glucose levels and insulin secretion, analyzing glycemic trajectories and indices of β-cell function, and insulin sensitivity/resistance assessed in steady state and during OGTT. The duration of progression from prediabetes to DM, expressed in years, showed a positive direct correlation with corrected insulin response (CIR-30 = r: 0.7606, P: 0.0065), insulinogenic index (IGI 0-120 = r: 0.6121, P:0.045), oral disposition index (oDI = r: 0.7119, P:0.013), insulin growth factor-1 (IGF-1= r: 0.6246, P: 0.039) and an inverse linear correlation with serum ferritin (SF = r: -0.7197, P: 0.012). The number of patients with 1-hour post-load PG value ≥ 155 mg/dL ( ≥ 8.6 mmol/L) was at -4 years: 4/9 (44.4%); -3 years: 8/9 (88.8%); - 2 years: 7/10 (70 %) and at -1 year: 11/11 (100%) (PG range:162-217 mg/dL). A progressive increase in 1-hour PG in response to OGTT is associated with progressive β-cell failure, peripheral resistance to insulin action, and reduced oDI and may be considered a relevant marker for incipient DM in β-TDT patients with prediabetes.

250-LB: Ethnic Disparities in Insulin Secretion and Clearance in Normoglycemic Adults with Parental Type 2 Diabetes

Background: To determine the role of ethnicity vs. heredity in glucoregulation, we assessed insulin secretion in healthy Black and White offspring of parents with T2DM. Methods: Participants were screened with 75-g OGTT, and normoglycemic enrollees underwent assessments, including anthropometry, insulin sensitivity and secretion. Basal insulin secretion (fasting insulin {FI} and HOMA-B) and dynamic secretion (insulinogenic index; corrected insulin response {CIR} from OGTT data; acute insulin response to i.v. glucose {AIR}, insulin-AUC during FSIGT, and disposition index {DI} were quantified. Insulin sensitivity (ISI) was measured with euglycemic clamp. Basal insulin clearance (molar ratio of fasting C-peptide to insulin) and dynamic clearance (molar ratio of plasma C-peptide to insulin levels during FSIGT) were determined. Results: We studied 145 Black and 123 White adults (N=268); 72% women; mean age 44.6±10.1 y. At baseline, fasting glucose (91.0 ± 7.26 vs.93.1 ± 6.31 mg/dl, P=0.012) and ISI (0.062 ± 0.048 vs. 0.077 ± 0.04, P=.014) were lower, and BMI (31.6 ± 7.64 vs. 28.9 ± 6.79, P=.0032) higher, in Black vs. White subjects. Basal insulin secretion was similar, but all measures of dynamic secretion were higher in Black vs. White offspring (Table 1). Conclusions: Insulin clearance is lower but dynamic insulin secretion is greater in Black versus White individuals with parental diabetes. Disclosure P. Asuzu: None. A. Patel: None. J. Y. Wan: None. S. Dagogo-jack: None.

287-OR: An ABCC8 R1420H Loss-of-Function Variant Affects Insulin Secretory Function and Microvascular Disease in American Indians

The ABCC8 gene regulates insulin secretion and plays a critical role in glucose homeostasis. An R1420H loss-of-function variant in ABCC8 was previously detected in ~3% of people in an American Indian Community with a high prevalence of type 2 diabetes (T2D); heterozygous carriers had a doubling in T2D risk and developed this disease at younger ages and lower BMIs. To further examine the phenotype of this variant, we analyzed the relationship between insulin secretion (2-h post-load corrected insulin response) and insulin sensitivity index [104/(fasting insulin*glucose)] in 5701 members of this population without diabetes aged ≥5 years using standard major axis regression, which adjusts insulin secretion for sensitivity. We used hierarchical logistic regression models in up to 7672 individuals to study cross-sectional associations with diabetes complications including increased albuminuria [albumin to creatinine ratio (ACR) ≥30 mg/g], severe albuminuria (ACR ≥ 300 mg/g), reduced eGFR (eGFR<60 mL/min/1.73m2), and retinopathy assessed by fundoscopic examination. Variant carriers had worse beta-cell function than non-carriers both in children and adults (p=0.0003) with no difference in insulin sensitivity (p=0.50). This variant did not associate significantly with increased albuminuria, severe albuminuria or reduced eGFR after adjustment for age, sex, and presence and duration of diabetes. By contrast, carriers had significantly higher odds of retinopathy (OR=1.74, 95% CI: 1.19, 2.53). Increased odds of retinopathy were also observed among individuals with and without diabetes, and when adjusted for fasting plasma glucose (FPG) [carriers had higher FPG (b=6.1 mg/dl, 95% CI: 3.0, 9.2) adjusted for age, sex, and presence and duration of diabetes]. In sum, carriers of the R1420H ABCC8 variant have a higher risk of retinopathy but not of abnormal ACR or eGFR; this may be partially explained by higher glycemia levels and worse beta-cell function. Disclosure E.Vazquez arreola: None. W.C.Knowler: None. L.Baier: None. R.L.Hanson: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases

Association between serum S100A11 levels and glucose metabolism in diabetic process

BackgroundDiabetes mellitus (DM) is a prevalent non-communicable metabolic disease, and S100A11 is a newly identified gene closely related to metabolism. The association of S100A11 with diabetes is unclear. This study aimed to assess the relationship between S100A11 and markers of glucose metabolism in patients with different glucose tolerance and gender.MethodsThis study included 97 participants. Baseline data were obtained, and the serum levels of S100A11 and metabolic markers (glycated hemoglobin [HbA1c], insulin release test, and oral glucose tolerance test) were measured. Linear and nonlinear correlations between serum S100A11 levels and HOMA-IR, HOMA of β, HbA1c, insulin sensitivity index (ISI), corrected insulin response (CIR), and oral disposition index (DIo) were analyzed. The expression of S100A11 was also detected in mice.ResultsSerum S100A11 levels increased in patients with impaired glucose tolerance (IGT) of both genders. S100A11 mRNA and protein expression increased in obese mice. There were nonlinear correlations between S10011 levels and CIR, FPI, HOMA-IR, whole-body ISI in the IGT group. S100A11 was nonlinearly correlated with HOMA-IR, hepatic ISI, FPG, FPI, and HbA1c in the DM group. In the male group, S100A11 was linearly correlated with HOMA-IR and nonlinearly correlated with DIo (derived from hepatic ISI) and HbA1c. In the female population, S100A11 was nonlinearly correlated with CIR.ConclusionsSerum S100A11 levels were highly expressed in patients with IGT and in the liver of obese mice. In addition, there were linear and nonlinear correlations between S100A11 and markers of glucose metabolism, demonstrating that S100A11 has a role in diabetes.Trial registration ChiCTR1900026990

Insulin Response to Oral Glucose and Cardiometabolic Disease: A Mendelian Randomization Study to Assess Potential Causality

Mendelian randomization (MR) suggests post-prandial hyperinsulinemia (unadjusted for plasma glucose) increases body mass index (BMI) but its impact on cardiometabolic disease (CMD), a leading cause for mortality and morbidity in people with obesity, is not established. Fat distribution, i.e. increased centripetal and/or reduced femoro-gluteal adiposity, is causally associated with and better predicts CMD than BMI. We therefore undertook bi-directional MR to assess the effect of corrected insulin response (CIR, insulin 30 minutes after a glucose challenge adjusted for plasma glucose) on BMI, waist–to-hip ratio (WHR), leg fat, type 2 diabetes (T2D), triglyceride (TG), high-density lipoprotein (HDL), liver fat, hypertension and CAD in people of European descent.

Rs864745 in JAZF1, an Islet Function Associated Variant, Correlates With Plasma Lipid Levels in Both Type 1 and Type 2 Diabetes Status, but Not Healthy Subjects.

ObjectiveThis study aims to reveal the association between JAZF1 rs864745 A>G variant and type 2 diabetes (T2D), type 1 diabetes (T1D) risk, and their correlation with clinical features, including islet function, islet autoimmunity, and plasma lipid levels.MethodsWe included 2505 healthy controls based on oral glucose tolerance test (OGTT), 1736 unrelated T2D, and 1003 unrelated autoantibody-positive T1D individuals. Binary logistic regression was performed to evaluate the relationships between rs864745 in JAZF1 and T2D, T1D, and islet-specific autoantibody status under the additive model, while multiple linear regression was used to assess its effect on glycemic-related quantitative traits and plasma lipid levels.ResultsWe did not find any association between rs864745 in JAZF1 and T2D, T1D, or their subgroups (All P > 0.05). For glycemic traits, we found that the G allele of this variant was significantly associated with higher 120 min insulin level, insulinogenic index (IGI), corrected insulin response (CIR), and acute insulin response (BIGTT-AIR) (P = 0.033, 0.006, 0.009, and 0.016, respectively) in healthy individuals. Similar associations were observed in newly diagnosed T2D but not T1D individuals. Although this variant had no impact on islet autoimmunity (All P > 0.05), significant associations with plasma total cholesterol (TC) and low-density lipoprotein (LDL) level stratified by JAZF1 rs864745 variant were observed in the disease status of T2D (P = 0.002 and 0.003) and T1D (P = 0.024 and 0.009), with significant heterogeneity to healthy individuals.ConclusionsThe common JAZF1 rs864745 variant contributes to islet function and lipid metabolism, which might be put into genetic risk scores to assess the risk of related clinical features.

Insulin Response to Oral Glucose and Cardiometabolic Disease: A Mendelian Randomization Study to Assess Potential Causality.

Mendelian randomization (MR) suggests that postprandial hyperinsulinemia (unadjusted for plasma glucose) increases BMI, but its impact on cardiometabolic disease, a leading cause for mortality and morbidity in people with obesity, is not established. Fat distribution i.e., increased centripetal and/or reduced femoro-gluteal adiposity, is causally associated with and better predicts cardiometabolic disease than BMI. We therefore undertook bidirectional MR to assess the effect of corrected insulin response (CIR) (insulin 30 min after a glucose challenge adjusted for plasma glucose) on BMI, waist-to-hip ratio (WHR), leg fat, type 2 diabetes (T2D), triglyceride (TG), HDL, liver fat, hypertension (HTN), and coronary artery disease (CAD) in people of European descent. Inverse variance-weighted MR suggests a potential causal association between increased CIR and increased BMI (b = 0.048 ± 0.02, P = 0.03), increased leg fat (b = 0.029 ± 0.012, P = 0.01), reduced T2D (b = -0.73 ± 0.15, P = 6 × 10-7, odds ratio [OR] 0.48 [95% CI 0.36-0.64]), reduced TG (b = -0.07 ± 0.02, P = 0.003), and increased HDL (b = 0.04 ± 0.01, P = 0.006) with some evidence of horizontal pleiotropy. CIR had neutral effects on WHR (b = 0.009 ± 0.02, P = 0.69), liver fat (b = -0.08 ± 0.04, P = 0.06), HTN (b = -0.001 ± 0.004, P = 0.7, OR 1.00 [95% CI 0.99-1.01]), and CAD (b = -0.002 ± 0.002, P = 0.48, OR 0.99 [95% CI 0.81-1.21]). T2D decreased CIR (b -0.22 ± 0.04, P = 1.3 × 10-7), with no evidence that BMI, TG, HDL, liver fat, HTN, and CAD modulate CIR. In conclusion, we did not find evidence that increased CIR increases cardiometabolic disease. It might increase BMI with favorable fat distribution, reduce T2D, and improve lipids.

Oral Glucose Tolerance Test-based Measures of Insulin Secretory Response in Pregnancy.

Oral glucose tolerance test (OGTT)-based measures of insulin secretory response have not been validated in pregnancy. In a secondary analysis of a longitudinal study, participants were studied prepregnancy (n = 40), in early pregnancy (n = 36; 12-14 weeks' gestation), and in late pregnancy (n = 36; 34-36 weeks' gestation). Participants underwent an OGTT, an intravenous glucose tolerance test (IVGTT), and a hyperinsulinemic-euglycemic clamp at each timepoint. We calculated homeostatic model assessment of beta-cell function (HOMA-2B), insulinogenic index (IGI), corrected insulin response (CIR), ratio of the area under the insulin curve and the area under the glucose curve (AUCins/AUCglu), and Stumvoll first-phase estimate (Stumvoll) from OGTT insulin and glucose levels. We used Pearson correlation to compare measures from OGTT and IVGTT. We used mixed effects models to examine longitudinal changes in insulin secretory response. Stumvoll was the only OGTT-based measure that was significantly correlated with first-phase insulin response prior to and across gestation (prepregnancy: r = 0.44, P = 0.01; early pregnancy: r = 0.67, P = 0.0001; late pregnancy: r = 0.67, P = 0.0001). In early and late pregnancy, AUCins/AUCglu had the strongest correlation with first-phase insulin response (early pregnancy: r = 0.79, P < 0.0001; late pregnancy: r = 0.69, P < 0.0001) but was not significantly correlated prepregnancy. IGI and CIR were significantly correlated with first-phase insulin response prepregnancy (IGI: r = 0.50, P = 0.005; CIR r = 0.47, P = 0.008) and in late pregnancy (IGI: r = 0.68, P = 0.0001; CIR r = 0.57, P = 0.002) but not in early pregnancy. HOMA-2B was the weakest correlate of first-phase insulin response. Stumvoll and AUCins/AUCglu recapitulated the longitudinal changes in insulin secretory response observed by IVGTT. Stumvoll and AUCins/AUCglu are valid OGTT-based insulin secretory response measures for pregnancy studies.

Interplay of Dinner Timing and MTNR1B Type 2 Diabetes Risk Variant on Glucose Tolerance and Insulin Secretion: A Randomized Crossover Trial.

We tested whether the concurrence of food intake and elevated concentrations of endogenous melatonin, as occurs with late eating, results in impaired glucose control, in particular in carriers of the type 2 diabetes-associated G allele in the melatonin receptor-1B gene (MTNR1B). In a Spanish natural late-eating population, a randomized, crossover study was performed. Each participant (n = 845) underwent two evening 2-h 75-g oral glucose tolerance tests following an 8-h fast: an early condition scheduled 4 h prior to habitual bedtime ("early dinner timing") and a late condition scheduled 1 h prior to habitual bedtime ("late dinner timing"), simulating an early and a late dinner timing, respectively. Differences in postprandial glucose and insulin responses between early and late dinner timing were determined using incremental area under the curve (AUC) calculated by the trapezoidal method. Melatonin serum levels were 3.5-fold higher in the late versus early condition, with late dinner timing resulting in 6.7% lower insulin AUC and 8.3% higher glucose AUC. The effect of late eating impairing glucose tolerance was stronger in the MTNR1B G-allele carriers than in noncarriers. Genotype differences in glucose tolerance were attributed to reductions in β-cell function (P for interaction, Pint glucose area under the curve = 0.009, Pint corrected insulin response = 0.022, and Pint disposition index = 0.018). Concurrently high endogenous melatonin and carbohydrate intake, as typical for late eating, impairs glucose tolerance, especially in MTNR1B G-risk allele carriers, attributable to insulin secretion defects.

Insulin action and secretion independent of traditional risk factors predict new-onset type 2 diabetes in Iraqi and Swedish born citizens - The MEDIM cohort study.

Our aim was to study the incidence of type 2 diabetes in a population-based cohort of Swedish and Iraqi born individuals, focussing on traditional risk factors, insulin action, insulin secretion and ethnicity. The cohort consisted of 1164 Iraqi and 693 Swedish-born citizens. We investigated the association between new-onset type 2 diabetes and the predictors including lifestyle factors, metabolic risk markers, country of birth, insulin sensitivity and secretion assessed by Matsuda index with Cox regression. Eighty-nine individuals were diagnosed with type 2 diabetes with a mean follow-up of 7.5years. Both lower insulin sensitivity (ISI, HR 0.02 [0.01-0.08]) as well as insulin secretion (CIR, HR 0.13 [0.07-0.24]) at baseline predicted type 2 diabetes onset, independent of traditional risk factors. Our results were not modified by country of birth. Regarding traditional risk factors, WHR (1.05 [1.00-1.09]), blood glucose (3.27 [2.35-4.55]), LDL/HDL (1.46 [1.20-1.78]) and diastolic blood pressure (1.04 [1.00-1.07]) predicted diabetes incidence in the full model. Both impaired insulin sensitivity index and corrected insulin response predicted type 2 diabetes onset, independent of traditional risk factors. We conclude that insulin secretion and action might be useful additional predictors for type 2 diabetes in populations of European and Middle Eastern ethnicities.

Dietary Macronutrient Intake May Influence the Effects of TCF7L2 rs7901695 Genetic Variants on Glucose Homeostasis and Obesity-Related Parameters: A Cross-Sectional Population-Based Study.

Transcription factor-7–like 2 (TCF7L2) is one of the most important susceptibility genes for type 2 diabetes mellitus (T2DM). The aim of our cross-sectional population-based study was to analyze whether daily macronutrient intake may influence the effects of the TCF7L2 rs7901695 genotype on glucose homeostasis and obesity-related parameters. We recruited 810 participants (47.5% men and 52.5% women), 18–79 years old (mean age, 42.1 (±14.5) years), who were genotyped for the common TCF7L2 rs7901695 single-nucleotide polymorphism (SNP), and anthropometric measurements, body composition, body fat distribution (visceral (VAT) and subcutaneous adipose tissue (SAT) content), blood glucose and insulin concentrations after fasting and during OGTTs, and HbA1c were assessed. The VAT/SAT ratio, HOMA-IR (homeostatic model assessment of insulin resistance), HOMA-B (homeostatic model assessment of β-cell function), and CIR30 (corrected insulin response) were calculated. The daily macronutrient intake was evaluated based on 3-day food-intake diaries. Daily physical activity was evaluated based on a validated questionnaire. We performed ANOVA or Kruskal–Wallis tests, and multivariate linear regression models were created to evaluate the effects of dietary macronutrient intake on glucose homeostasis and obesity-related parameters in carriers of the investigated genotypes. This study was registered at ClinicalTrials.gov as NCT03792685. The TT-genotype carriers stratified to the upper protein intake quantiles presented higher HbA1c levels than the CT- and CC-genotype participants in the same quantiles (p = 0.038 and p = 0.022, respectively). Moreover, we observed higher HOMA-IR (p = 0.014), as well as significantly higher blood glucose and insulin concentrations, during the OGTTs for those in the upper quantiles, when compared to subjects from the lower quantiles of protein intake, while the CC-genotype carriers presented significantly lower HbA1c (p = 0.033) and significantly higher CIR30 (p = 0.03). The linear regression models revealed that an increase in energy derived from proteins in TT carriers was associated with higher HbA1c levels (β = 0.37 (95% CI: 0.01–0.74, p = 0.05)), although, in general, carrying the TT genotype, but without considering protein intake, showed an opposite tendency—to lower HbA1c levels (β = −0.22 (95% CI: 0.47 to −0.01, p = 0.05). Among the subjects stratified to the lower quantile of carbohydrate intake, the TT-genotype individuals presented higher HbA1c (p = 0.041), and the CC-genotype subjects presented higher VAT (p = 0.033), lower SAT (p = 0.033), and higher VAT/SAT ratios (p = 0.034). In both the CC- and TT-genotype carriers, we noted higher VAT (p = 0.012 and p = 0.0006, respectively), lower SAT (p = 0.012 and p = 0.0006, respectively) and higher VAT/SAT ratios (p = 0.016 and p = 0.00062, respectively) when dietary fat provided more than 30% of total daily energy intake, without any differences in total body fat content. Our findings suggest that associations of the common TCF7L2 SNP with glucose homeostasis and obesity-related parameters may be dependent on daily macronutrient intake, which warrants further investigations in a larger population, as well as interventional studies.

249-OR: Type 2 Diabetes (T2D) Genetic Clusters for Association with Glycemic Responses to Intervention for Diabetes Prevention

Polygenic scores (PS) of T2D genetic variants based on pathophysiologic mechanisms underlying diabetes have been developed. We investigated whether T2D cluster PS influences response to interventions for diabetes prevention. We examined 2,647 DPP participants with impaired glucose tolerance and genetic data randomized to intensive lifestyle, metformin or placebo arms for diabetes prevention. We generated five PS clusters including β-cell related clusters (β-cell, proinsulin) and insulin resistance clusters (liver/lipid, obesity, lipodystrophy). We examined associations of PS with baseline and 1-year glycemic traits after intervention derived from oral glucose tolerance tests using general linear models, and with diabetes incidence over an average period of 3 years using Cox Regression Models. Models were adjusted for sex, age, and 10 principal components, respective baseline trait, and treatment group. At one-year follow-up, β-cell PS was associated with reduction in the insulinogenic index and corrected insulin response, in each treatment group and, statistically significant, in all combined (P&amp;lt;0.001), with no statistically significant interaction term between treatment groups, a finding consistent with a slightly increased diabetes incidence (HR 1.02 per weighted allele [CI 95% 1.00, 1.03]). The remaining PS were associated with baseline participant features, but not with diabetes incidence or change in glycemic parameters from baseline. We conclude that high genetic burden in β-cell cluster PS is associated with greater risk of diabetes and a decrease in insulin secretion, seen across all treatment groups. Despite interventions with intensive lifestyle and metformin, participants with high β-cell cluster genetic burden had an increased risk of diabetes and worsening in insulin secretion similar to placebo group. These data suggest that alternate therapies may be needed to prevent β-cell decline in this subset of prediabetes patients. Disclosure L. K. Billings: Advisory Panel; Self; Bayer Inc., Lilly Diabetes, Novo Nordisk, Sanofi. S. Raghavan: None. S. Srinivasan: None. J. Xu: None. J. C. Florez: Consultant; Self; Goldfinch Bio, Inc., Other Relationship; Self; Novo Nordisk. M. Udler: None. D. Research group: None. K. A. Jablonski: None. P. W. Franks: Advisory Panel; Self; Zoe Global Limited, Consultant; Self; Eli Lilly and Company, Novo Nordisk. R. B. Goldberg: None. M. Hivert: None. S. E. Kahn: Advisory Panel; Self; Bayer AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck &amp; Co., Inc., Novo Nordisk, Pfizer Inc. W. C. Knowler: None. C. Lee: None. J. Merino: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (U01DK048489)

1384-P: Changes in OGTT-Based Measures of Insulin Secretory Response across Pregnancy

Background: We previously showed that insulin response to an IV glucose load increases in early pregnancy, independent of changes in insulin sensitivity. It is unknown whether oral glucose tolerance test (OGTT)-based measures of insulin secretory response (ISR) capture the same phenomenon. Methods: This is a secondary analysis of a longitudinal study. Participants (N=31) were studied pre-pregnancy and in early (12-14 wks) and late (34-36 wks) gestation. On separate days, after overnight fasts, an OGTT (75g pre-pregnancy/100g in pregnancy) and an hyperinsulinemic-euglycemic clamp were performed. We calculated Insulinogenic index (IGI), Corrected insulin response (CIR), insulin/glucose area under the curve (AUCins/AUCglu), and Stumvoll 1st Phase Estimate (Stumvoll) from OGTT insulin and glucose levels. Linear mixed effects models examined ISR in early as compared to pre- and late pregnancy; we adjusted p-values for 2 comparisons. Adjusted models included insulin sensitivity, measured with the clamp, as a time-dependent covariate. Results: IGI (adjusted mean ± SEM) increased between pre- and early pregnancy (1.25 ± 0.13 vs. 1.52 ± 0.15, P&amp;lt;0.05) and remained stable between early and late pregnancy (1.41 ± 0.14, P=0.42). Findings did not change after adjustment for insulin sensitivity (pre:1.29 ± 0.13 vs. early: 1.59 ± 0.16, P=0.03; early vs. late: 1.31 ± 0.16, P=0.32). Changes in CIR were similar. AUCins/AUCglu increased from pre- to early pregnancy (0.47 ± 0.05 vs. 0.55 ± 0.05 P=0.03) and increased further from early to late pregnancy (0.79 ± 0.07, P&amp;lt;0.01). The increase in AUCins/AUCglu between pre- and early pregnancy was independent of changes in insulin sensitivity (0.50 ± 0.04 vs. 0.66 ± 0.05, P&amp;lt;0.01), but the increase between early and late pregnancy (0.65 ± 0.07) was not apparent after adjusting for insulin sensitivity (P&amp;gt;0.99). The results for Stumvoll were similar. Conclusion: OGTT-based ISR indices capture an insulin sensitivity-independent augmentation of insulin secretion in early pregnancy. Disclosure C.E. Powe: None. J.J. Locascio: None. P. Catalano: None. Funding National Institutes of Health (K23DK113218); Robert Wood Johnson Foundation; Harold Amos Medical Faculty Development Award

Advancing Dinner Timing Is an Effective Strategy in Improving Glucose Tolerance in Free-Living Adults: A Randomized Cross-Over Trial

Abstract Objectives Eating at times that conflict with our physiology and coincide with the biological evening has been associated with increased disease risk. In free-living adults from the ONTIME-MT study (#NCT03036592) study, we tested the hypothesis that advancing the timing of dinner relative to bedtime, simulated by advancing an evening oral glucose tolerance test (OGTT), will result in improved glucose control. Methods In a randomized, cross-over study design, following an 8h fast, each participant underwent two evening 2-hour 75-gram oral OGTT: early and late (4h vs. 1h prior to habitual bedtime), simulating early and late dinner timing. Habitual bedtime was determined using one-week of electronic sleep logs via smartphone application. The OGTT order was randomized and separated by 1-week washout period. Light intensity was kept bright (≥450 lux) and dim (0–25 lux) in the early and late conditions, respectively. Melatonin was assessed at the start and end of each OGTT by radioimmunoassay. Postprandial glucose and insulin were determined using incremental area under the curve (AUC). Insulin sensitivity and beta-cell function were evaluated using standard metrices: insulin sensitivity index (ISI), corrected insulin response (CIR), and disposition index (DI). Values were compared using paired t-tests and differences were considered significant at P &amp;lt; 0.05. Results A total of 750 participants (mean age = 37 ± 14; 70% female; mean BMI = 26.12 ± 5.66) underwent OGTTs in two evening timing conditions. As expected, melatonin levels were higher in the late vs. early condition (4.49 ± 4.15-fold lower in the early vs. late meal condition. In the early condition, there was an 8.68% lower AUC for glucose (P = .0001) and 4.4% higher insulin AUC (P = 0.059), relative to the late condition. In addition, the CIR was 16% (P = .0001) higher and the DI was higher by 20% (P = .014) in the early compared to the late condition. The ISI was similar in both conditions (P = 0.66). Conclusions In this large study, glucose tolerance was better during early vs. late evening OGTT. Better glucose tolerance was primarily attributed to improved insulin secretion and beta-cell function. These results indicate that for the general population, advancing dinner relative to bedtime may be a novel and an effective strategy to improve glucose tolerance. Funding Sources ONTIME-MT was funded by the NIH R01 grant R01DK105072.

OR08-02 Do OGTT-based Insulin Secretory Response Measures Approximate 1st Phase Insulin Response in Pregnant Women?

Background: We previously showed that 1st phase insulin response increases dramatically in pregnancy, independent of changes in insulin sensitivity. Measurement of 1st phase insulin response requires the use of hyperglycemic clamps or intravenous glucose tolerance tests (IVGTTs) which are rarely performed in pregnant women. Oral glucose tolerance test (OGTT)-based measures of insulin secretory response have not been validated in pregnancy. Methods: In a secondary analysis of a longitudinal study of glucose metabolism in pregnancy, we examined Pearson correlations between OGTT-based insulin secretory response measures and 1st phase insulin response. Forty women were studied pre-pregnancy; 36 returned in early and late pregnancy (12–14 and 34–36 weeks gestation). At each time point, after overnight fasts, an IVGTT and an OGTT were performed on separate days. The 1st phase insulin response was calculated as the incremental area under the curve during the 1st 10 minutes after intravenous administration of a 0.5 g/kg glucose load (or 19g/m2 body surface area if weight >120% ideal body weight). Homeostatic Model Assessment (HOMAB), Insulinogenic index (IGI), Corrected insulin response (CIR), Insulin area under the curve/Glucose area under the curve (AUCins/AUCglu), and the Stumvoll 1st Phase Estimate (Stumvoll) were calculated from insulin and glucose levels measured fasting and 30, 60, 90, 120, and 180 minutes after an oral glucose load (75 grams pre-pregnancy, 100 grams in pregnancy). Results: The best OGTT-based measure for estimation of 1st phase insulin response differed across study timepoints. In early and late pregnancy, AUCins/AUCglu had the strongest correlation with 1st phase insulin response (early: R=0.79, P<0.0001; late: R=0.69, P<0.0001), but was not associated with 1st phase insulin response pre-pregnancy (R=0.32, P=0.08). IGI had the strongest correlation with first phase insulin response pre-pregnancy (R=0.50, P=0.005) and was correlated with 1st phase insulin response in late (R=0.68, P=0.0001), but not early (R=0.36, P=0.07) pregnancy. Stumvoll was the only OGTT-based measure that was significantly correlated with 1st phase insulin response at all timepoints (pre: R=0.44, P=0.01; early: R=0.67, P=0.0001; late: R=0.67, P=0.0001). HOMAB was the weakest correlate of 1st phase insulin response, though the correlation was significant in early pregnancy (pre: R=-0.04, P=0.82; early: R=0.33, P=0.05; late: R=0.18, P=0.28). Conclusion: OGTT-based measures of insulin secretion do not have a consistent relationship with 1st phase insulin response across pre-, early, and late pregnancy. Our findings suggest that Stumvoll can be used in OGTT-based longitudinal studies of insulin secretory response that begin prior to pregnancy and span gestation. For cross-sectional studies in pregnancy, AUCins/AUCglu are the best estimates of 1st phase insulin response.

The associations of daylight and melatonin receptor 1B gene rs10830963 variant with glycemic traits: the prospective PPP-Botnia study

Background: Seasonal variation in glucose metabolism might be driven by changes in daylight. Melatonin entrains circadian regulation and is directly associated with daylight. The relationship between melatonin receptor 1B gene variants with glycemic traits and type 2 diabetes is well established. We studied if daylight length was associated with glycemic traits and if it modified the relationship between melatonin receptor 1B gene rs10830963 variant and glycemic traits.Materials: A population-based sample of 3422 18–78-year-old individuals without diabetes underwent an oral glucose tolerance test twice, an average 6.8 years (SD = 0.9) apart and were genotyped for rs10830963. Daylight data was obtained from the Finnish Meteorological Institute.Results: Cross-sectionally, more daylight was associated with lower fasting glucose, but worse insulin sensitivity and secretion at follow-up. Longitudinally, individuals studied on lighter days at follow-up than at baseline showed higher glucose values during the oral glucose tolerance test and lower Corrected Insulin Response at follow-up. GG genotype carriers in the rs10830963 became more insulin resistant during follow-up if daylight length was shorter at follow-up than at baseline.Conclusions: Our study shows that individual glycemic profiles may vary according to daylight, MTNR1B genotype and their interaction. Future studies may consider taking daylight length into account.Key messagesIn Western Finland, the amount daylight follows an extensive annual variation ranging from 4 h 44 min to 20 h 17 min, making it ideal to study the associations between daylight and glycemic traits. Moreover, this allows researchers to explore if the relationship between the melatonin receptor 1B gene rs10830963 variant and glycemic traits is modified by the amount of daylight both cross-sectionally and longitudinally.This study shows that individuals, who participated in the study on lighter days at the follow-up than at the baseline, displayed to a greater extent worse glycemic profiles across the follow-up.Novel findings from the current study show that in the longitudinal analyses, each addition of the minor G allele of the melatonin receptor 1B gene rs10830963 was associated with worsening of fasting glucose values and insulin secretion across the 6.8-year follow-up.Importantly, this study shows that in those with the rs10830963 GG genotype, insulin sensitivity deteriorated the most significantly across the 6.8-year follow-up if the daylight length on the oral glucose tolerance testing date at the follow-up was shorter than at the baseline.Taken together, the current findings suggest that the amount of daylight may affect glycemic traits, especially fasting glucose and insulin secretion even though the effect size is small. The association can very according to the rs10830963 risk variant. Further research is needed to elucidate the mechanisms behind these associations.

Genome-Wide Association Study of Inflammatory Cytokines in Southwestern Native Americans Identifies Novel Association between WWOX and Serum TNF-? Levels

Inflammatory processes may contribute to type 2 diabetes (T2D), but there is limited information about genetic associations with circulating levels of inflammatory cytokines. We performed a genome-wide association study (GWAS) of cytokines in 1061 nondiabetic Southwestern Native Americans (500 women; 561 men). Fasting serum concentrations of interleukin-6 (IL-6), plasminogen activator inhibitor-1 (PAI-1) and tumor necrosis factor-α (TNF-α) were measured using EMD Millipore assays. Genotypic data on 496,190 single-nucleotide polymorphisms (SNPs) with minor allele frequency &amp;gt;1% were derived from an Affymetrix Axiom array designed to capture common variation in Pima Indians. Data were normalized and analyzed for associations using a mixed model accounting for familial relationships, adjusted for age, sex and genetic principal components 1-5. The strongest associations were on chromosome 3 near A4GNT with IL-6 levels (rs2724711 p=4.2×10-6), and on chromosome 7 with PAI-1 levels (rs1608488 (p=8.3×10-7). An association of genome-wide statistical significance (rs1862840; p=1.2×10-8) was observed on chromosome 16 near WWOX with TNF-α levels. Each copy of the G allele (frequency=0.12) confers a 0.41-SD increase in TNF-α levels. In a larger cohort of Southwestern Native Americans, rs1862840 was not associated with T2D (N=7,659; p=0.17). Among 3,983 nondiabetic subjects it did associate with 2 hour corrected insulin response (β=0.06-SD decrease per G allele copy, p=0.011). Among 300 normal glucose tolerant subjects it associated with the acute insulin response to intravenous glucose (β=20% decrease per G allele copy, p=0.045). This study identified a novel association for TNF-α levels at WWOX (a gene previously implicated in T2D and insulin secretion in Han Chinese study populations) and suggests potential genetic links between inflammation and insulin secretion. Disclosure L.E. Wedekind: None. M. Walter: None. S. Kobes: None. P. Chen: None. W. Hsueh: None. R. Nelson: None. L. Baier: None. W.C. Knowler: None. R.L. Hanson: None.

SNP x SNP Interactions Elucidate TCF7L2’s Physiology Conveying Incretin Action

Introduction: Genetic polymorphisms in TCF7L2 are the strongest common risk variants for type 2 diabetes. We and others had showed that genetic variation in TCF7L2 affects incretin-stimulated insulin secretion. A recent genome-wide association study discovered variants associated with incretin levels. We hypothesized that these SNPs interact with the well-known TCF7L2 variant rs7903146 on insulin secretion due to their incretin altering effect. Methods: Insulin secretion was measured with OGTT-based indices that were calculated from insulin, C-peptide and glucose levels in the cross-sectional TUEF-cohort (n=2929). We also measured insulin secretion in a modified hyperglycemic clamp at 10 mmol/l, using additional GLP-1 infusion at the end of the clamp (n=76). Besides rs7903146 in TCF7L2, we genotyped rs17681684 in GLP2R, rs1800437 in GIPR, rs17683011 in SLC5A1, as well as 3 additional variants associated with GIP levels. Results: Four of the 6 incretin-associated SNPs exhibited at least nominally significant SNP x SNP interactions with rs7903146 in TCF7L2 on insulin secretion measured by the corrected insulin response (CIR). In the hyperglycemic clamp study, rs7903146 in TCF7L2 interacted with rs1800437 (GIPR) on both AUC insulin and C-peptide, and rs17681684 (GLP2R) on AUC C-peptide during the GLP-1 stimulation phase (p&amp;lt;0.05). Conclusion: These findings corroborate the role of the TCF7L2 variant in mediating incretin action to increase diabetes risk. They highlight the importance of SNP x SNP interactions in the assessment of the genetic architecture of type 2 diabetes. Disclosure B. Jaghutriz: None. M. Heni: Research Support; Self; Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Boehringer Ingelheim GmbH, Merck Sharp &amp; Dohme Corp., Novo Nordisk Inc.. S.Z. Lutz: None. H. Staiger: None. A. Peter: None. H. Haering: None. A. Fritsche: Advisory Panel; Self; Sanofi-Aventis Deutschland GmbH, Novo Nordisk A/S, Eli Lilly and Company, Boehringer Ingelheim GmbH. R. Wagner: None.

Family history of diabetes and its relationship with insulin secretion and insulin sensitivity in Iraqi immigrants and native Swedes: a population-based cohort study

AimsMiddle Eastern immigrants to western countries are at high risk of developing type 2 diabetes. However, the heritability and impact of first-degree family history (FH) of type 2 diabetes on insulin secretion and action have not been adequately described.MethodsCitizens of Malmö, Sweden, aged 30–75 years born in Iraq or Sweden were invited to participate in this population-based study. Insulin secretion (corrected insulin response and oral disposition index) and action (insulin sensitivity index) were assessed by oral glucose tolerance tests.ResultsIn total, 45.7% of Iraqis (616/1348) and 27.4% of native Swedes (201/733) had FH in parent(s), sibling(s) or single parent and sibling, i.e., FH+. Approximately 8% of Iraqis and 0.7% of Swedes had ≥ 3 sibling(s) and parent(s) with diabetes, i.e., FH++. Irrespective of family size, prediabetes and diabetes increased with family burden (FH− 29.4%; FH+ 38.8%; FH++ 61.7%) without significant differences across ethnicities. With increasing level of family burden, insulin secretion rather than insulin action decreased. Individuals with a combination of ≥ 3 siblings and parents with diabetes presented with the lowest levels of insulin secretion.ConclusionsThe Iraqi immigrant population often present with a strong familial burden of type 2 diabetes with the worst glycemic control and highest diabetes risk in individuals with ≥ 3 siblings and parents with diabetes. Our data show that in a population still free from diabetes familial burden influences insulin secretion to a higher degree than insulin action and may be a logical target for intervention.