Insulin Secretion Index Research Articles

Serum Uric Acid concentration is associated with insulin resistance and impaired insulin secretion in adults at risk for Type 2 Diabetes

AimsInsulin resistance (IR) predisposes to type 2 diabetes mellitus (T2DM). Although previous studies have associated serum uric acid concentration with IR in T2DM, its association with impaired insulin secretion and beta-cell dysfunction in subjects at risk for developing T2DM remains uncertain. Thus, we aimed to analyze the association of serum uric acid concentration with IR using surrogate insulin resistance/secretion and beta-cell function indices in subjects at risk for developing T2DM. MethodsThis is a cross-sectional study that included 354 subjects who underwent an oral glucose tolerance test who had at least two risk factors for T2DM without any chronic disease. ResultsParticipants were 51±8 years old, 72.2% were women, had a mean body mass index of 29.9±6.5kg/m2 and mean serum uric acid concentration of 5.7±1.3mg/dL. HOMA-IR, first-phase insulin secretion (S1PhOGTT), second-phase insulin secretion (S2PhOGTT), Matsuda and disposition indices were significantly correlated with serum uric acid concentrations (r=0.239, r=0.225, r=0.201, r=−0.287, r=−0.208; respectively). After multiple linear regression analysis, serum uric acid concentration was independently associated with HOMA-IR (β=0.283), HOMA-B (β=0.185), S1PhOGTT (β=0.203), S2PhOGTT (β=0.186), and Matsuda Index (β=−0.322). A serum uric acid concentration of 5.5mg/dL had the best sensitivity/sensibility to identify subjects with IR (HOMA-IR ≥2.5). ConclusionsSerum uric acid concentration is significantly associated with IR and impaired insulin secretion, but not with beta-cell dysfunction, in subjects at risk for developing T2DM.

The tyrosine kinase inhibitor crizotinib influences blood glucose and mRNA expression of GLUT4 and PPARs in the heart of rats with experimental diabetes.

Tyrosine kinases inhibitors (TKIs) may alter glycaemia and may be cardiotoxic with importance in the diabetic heart. We investigated the effect of multi-TKI crizotinib after short-term administration on metabolic modulators of the heart of diabetic rats. Experimental diabetes mellitus (DM) was induced by streptozotocin (STZ; 80mg·kg-1, i.p.), and controls (C) received vehicle. Three days after STZ, crizotinib (STZ+CRI; 25mg·kg-1 per day p.o.) or vehicle was administered for 7days. Blood glucose, C-peptide, and glucagon were assessed in plasma samples. Receptor tyrosine kinases (RTKs), cardiac glucose transporters, and peroxisome proliferator-activated receptors (PPARs) were determined in rat left ventricle by RT-qPCR method. Crizotinib moderately reduced blood glucose (by 25%, P< 0.05) when compared to STZ rats. The drug did not affect levels of C-peptide, an indicator of insulin secretion, suggesting altered tissue glucose utilization. Crizotinib had no impact on cardiac RTKs. However, an mRNA downregulation of insulin-dependent glucose transporter Glut4 in the hearts of STZ rats was attenuated after crizotinib treatment. Moreover, crizotinib normalized Ppard and reduced Pparg mRNA expression in diabetic hearts. Crizotinib decreased blood glucose independently of insulin and glucagon. This could be related to changes in regulators of cardiac metabolism such as GLUT4 and PPARs.

Serum Kisspeptin and Its Relation to Metabolic Parameters and Glucose Metabolism in Prepubertal and Pubertal Obese Children.

Objective Kisspeptin, a puberty control neuropeptide, has been discovered to have an additional role in metabolism and glucose homeostasis regulation. This study aimed to determine the association of serum kisspeptin with metabolic parameters and glucose metabolism in obese children. Design, Patients and Measurements. A cross-sectional study of 270 obese children was conducted. All children underwent an oral glucose tolerance test and had serum kisspeptin, glycated hemoglobin (HbA1c), and lipid profile measurements. Body fat mass was assessed by bioelectrical impedance analysis. Serum kisspeptin levels of both prepubertal and pubertal children with two HbA1c ranges, <5.7% (normal range) and 5.7–6.4% (prediabetes range), were analyzed and correlated with metabolic parameters and glucose metabolism status. Results The median (IQR) serum kisspeptin level of only pubertal (not prepubertal) children with prediabetes HbA1c was higher than those with normal HbA1c (53.2 (33.9, 69.8) and 37.8 (29.6, 67.5) pg/mL; p = 0.015, respectively). There were no differences in serum kisspeptin levels among children with different glucose metabolism status. During pubertal progression, serum kisspeptin reached the highest level at Tanner stage II only in obese boys. Additionally, there was a positive correlation between serum kisspeptin and HbA1c after adjusting for puberty (β = 12.87; p = 0.001). No correlations between serum kisspeptin and insulin sensitivity indices, insulin secretion indices, lipid profile, blood glucose, as well as percentage of body fat were demonstrated. Conclusions Serum kisspeptin levels in pubertal obese children with prediabetes HbA1c were greater than those with normal HbA1c. Serum kisspeptin was positively associated with HbA1c, but not with glucose metabolism status.

Diabetes mellitus in pheochromocytoma and paraganglioma: Prevalence, dynamics of insulin secretion / sensitivity and predictors of remission

Background and aimsPheochromocytoma and paraganglioma (PPGL) are associated with dysglycemia and diabetes mellitus (DM) much of which improves post operatively. In this study, we set out to ascertain pre and post-operative prevalence of DM in patients with PPGL based on oral glucose tolerance test (OGTT) and HbA1c and to evaluate effect of insulin secretion and sensitivity indices on DM pre-operatively. MethodsClinical and anthropometric data collection, HbA1c, 75 g OGTT with serum insulin estimation were done pre-operatively (n = 34) and at follow-up after successful surgery (n = 24) in patients with PPGL. ResultsPre and post-operative prevalence of DM were 48%(18/37) and 17% (4/24) respectively. Comparison of patients with highest (Q4) and lowest (Q1) quartiles of insulinogenic index (IGI),a parameter of insulin secretion, revealed trends towards higher prevalence of DM in patients with lower IGI (Q4 to Q1: 29% versus 71%,n = 28, p = 0.24)but no association was observed with HOMA-IR (Q4 to Q1:50% versus 57%, n = 28, p = 1.00), an insulin sensitivity index. DM remitted in 77% patients post-operatively, predicted by duration of DM of<3 years. ConclusionThere is high prevalence of DM in PPGL, with marked remission post-operatively, especially predicted by shorter duration of DM. Impaired insulin secretion is more strongly associated with pre-operative DM than increased insulin resistance.

Advanced Glycation End Products as a Predictor of Diabetes Mellitus in Chronic Hepatitis C-Related Cirrhosis.

Background and Aims: Advanced glycation end products (AGEs) were found to be involved in the pathogenesis of various disorders. Chronic hepatitis C virus infection is the major cause of liver cirrhosis development and glucose metabolism alteration. We aimed to explore the association of AGEs with the development of diabetes mellitus (DM) in patients with cirrhosis in this study.Methods: Only 144 of the 165 non-diabetic patients with cirrhosis were consecutively included in this prospective cohort pilot study, in addition to 72 healthy control subjects. Clinical data and biochemical parameters including basal insulin secretion and insulin sensitivity indices together with AGEs were evaluated in all participants at baseline and every 1 year thereafter for 2 years. Multivariable Cox regression analysis was used to determine the parameters that could predict the development of DM within this period.Results: DM developed in 14 (10%) patients only. Univariate Cox regression analysis showed that AGEs (P = 0.004), Homeostatic Model Assessment-Insulin Resistance (HOMA-IR) (P = 0.018), HOMA-β (P = 0.015), and age (P = 0.012) were associated with DM. After adjusting multiple confounders, the multivariable Cox regression model showed that AGEs, HOMA-IR, and age were the strongest variables associated with DM (all P < 0.05). Using the receiver operating characteristic curve, AGEs at a cutoff value of more than 82.4 ng/ml had 99.23% specificity, 100% sensitivity, and 0.992 area under the curve (AUC) (all P < 0.001) for DM prediction.Conclusion: Our study suggests that AGEs are related to increased incidence of DM, especially in patients with cirrhosis, which is very promising in lowering the risk of DM in these patients.

Abnormal post-prandial glucagon-like peptide release in patients with Crohn's disease

Background and aimsGlucagon-like peptide GLP-1 and -2 have been shown to regulate immune responses in immune-mediated disorders, including Crohn’s disease (CD). Our aim was to investigate post-prandial GLP release and its potential link to chronic inflammation, insulin secretion/sensitivity and body composition changes in CD patients. MethodsFifteen patients with CD, 15 healthy controls (HC) and 15 patients with metabolic syndrome (MS) were recruited. All patients underwent assessment of body composition by means of bio-impedance followed by a meal tolerance test (MTT). Only one CD patient did not tolerate the MTT and was excluded. ResultsBasal GLP-1 levels were up-regulated in CD, however, as compared to HC, stimulated GLP-1 secretion was significantly reduced in CD (-31 %, p < 0.05) as in MS (-52 %, p < 0.003). Similarly, basal GLP-2 levels were comparable to that of HC, while response to MTT in CD was virtually absent (p < 0.05). Similar fasting insulin sensitivity, estimated 1st and 2nd phase insulin secretion and insulinogenic index were found in CD and in HC. Post-prandial GLP secretion was positively correlated to insulin secretion indices, both in CD and MS. In CD, high-sensitive C reactive protein levels (hsCRP) and extra-cellular to intra-cellular water ratio (ECW/ICW), an index of cellular inflammation, were inversely correlated with stimulated GLP-1 (p < 0.05 and p < 0.01, respectively) levels. ConclusionCD is characterized by abnormal fasting and post-prandial GLP levels. Circulating GLP influences subclinical inflammation and glucose metabolism in CD patients, but not their body composition parameters.

Nutrient consumption-dependent association of a glucagon-like peptide-1 receptor gene polymorphism with insulin secretion

Since type 2 diabetes (DM) is a life-style related disease, life-style should be considered when association between genetic factors and DM are examined. However, most studies did not examine genetic associations in consideration with lifestyle. Glucagon-like peptide-1 (GLP-1) receptor (GLP1R) mediates the insulinotropic action of GLP-1 in β-cells. We here examined the association while taking into consideration of interactions between the gene polymorphism and various nutrient factors. Participants from the population-based Iwaki study of Japanese subjects held in 2014–2017 with information on nutritional intake evaluated by self-administered dietary history questionnaire, and GLP1R genotype (rs3765467: A/G), were included (n = 1,560). Although not significant, insulin secretion indices assessed by homeostasis model assessment of β-cell function (HOMA-β) in subjects with the GG genotype tended to be lower than in those with the AA+AG genotypes in most groups stratified into tertiles based on daily nutrient consumptions (high, middle, and low). Stratification also showed that the GG genotype was a significant risk for decreased insulin secretion (HOMA-β ≤ 30) even after adjustment for multiple factors (age, body mass index, alcohol consumption), but only in the highest tertiles of energy, protein and carbohydrate consumption in men [odds ratios (95% confidence interval) 3.95 (1.03–15.1), 15.83 (1.58–158.9), and 4.23 (1.10–11.2), respectively]. A polymorphism of the GLP1R gene was associated with decreased insulin secretion in a nutrient consumption-dependent manner in Japanese men, indicating an interaction between GLP1R and nutritional factors in the pathophysiology of DM.

Rationale, design and baseline characteristics of the Microbiome and Insulin Longitudinal Evaluation Study (MILES).

To investigate the role of the gut microbiome in regulating key insulin homeostasis traits (insulin sensitivity, insulin secretion and insulin clearance) whose dysfunction leads to type 2 diabetes (T2D). The Microbiome and Insulin Longitudinal Evaluation Study (MILES) focuses on African American and non-Hispanic white participants aged 40-80 years without diabetes. Three study visits are planned (at baseline, 15 and 30 months). Baseline measurements include assessment of the stool microbiome and administration of an oral glucose tolerance test, which will yield indexes of insulin sensitivity, insulin secretion and insulin clearance. The gut microbiome profile (composition and function) will be determined using whole metagenome shotgun sequencing along with analyses of plasma short chain fatty acids. Additional data collected include dietary history, sociodemographic factors, health habits, anthropometry, medical history, medications and family history. Most assessments are repeated 15 and 30 months following baseline. After screening 875 individuals, 129 African American and 224 non-Hispanic white participants were enrolled. At baseline, African American participants have higher blood pressure, weight, body mass index, waist and hip circumferences but similar waist-hip ratio compared with the non-Hispanic white participants. On average, African American participants are less insulin-sensitive and have higher acute insulin secretion and lower insulin clearance. The longitudinal design and robust characterization of potential mediators will allow for the assessment of glucose and insulin homeostasis and gut microbiota as they change over time, improving our ability to discern causal relationships between the microbiome and the insulin homeostasis traits whose deterioration determines T2D, setting the stage for future microbiome-directed therapies to prevent and treat T2D.

Birth weight, childhood and adolescent growth and diabetes risk factors in 21-year-old Asian Indians: the Pune Children's Study.

Our objective was to investigate associations of body size (birth weight and body mass index (BMI)) and growth in height, body fat (adiposity) and lean mass during childhood and adolescence, with risk markers for diabetes in young South Asian adults. We studied 357 men and women aged 21 years from the Pune Children's Study birth cohort. Exposures were 1) birth weight, 21-year BMI, both of these mutually adjusted, and their interaction, and 2) uncorrelated conditional measures of growth in height and proxies for gain in adiposity and lean mass from birth to 8 years (childhood) and 8 to 21 years (adolescence) constructed from birth weight, and weight, height, and skinfolds at 8 and 21 years. Outcomes were plasma glucose and insulin concentrations during an oral glucose tolerance test and derived indices of insulin resistance and secretion. Higher 21-year BMI was associated with higher glucose and insulin concentrations and insulin resistance, and lower disposition index. After adjusting for 21-year BMI, higher birth weight was associated with lower 120-min glucose and insulin resistance, and higher disposition index. In the growth analysis, greater adiposity gain during childhood and adolescence was associated with higher glucose, insulin and insulin resistance, and lower disposition index, with stronger effects from adolescent gain. Greater childhood lean gain and adolescent height gain were associated with lower 120-min glucose and insulin. Consistent with other studies, lower birth weight and higher childhood weight gain increases diabetes risk. Disaggregation of weight gain showed that greater child/adolescent adiposity gain and lower lean and height gain may increase risk.

Higher toenail selenium is associated with increased insulin resistance risk in omnivores, but not in vegetarians

BackgroundThe relationship between selenium (Se) and insulin resistance remains unclear. We aim to explore the association between toenail Se levels and insulin resistance through a cross-sectional study comprising Chinese vegetarians and matched omnivores.MethodsIn this study, we enrolled 220 vegetarians and 220 omnivores matched by age and sex from Shanghai. The inductively coupled plasma mass spectrometry method was used to measure toenail Se levels. Dietary Se intakes were assessed by the 24-h dietary recall method. Blood samples were collected to measure fasting blood glucose level and fasting insulin concentrations. Insulin resistance index (HOMA-IR) and insulin secretion index (HOMA-B) were calculated to evaluate insulin resistance. Multi-linear regression analysis was performed to determine the association between toenail Se levels and insulin resistance, after adjusting for confounders.ResultsThe mean ages of vegetarians (76 vegans, 144 lacto-ovo-vegetarians) and omnivores were 35.96 ± 8.73 years and 35.23 ± 8.93 years, respectively. Of these, 180 (81.8%) were female and 40 (18.2%) were male. No association was found between toenail Se levels and insulin resistance in vegetarians. However, the concentration of Se in toenails was positively correlated with fasting insulin levels (β = 1.030, 95%CI: 0.393 to 1.667) and HOMA-IR (β = 0.245, 95%CI: 0.098 to 0.392) in omnivores, after multivariate adjustment for age, sex, BMI, alcohol consumption, income, and daily dietary intakes (energy, protein, fat, carbohydrate, and fiber). This positive relationship persisted only in omnivores whose dietary Se intake was above 60 μg/d.ConclusionsHigher toenail Se levels were associated with increased insulin resistance risk in Chinese omnivores whose dietary Se intake was above 60 μg/d, but not in vegetarians. These findings create awareness on the association of dietary Se intake above 60 μg/d with the risk of insulin resistance.

Association between small intestinal bacterial overgrowth and beta-cell function of type 2 diabetes.

AimsPrevious studies suggest that small intestinal bacterial overgrowth (SIBO) is associated with type 2 diabetes. However, few studies have evaluated the association between SIBO and beta-cell function in type 2 diabetes. The aim of this study was to evaluate whether beta-cell function was associated with SIBO.Materials and methodsOne hundred four patients with type 2 diabetes were included in this study. Based on the presence of SIBO, the patients were divided into SIBO-positive and SIBO-negative groups. Oral glucose tolerance tests were performed. Insulin sensitivity was measured using 1/homeostasis model assessment of insulin resistance (1/HOMA-IR) and the insulin sensitivity index (ISIM). Insulin release was calculated by HOMA-β, early-phase insulin secretion index InsAUC30/GluAUC30, and total-phase insulin secretion index InsAUC120/GluAUC120.ResultsCompared with the SIBO-negative group, patients in the SIBO-positive group showed a higher glucose level at 120 minutes, HbA1c, 1/HOMA-IR, and ISIM and a lower HOMA-β level, early-phase InsAUC30/GluAUC30, and total-phase InsAUC120/GluAUC120. Multiple linear regression analysis showed that body mass index, glucose at 0 minutes, and SIBO were independently associated with the early-phase and total-phase insulin secretion.ConclusionSIBO may be involved in lower levels of insulin release and worse glycemic control.

Reduced Skeletal Muscle Volume and Increased Skeletal Muscle Fat Deposition Characterize Diabetes in Individuals after Pancreatitis: A Magnetic Resonance Imaging Study.

Background: Skeletal muscle has been implicated in the pathogenesis of type 2 diabetes but it has never been investigated in diabetes after pancreatitis. The aim was to investigate the relationship between psoas muscle volume (PMV) and diabetes in individuals after pancreatitis, as well as its associations with ectopic fat phenotypes and insulin traits. Methods: Individuals after an attack of pancreatitis and healthy individuals were studied in a cross-sectional fashion. All participants underwent magnetic resonance imaging, based on which PMV, skeletal muscle fat deposition (SMFD), as well as liver and intra-pancreatic fat depositions were derived. Fasting and postprandial blood samples were collected to calculate indices of insulin sensitivity and secretion. Linear regression analyses were conducted, adjusting for possible confounders (age, sex, body composition, comorbidities, use of insulin, and others). Results: A total of 153 participants were studied. PMV was significantly decreased in the diabetes group compared with healthy controls (β = −30.0, p = 0.034 in the most adjusted model). SMFD was significantly inversely associated with PMV (β = −3.1, p < 0.001 in the most adjusted model). The Matsuda index of insulin sensitivity was significantly directly associated with PMV (β = 1.6, p = 0.010 in the most adjusted model). Conclusions: Diabetes in individuals after pancreatitis is characterized by reduced PMV. Reduced PMV is associated with increased SMFD and decreased insulin sensitivity in individuals after pancreatitis.

Insulin and Proinsulin Dynamics Progressively Deteriorate From Within the Normal Range Toward Impaired Glucose Tolerance.

ContextSlight elevations in plasma glucose (PG) manifest in advance of diabetes onset, but abnormalities in immunoreactive insulin (IRI), proinsulin (Pro), and adiponectin dynamics during this stage remain poorly understood.ObjectiveThe objective of this work is to investigate whether IRI and Pro dynamics become abnormal as glucose tolerance deteriorates from within the normal range toward impaired glucose tolerance (IGT), as well as the relationship between PG, and these dynamics and serum adiponectin levels.DesignA cross-sectional study was designed.SettingThis study took place at Jichi Medical University in Japan.Participants and MeasurementsPG, IRI, and Pro levels were determined in 1311 young Japanese individuals (age < 40 years) with normal or IGT before and at 30, 60, and 120 minutes during a 75-g oral glucose tolerance test. Participants were assigned to 4 groups according to glucose tolerance, and then background factors, adiponectin levels, insulin sensitivity (SI), and insulin secretion (β) indexes were determined.ResultsPG levels as well as IRI and Pro levels 60 and 120 minutes after glucose-loading increased incrementally with deteriorating glucose tolerance. All measures of β and the SI measure index of insulin sensitivity (ISI)-Matsuda decreased incrementally. Serum adiponectin levels were not significantly different among the glucose tolerance groups, but were independently and negatively correlated with fasting glucose.ConclusionsEarly β decreased and postloading Pro levels became excessive in a progressive manner as glucose tolerance deteriorated from within the normal range toward IGT.

Data mining: The association of 2-h postprandial plasma glucose with the fasting plasma glucose in a large Chinese population.

BackgroundIt is generally believed that the lower limit of postprandial plasma glucose is the same or higher than that of fasting plasma glucose (FPG). This study aimed to investigate the relationship between 2‐h postprandial plasma glucose (2‐hPG) and FPG. Insulin sensitivity and β‐cell function were also evaluated.MethodsAnalytical data from January 2013 to August 2018 included 10 465 participants’ 2‐h OGTT results and 19 518 participants’ FPG and 2‐hPG values after autonomous self‐feeding. Participants were divided into two groups based on the relationship between FPG and 2‐hPG (OGTT‐A1/Postprandial‐B1:FPG > 2‐hPG;OGTT‐A2/Postprandial‐B2:FPG ≤ 2‐hPG).Insulin sensitivity was evaluated by Matsuda index and homeostasis model assessment of insulin resistance (HOMA‐IR). β‐cell function was estimated by homeostasis model assessment of β‐cell function (HOMA‐β) and early‐phase insulin secretion index (ΔI30/ΔG30).ResultsThe ratio of OGTT‐A1 and OGTT‐A2 is 11.1%; the ratio of postprandial B1 and postprandial B2 is 13.7%. HOMA‐IR and HOMA‐β values were lower, while Matsuda index and ΔI30/ΔG30 values were higher in the non‐diabetic OGTT‐A1 group than those in the OGTT‐A2 group. The value of Matsuda index in women was 0.368 times higher than that in men in group OGTT‐A1. In group OGTT‐A2, the values of HOMA‐IR (0.346), HOMA‐β (9.096), and ΔI30/ΔG30 (3.575) in women were lower, higher, and higher than those in men, respectively. Both HOMA‐β and ΔI30/ΔG30 decreased with age in OGTT groups.ConclusionIt existed that FPG was >2‐hPG, and this group had better insulin sensitive and β‐cell function. The influence of age on insulin sensitivity and β‐cell function was greater than that of gender.

110-OR: Type 2 Diabetes (T2D)–Associated TCF7L2 Genetic Variants and Indices of Insulin Secretion and Sensitivity in Individuals at Risk for Type 1 Diabetes (T1D)

In individuals with new onset T1D, T2D-associated TCF7L2 genetic variants are associated with lower area-under-the curve (AUC) glucose and higher AUC C-peptide responses to a mixed meal. We aimed to test whether TCF7L2 variants affect glucose metabolism in nondiabetic islet autoantibody-positive (AbPos) individuals. We studied 1065 TrialNet Pathway to Prevention Study participants (AbPos relatives of persons with T1D) with TCF7L2 SNPs who underwent oral glucose tolerance tests (OGTT) (mean age 16.3 yrs, 63% &amp;lt;18 years old, 91.1% non-Hispanic, 47.7% male; T2D-associated TCF7L2 SNP: 48.1% 0 alleles, 43.9% 1 allele, 8% 2 alleles). We assessed the contribution of TCF7L2 SNP variants on Fasting (FIIS) and OGTT Index of Insulin Sensitivity (OIIS), Insulin Secretion (OIISec), and Disposition Index (ODI) with univariate and multivariate analyses. Then we studied the interaction between TCF7L2 SNP and BMI. With Bonferroni correction for multiple comparisons, p-values &amp;lt;0.0086 were considered statistically significant. Insulin sensitivity and secretion indices were significantly associated with age (FIIS, OIIS, OIISec), BMI Z-score (FIIS, OIIS, OIISec, ODI) and Hispanic ethnicity (FIIS, OIIS) but not sex in univariate analyses. TCF7L2 SNP was not significantly associated with these indices in univariate or multivariate analyses adjusting for BMI, age, sex and race-ethnicity. There was a significant interaction between BMI and presence of 2 (vs. 0) TCF7L2 SNP alleles on insulin sensitivity (OIIS) in children (p=0.0079) but not adults (p=0.94). After adjusting for age, ethnicity and sex, the difference did not reach statistical significance (p=0.0135). Restricting to non-obese participants, the results were similar. In sum, in nondiabetic AbPos individuals, the TCF7L2 variant does not appear to impact insulin sensitivity or secretion indices after accounting for BMI, age, sex and race-ethnicity. Disclosure M.J. Redondo: None. M.V. Warnock: None. L.E. Bocchino: None. S. Geyer: None. A. Pugliese: None. A. Steck: None. I. Libman: Consultant; Self; Novo Nordisk A/S. C. Evans-Molina: Consultant; Self; Bristol-Myers Squibb. D.J. Becker: None. J. Sosenko: None. F. Bacha: Research Support; Self; AstraZeneca, Takeda Development Center Americas, Inc. Funding National Institute of Diabetes and Digestive and Kidney Diseases

1324-P: GLP-1 Hypersecretion in Gestational Diabetes

Background and Aims: Incretins are crucial for an adequate insulin secretion in response to ingestions of nutrients. In patients with diabetes, prediabetes or a specific genetic background, this incretin effect is blunted. Data on incretin secretion and action during pregnancy are scarce. Here we investigated the incretin response during an oral glucose tolerance test (OGTT) in pregnant women with and without gestational diabetes. Methods: Pregnant women from the ongoing PREG study underwent 5-point OGTT with 75 g glucose. We measured plasma glucose, insulin and C-peptide at all time points and total GLP-1 at minute 0, 30 and 120. Indices of insulin secretion and GLP-1 increase were calculated from the difference at min 0 and 30. We used linear regression to analyze the relation of GLP-1 and glucose with insulin secretion. Results: We examined 163 women during gestational week 26.8 (±2.0 SD), GDM was present in 30 (18.4%) women. Insulin secretion was significantly lower in women with GDM (p=0.04, adjusted for BMI, age, week of gestation, insulin sensitivity). GLP-1 levels increased after glucose intake with a peak at 30 min. GLP-1 levels at minute 30 and AUCGLP-1 was significantly higher in women with GDM (by ∼20%, both p=0.03, adjusted for age, BMI and week of gestation). The GLP-1 increase was associated with insulin secretion only in GDM, but not in women with normal glucose tolerance. This association remained significant even after adjustment for increase of glucose and basal insulin levels (GDM group: p&amp;lt;0.001, non GDM: p=0.69). Conclusion: Women with GDM had lower insulin secretion despite increased GLP-1 levels during OGTT. The more pronounced GLP-1 increase in women with GDM could be part of a compensatory mechanism counteracting GLP-1 resistance. In addition to incretin resistance, this phenomenon suggests a dysfunction of glucose stimulated insulin secretion. Disclosure L. Fritsche: None. M. Heni: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi. Speaker’s Bureau; Self; Novo Nordisk A/S. S.S. Eckstein: None. M.J. Winzenried: None. J. Hummel: None. A.L. Birkenfeld: None. H. Preissl: None. H. Haering: None. A. Peter: None. A. Fritsche: None. R. Wagner: Advisory Panel; Self; Novo Nordisk A/S. Speaker’s Bureau; Self; Novo Nordisk A/S. Other Relationship; Self; Eli Lilly and Company. Funding German Federal Ministry of Education and Research (01GI0925)

1618-P: Insulin Secretion Variability According to the Specific Type 1 Diabetes (T1D) Risk Predictor

The risk for T1D, a major criterion for entry into disease prevention trials, can be assessed in various ways, but usually includes autoantibody (Ab) and/or metabolic measures. Given inherent variations in these biomarkers, it is possible that informative characteristics differ between populations selected by different risk measures. Thus, we assessed whether indices of insulin secretion [C-pep; first phase insulin response (FPIR)] vary between groups defined by distinctive risk measures. We used data from Diabetes Prevention Trial-Type 1 (DPT-1) participants, all being ICA positive subjects with or without biochemical Ab (bAb) positivity (GADA, IA-2A, mIAA). C-pep and FPIR values from baseline oral and intravenous glucose tolerance tests were compared between those who had 2-3 bAbs (≥2bAb) and those who had 0-1 bAb plus Index60≥0.40 (≤1bAb+Ind60). Index60 is a composite C-pep and glucose measure. These groups were chosen so that T1D risk would be similar (50% 5-year risk for both, log rank p=0.95). Ages (mean±SD) for ≥2bAb (n=289) and ≤1bAb+Ind60 (n=175) were 12.8±8.2 and 13.3±9.6 yrs, respectively (p=0.53). BMI Z-score was greater for ≥2bAb (0.42±1.12 vs. 0.15±1.09, p=0.01). C-pep levels were consistently higher for ≥2bAb than ≤1bAb+Ind60 [30-0 minute C-pep: 2.73±1.58 vs. 2.04±1.12 ng/mL, p&amp;lt;0.0001; area under the curve (AUC) C-pep: 3.70±1.55 vs. 3.27±1.12 ng/ml, p=0.013; AUC C-pep/AUC glucose: 0.030±0.013 vs. 0.025±0.007 (ng/ml)/(mg/dl), p&amp;lt;0.001]. FPIR was also higher for ≥2bAb (122.0±87.3 vs. 96.2±47.1 µU/ml, p&amp;lt;0.01). All comparisons remained significant with adjustments for age and BMI Z-score. Of those with ≤1bAb+Ind60, 0 bAb did not differ from 1 bAb for C-pep indices or FPIR. In conclusion, C-pep and FPIR values can differ appreciably according to the measure that defines risk. This should be considered in choosing risk measures for prevention trials. Disclosure L.M. Jacobsen: None. B.M. Nathan: None. H.M. Ismail: None. M.J. Redondo: None. D. Schatz: None. M.J. Haller: Advisory Panel; Self; SAB Biotherapeutics, Inc. E.K. Sims: None. J.S. Skyler: Advisory Panel; Self; Abvance Therapeutics, ADOCIA, Avotres, Boehringer Ingelheim Pharmaceuticals, Inc., Dance Biopharm Holdings, Inc., Immunomolecular Therapeutics, Intrexon, Oramed Pharmaceuticals, Orgenesis Inc., Sanofi, Tolerion, Inc., Viacyte, Inc. Board Member; Self; Applied Therapeutics, Dexcom, Inc., Intarcia Therapeutics. Consultant; Self; Novo Nordisk A/S. Research Support; Self; Tolerion, Inc. Stock/Shareholder; Self; Applied Therapeutics, Dexcom, Inc., Intarcia Therapeutics. J.P. Palmer: None. K.C. Herold: Consultant; Self; Provention Bio, Inc. J. Sosenko: None.

1659-P: Nutrients Consumption Dependent Association of the Glucagon-Like Peptide-1 Receptor Gene Polymorphism with Insulin Secretion

Objective: Since type 2 diabetes (DM) is a life-style related disease, life-style should be considered, when association between genetic factors and DM are examined. However, most studies did not examine genetic associations with such consideration, as the case of glucagon-like peptide-1 receptor (GLP-1R) gene. We examined the association in consideration with the interaction between the gene polymorphism and various nutrient factors. Research Design and Methods: Among participants of the population-based Iwaki study of Japanese held in 2014-2017, those with information of the genotype of GLP-1R polymorphism (db SNP ID: rs3765467: A/G)(p.Alg131Gln) as well as nutrients consumed (n=1817) were included. The following individuals were also excluded: 64 on medication for DM, and 52 with FBG levels below 63 mg/dl or over 140 mg/dl (to evaluate HOMA indices precisely). After these exclusions, 1,560 individuals (587 men, 973 women) aged 53.3± 16.1 years were included in the study. Results: Though not significant, insulin secretion indices assed by homeostasis model assessment (HOMA- ß) in subjects with the GG genotype tended to be lower than in those with the AA+AG genotypes in most groups stratified into tertiles based on their daily nutrients consumptions (high, middle, and low groups). The stratification also showed that the genotype GG was a significant risk for a decreased insulin secretion (HOMA-ß ≤ 30) even after adjustment for multiple factors (age, BMI, drinking alcohol) only in the highest tertiles of energy, protein and carbohydrate consumption in men (odds ratios (95% CI) in high energy, protein and carbohydrate consumption groups: 3.95 (1.03-15.1), 15.83 (1.58-158.9), and 4.23 (1.10-11.2), respectively). Conclusions: The GLP-1R gene was associated with a decreased insulin secretion dependently of nutrients consumption, which indicates interaction between GLP-1R and nutrient factors on pathophysiology leading to DM. Disclosure Y. Nishiya: None. M. Daimon: None. H. Murakami: None. M. Murabayashi: None. S. Mizushiri: None. T. Fujita: None. Y. Matsuhashi: None.

Association between the rs1544410 polymorphism in the vitamin D receptor (VDR) gene and insulin secretion after gestational diabetes mellitus.

Genetic variants involved in vitamin D metabolism have been associated with diabetes and related syndromes/diseases. We wanted to investigate possible associations of polymorphisms in genes involved in vitamin D metabolism with indices of insulin resistance and insulin secretion, and also with development of diabetes after gestational diabetes mellitus (GDM). We have studied 376 women with previous GDM. Eight single nucleotide polymorphisms (SNPs) in the genes for vitamin D receptor (VDR) [rs731236, rs7975232, rs10735810, and rs1544410], vitamin D binding protein (DBP) [rs7041 and rs4588], and cytochrome P450 family 27 subfamily B member 1 (CYP27B1) [rs10877012 and rs4646536] were genotyped by TaqMan Allelic Discrimination Assay using the Quantstudio 7 Flex system. A 75-g oral glucose tolerance test (OGTT) was performed 1-2 years postpartum. The homeostasis model assessment of insulin resistance (HOMA-IR) and the disposition index [(insulinogenic index: I30/G30)/HOMA-IR] were used to calculate insulin resistance and insulin secretion, respectively. Serum samples for determination of 25(OH)D3 were collected at the time of the OGTT. Manifestation of diabetes was followed up to five years postpartum. After adjustment for BMI, age, and ethnicity, the A-allele of the VDR rs1544410 polymorphism was found to be associated with increased disposition index (difference per allele = 3.56, 95% CI: 0.4567-6.674; p = 0.03). The A-allele of the DBP rs7041 polymorphism was found to be associated with 25(OH)D3 levels (difference [in nmol/L] per allele = -5.478, 95% CI: -8.315 to -2.641; p = 0.0002), as was the T-allele of the DBP rs4588 polymorphism (OR = -6.319, 95% CI: -9.466 to -3.171; p = 0.0001). None of the SNPs were significantly associated with HOMA-IR or postpartum diabetes. This study provides evidence that the rs1544410 polymorphism of the VDR gene may be associated with increased insulin secretion in women after pregnancy complicated by GDM. Further studies in other populations are needed to confirm the results.

MON-215 Clinical Factors Associated with Insulin Secretion and Sensitivity in Patients with Primary Aldosteronism

Introduction: Primary aldosteronism (PA) is associated with an increased risk of impaired glucose tolerance or type 2 diabetes mellitus. Previous studies have reported that impaired insulin secretion and insulin sensitivity in PA may lead to impaired glucose tolerance. However, the relationship between PA and glucose tolerance, and the factor associated with these glucose metabolism abnormalities is not well understood. In particular, few studies have analyzed the association between aldosterone excess and insulin sensitivity or resistance after the adjustment for other clinical variables. In this study, we analyzed the associations between multiple clinical variables observed in PA and the indices of insulin sensitivity and resistance, using the result of 75 g oral glucose tolerance test (OGTT).Method: This was a retrospective observational study that analyzed the data of 646 patients with PA who underwent adrenal venous sampling and 75 g OGTT. The insulinogenic index and Matsuda index, indices of insulin secretion and sensitivity, respectively, were calculated from the results of a 75 g OGTT. Correlations between these indices and the multiple clinical variables were analyzed. In addition, we performed multiple regression analyses to identify the independent explanatory variables of these indices.Results: Insulinogenic index had positive correlations with the body mass index (BMI), alanine aminotransferase (ALT) level, triglyceride (TGL) level, and potassium level, and negative correlations with both age and plasma aldosterone concentration (PAC). In a multiple regression analysis, both the age (β = -0.231, p < 0.001) and potassium level (β = 0.175, p = 0.002) were selected as the independent explanatory factors. The Matsuda index had positive correlations with the PAC and cortisol level after a 1 mg dexamethasone suppression test (DST), and negative correlations with BMI, ALT level, TGL level, plasma renin activity (PRA), and potassium level. In a multiple regression analysis, BMI (β = -0.216, p < 0.001), ALT level (β = -0.290, p < 0.001), TGL level (β = -0.225, p < 0.001), the cortisol level after 1 mg DST (β = 0.124, p = 0.009), and PRA (β = -0.119, p = 0.019) were selected as the independent explanatory factors.Conclusion: In PA patients, older age and decreased potassium levels were associated with impaired insulin secretion. An increase in the variables associated with metabolic abnormalities such as BMI, ALT, and TGL were associated with decreased insulin sensitivity. In addition, we found that decreased PRA was associated with increased insulin sensitivity.