Insulin Disposition Research Articles

Effect of almond consumption on insulin sensitivity and serum lipids among Asian Indian adults with overweight and obesity- A randomized controlled trial.

Asian Indians have an increased susceptibility to type 2 diabetes and premature coronary artery disease. Nuts, like almonds, are rich in unsaturated fat and micronutrients with known health benefits. This study aimed to assess the efficacy of almonds for reduction of insulin resistance and improving lipid profile in overweight Asian Indian adults. This parallel-arm, randomized, controlled trial was conducted in Chennai, India on 400 participants aged 25-65 years with a body mass index ≥ 23 kg/m2. The intervention group received 43 g of almonds/day for 12 weeks, while the control group was advised to consume a customary diet but to avoid nuts. Anthropometric, clinical, and dietary data were assessed at periodic intervals. Glucose tolerance, serum insulin, glycated hemoglobin, C-peptide and lipid profile were assessed at baseline and end of the study. Insulin resistance (homeostasis assessment model-HOMA IR) and oral insulin disposition index (DIo) were calculated. A total of 352 participants completed the study. Significant improvement was seen in DIo [mean (95% CI) = + 0.7 mmol/L (0.1, 1.3); p = 0.03], HOMA IR (-0.4 (-0.7, -0.04; p = 0.03) and total cholesterol (-5.4 mg/dl (-10.2, -0.6); p = 0.03) in the intervention group compared to the control group. Incremental area under the curve (IAUC) and mean amplitude of glycemic excursion (MAGE) assessed using continuous glucose monitoring systems were also significantly lower in the intervention group. Dietary 24-h recalls showed a higher significant reduction in carbohydrate and increase in mono unsaturated fatty acid (MUFA) and polyunsaturated fatty acids (PUFA) intake in the intervention group compared to the control group. Daily consumption of almonds increased the intake of MUFA with decrease in carbohydrate calories and decreases insulin resistance, improves insulin sensitivity and lowers serum cholesterol in Asian Indians with overweight/obesity. These effects in the long run could aid in reducing the risk of diabetes and other cardiometabolic disease.

988-P: Higher Environmental Pollution Burden Scores Associate with Lower Insulin Sensitivity in Minority Children with Overweight and Obesity

Background: Epidemiological evidence in children suggests that environmental pollution, such as ambient and traffic air pollution exposure, is associated with type 2 diabetes risk; however cumulative exposure to various environmental pollutants has not been well examined. The objective of this study was to determine if cumulative measures of environmental pollutants were associated with insulin sensitivity (SI) , acute insulin response (AIR) and disposition index (DI) in minority children. Methods: Participants (N=135, Mage = 14.4 ± 2.9 years; 59% male; 57% Latinx and 43% Black) had a 13-time point frequently sampled intravenous glucose tolerance test. Glucose and insulin values were used in minimal modelling (MinMod Millennium) for determination of SI, AIR, and DI. Self-reported mailing addresses were geocoded to identify census tract number and associated pollution burden scores (1-10) derived by CalEnviroScreen 3.0 (CES 3.0) . Multivariable linear regression was used to test relationships while considering for age, ethnicity, sex, and total body fat percentage (by DEXA) . Due to positive skewness, SI, AIR and DI were natural log transformed. Results: Higher pollution burden score was associated with lower lnSI, after adjusting for covariates (β= -0.150, 95%CI= -0.280, -0.020, p=0.024) . There was a positive, but non-significant association with pollution burden score and lnAIR (β= 0.114, 95%CI= -0.006, 2.35, p=0.063) . An inverse, but non-significant, association was observed between pollution burden scores and lnDI (β= -0.34, 95%CI= -.140, 0.71, p=0.518) . Conclusion: Using a publicly available environmental pollution risk score, we show that high environmental pollution exposures associated with lower SI, but not AIR or DI. Our findings provide further evidence of the link between ambient environmental factors and type 2 diabetes risk. Disclosure K.Barragan: None. M.Weigensberg: None. C.M.Toledo-corral: None. Funding NIH P60MD00254

57-OR: Responses to Lifestyle Intervention (LI) Are Associated to the Inter-Individual Variability in Glucose Metabolism at Baseline for Individuals at High Risk of Type 2 Diabetes (T2D)

LI can delay the onset of T2D. How inter-individual variability in response to LI relates to baseline phenotypic characteristics would help clinicians to advise on risk reduction. 328 subjects at high risk of T2D underwent a 12-weeks LI. Before and after LI, subjects were profiled for glucose and insulin measured through 75g-OGTT, peripheral (Matsuda (ISI) and HOMA) and hepatic (Hep-IR) insulin resistance indexes, insulinogenic index (IGI) , disposition index (DI=MI x dAUC0-180-Ins/glu) and target metabolomics. Hierarchical cluster analysis, based on indexes of insulin resistance (HOMA and ISI) and secretion (AUCins and IGI) , was performed to stratify the subjects at baseline. Pre vs. post values were compared in each cluster. Cluster analysis identified 4 groups with different degrees of glucose tolerance, insulin sensitivity and secretion (Figure A-D) , CL1 being the best. The 4 clusters showed different responses to LI: CL2-4 significantly improved insulin and reduced AUCins and α-ketoglutarate (p<0.05) , while no significant changes in CL1 (Figure E) . Conclusions: Hierarchical clustering identified phenotypes that might predict metabolic responses to LI. Disclosure S.Sabatini: None. J.J.Nolan: Consultant; My Way Digital Health, Speaker's Bureau; Novo Nordisk A/S. D.O'gorman: None. A.Gastaldelli: Advisory Panel; Boehringer Ingelheim International GmbH, Novo Nordisk Global Business Services, Consultant; Boehringer Ingelheim International GmbH, Inventiva Pharma, Other Relationship; Eli Lilly and Company, Gilead Sciences, Inc., Pfizer Inc., Speaker's Bureau; Novo Nordisk.

120-OR: Hepatic Steatosis Is Inversely Associated with Improvement of Pancreatic Beta-Cell Function after Vertical Sleeve Gastrectomy in Patients with Type 2 Diabetes

Background: Improvement of beta-cell function is reportedly involved in the improvement of glucose tolerance and remission of diabetes after bariatric and metabolic surgery. However, the impact of this surgery on beta-cell function in Japanese patients is not clear. The objective of this study was to investigate the effect of this surgery on beta-cell function and the characteristics and factors related to changes in beta-cell function. Methods: We conducted a prospective study of patients with type 2 diabetes who underwent vertical sleeve gastrectomy. A 75-g OGTT was performed before and 1 year after this surgery. Glucose tolerance was evaluated using the area under the blood glucose curve (AUCglu) during the OGTT. Insulin secretion was evaluated by the insulin secretion-sensitivity index-2 (ISSI-2) and disposition index (DI) , and insulin sensitivity was estimated using the Matsuda index (MI) and HOMA-IR. Visceral fat and subcutaneous fat area were quantified by abdominal CT examination, and hepatic fat content was quantified using the MRI proton density fat fraction. Results: The mean age of 15 patients (6 females) was 41.9 ± 8.8 years. After 1 year of the surgery, BMI (Before 42.0±8.2 kg/m2, After 32.7±7.2 kg/m2; P < 0.01) , HbA1c, and AUCglu were significantly reduced. ISSI-2 and DI were significantly increased, with no significant changes in the MI or HOMA-IR. Changes in ISSI-2 and DI were inversely associated with hepatic fat content before the surgery (ISSI-2: r = -0.63, P < 0.05; DI: r = -0.59, P < 0.05) , but not with age, BMI, visceral fat area, AUCglu, ISSI-2, DI, MI or HOMA-IR before the surgery. Conclusion: Our results showed that beta-cell function was improved by vertical sleeve gastrectomy even in Japanese obese patients with type 2 diabetes. The degree of improvement in beta-cell function was associated with the degree of preoperative hepatic steatosis, suggesting that a hepatic-pancreatic association may exist. Disclosure A. Nakamura: Research Support; Kissei Pharmaceutical Co., Ltd., MSD, Nippon Boehringer Ingelheim, Taisho Pharmaceutical Holdings Co., Ltd. Y. Oe: None. M. Kusumi: None. H. Nomoto: None. H. Kameda: None. K. Cho: None. K. Ogawa: None. Y. Ebihara: None. T. Atsumi: Consultant; AbbVie Inc., AstraZeneca, MEDICAL & BIOLOGICAL LABORATORIES CO., Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Pfizer Inc. Research Support; AbbVie Inc., Alexion Pharmaceuticals, Inc., Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Otsuka Pharmaceutical Co., Ltd., Pfizer Inc., Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited. Speaker's Bureau; AbbVie Inc., Astellas Pharma Inc., Bristol-Myers Squibb Company, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Eisai Co., Ltd., Eli Lilly and Company, Kyowa Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., Pfizer Inc., Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Company Limited, UCB, Inc. H. Miyoshi: Research Support; Abbott Japan Co., Ltd., Boehringer Ingelheim International GmbH, Daiichi Sankyo, Kowa Company, Ltd., LifeScan, Mitsubishi Tanabe Pharma Corporation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd. Speaker's Bureau; Astellas Pharma Inc., Boehringer Ingelheim International GmbH, Eli Lilly and Company, Kowa Company, Ltd., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sanofi K.K., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd.

Kinin B1 receptor deficiency protects mice fed by cafeteria diet from abnormal glucose homeostasis.

The kallikrein–kinin system has been implicated in body weight and glucose homeostasis. Their major effectors act by binding to the kinin B2 and B1 receptors. It was assessed the role of the kinin B1 receptor in weight and glucose homeostasis in B1 receptor knockout mice (B1RKO) subjected to a cafeteria diet (CAF). Wild-type (WT) and B1RKO male mice (C57BL/6 background; 8 weeks old) were fed a standard diet (SD) or CAF for 14 weeks, ad libitum, and four groups were formed: WT-SD; B1RKO-SD; WT-CAF; B1RKO-CAF. Body weight and food intake were assessed weekly. It was performed glucose tolerance (GTT) and insulin tolerance tests (ITT), and HOMA-IR, HOMA-β and HOMA-β* 1/HOMA-IR were calculated. Islets from WT and B1RKO were isolated in order to measure the insulin secretion. Western blot was used to assess the hepatic AKT phosphorylation and qPCR to assess gene expression. CAF induced a higher body mass gain in B1RKO compared to WT mice. CAF diet increased epididymal fat depot mass, hepatic fat infiltration and hepatic AKT phosphorylation in both genotypes. However, B1RKO mice presented lower glycemic response during GTT when fed with CAF, and a lower glucose decrease in the ITT. This higher resistance was overcomed with higher insulin secretion when stimulated by high glucose, resulting in higher glucose uptake in the GTT when submitted to CAF, despite lower insulin sensitivity. Islets from B1RKO delivered 4 times more insulin in 3-month-old mice than islets from WT. The higher insulin disposition index and high insulin delivery of B1RKO can explain the decreased glucose excursion during GTT. In conclusion, CAF increased the β-cell function in B1RKO mice, compensated by the diet-induced insulin resistance and resulting in a healthier glycemic response despite the higher weight gain.

Increased basal insulin sensitivity in late pregnancy in women carrying a male fetus: a cohort study

BackgroundIt has been suggested that fetal sex may be able to modify maternal metabolism and physiology during pregnancy. Recently pregnant women carrying a male fetus were reported to be more insulin sensitive than those carrying females, although related evidence is inconsistent.MethodsIn this study we administered a 75 g oral glucose tolerance test at around week 28 of pregnancy in 813 pregnant women from a contemporary birth cohort (the Cambridge Baby Growth Study), derived surrogate indices of insulin secretion and sensitivity, and related them to the fetal sex.ResultsCarrying a male fetus was associated with lower fasting glucose (difference in mean concentrations ≈ 0.1 mmol/L; β′ = 0.063; p = 0.02) and insulin (≈ 1.1 pmol/L; β′ = 0.075; p = 0.01) concentrations but not with post-load glucose or insulin concentrations. Male fetal sex was also associated with lower HOMA IR (≈ 1.08 units; β′ = 0.071; p = 0.02) and higher QUICKI (≈ 1.06 units; β′ = 0.080; p = 0.007) values suggesting increased basal insulin sensitivity. There were no differences in indices of insulin secretion, except for the insulin disposition index which was higher in women carrying a male fetus (≈ 1.15 units; β′ = 0.090; p = 0.007). Birth weights were higher in male offspring.ConclusionsWomen carrying a male fetus were relatively more insulin sensitive in the fasting state and secreted more insulin relative to this degree of insulin sensitivity. These results are consistent with the idea that the fetal sex may be able to modify the maternal glucose-insulin axis.

Effect of dietary chia supplementation on glucose metabolism and adipose tissue function markers in non-alcoholic fatty liver disease subjects.

Background: adipose tissue dysfunction is a key factor for diabetes and non-alcoholic fatty liver disease (NAFLD) development. Chia (Salvia hispanica) is an abundant source of omega-3 fatty acids, antioxidants, and fiber which could improve adipose tissue functionality. Aim: to analyze the effect of an isocaloric chia-supplemented diet on glucose metabolism, adipose tissue inflammation, and endothelial function markers in patients with NAFLD and early stages of diabetes. Methods: in 32 patients with previous NAFLD diagnosis, without known diabetes, the effect of a diet supplemented with ground chia (25 g/day/8 weeks) was evaluated. Visceral (VAF) and liver fat, plasma lipids, fatty acids, and cytokine profiles, oral glucose tolerance test (OGTT), insulinogenic index (IGI30), insulin disposition index (DIO), and endothelial progenitor cells (EPC) were analyzed. Before and after eight weeks of diet supplementation. Results: chia supplementation promoted increases in plasma alpha-linolenic acid (75 %) and fiber consumption (55 %), and a higher number of EPC (+126 %). Basal OGTT showed that nine patients had normal OGTT, 17 pre-diabetes, and six newly diagnosed diabetes. In patients with diabetes, chia favored a healthier adipose tissue (VAF -7 %, NAFLD -100 %, adiponectin +47 %, resistin -30 %, IL-6 -44 %, IL-1β -22 %) and upturn glucose metabolism through the improvement of beta-cell function (IGI30 +50 %, DIO +66 %). Conclusions: dietary supplementation with 25 g/day of ground chia may promote a healthier adipose tissue and improve pancreatic β-cell and endothelial function. Among patients with early metabolic abnormalities, phytochemical properties of chia may retard diabetes progression and advanced stages of liver damage.

HDL associates with insulin resistance and beta-cell dysfunction in South Asian families at risk of type 2 diabetes

Dyslipidemia precedes type 2 diabetes (T2D) and worsens with increasing glucose intolerance. First degree relatives of T2D patients have an increased risk to develop dyslipidemia and glucose intolerance. The aim of the present study was to assess the relation between the development of dyslipidemia and glucose intolerance in first-degree relatives of T2D patients. Fasting lipoprotein profiles were determined by density gradient ultracentrifugation in T2D patients and their first-degree relatives (42 Caucasians and 33 South Asians), and in 29 normoglycemic controls from non-T2D families. Glucose tolerance, insulin sensitivity index (ISI) and insulin disposition index (DI) were assessed by an extended, frequently sampled oral glucose tolerance test (OGTT), and fractional insulin synthesis rate (FSR) was measured by 13C-leucine enrichment in urinary C-peptide during the OGTT. Of the first-degree relatives, 40, 16 and 19 had NGT, prediabetes and T2D, respectively. NGT family members had lower plasma HDL-cholesterol (HDLC) (1.34±0.07 vs 1.58±0.06 mmol/L; p=0.015), HDL2-C (0.41±0.05 vs 0.57±0.05mmol/L; p=0.021) and HDL3-C (0.62±0.03 vs 0.72±0.02mmol/L; p=0.043) than controls. HDL2-C levels tended to decrease with increasing glucose intolerance state. In South Asians, buoyant LDL-C levels decreased with increasing glucose intolerance state (p=0.006). In South Asian families, HDL-C correlated with both ISI and DI (β 0.42; p=0.04 and β 0.53; p=0.01, respectively), whereas HDL2-C and HDL3-C levels correlated with DI (β 0.64; p=0.002 and β 0.57; p=0.005, respectively). HDL2-C and plasma triglyceride correlated with FSR (β 0.48; p=0.033 and β -0.50; p=0.029, respectively). Low HDL2-C and HDL3-C levels are present in NGT first-degree relatives of T2D patients, and HDL2-C tend to decrease further with increasing glucose intolerance. In South Asian families HDL2-C and HDL3-C levels linked predominantly to deteriorating beta cell function.

79-OR: Butyrate Producing Bacteria and Insulin Homeostasis: The Microbiome and Insulin Longitudinal Evaluation Study (MILES)

Several studies have compared the stool microbiomes of people with and without type 2 diabetes (T2D), from which a pattern of depletion of butyrate producing taxa in T2D has emerged. Seventeen taxa encompass ~85% of the total butyrate producing potential in humans (mSystems 2017;2:e00130). The goal of MILES is to elucidate the effect of diet and gut microbiota on the components of insulin homeostasis (insulin sensitivity, secretion, clearance) whose dysfunction underlies T2D. MILES consists of 224 non-Hispanic Whites and 129 African Americans (mean age 59, 62% female), all of whom have completed an oral glucose tolerance test from which insulin homeostasis traits were calculated. Stool microbiome was assessed by whole metagenome shotgun sequencing (10 Gb depth), with taxonomic profiling using MetaPhlAn3. Spearman correlation was used to assess associations between the 17 dominant butyrate producing taxa (8 genera, 9 species) and insulin sensitivity, insulin secretion, disposition index (product of insulin sensitivity and insulin secretion), and insulin clearance. The Wilcoxon test was used to associate taxa with dysglycemia (prediabetes plus diabetes, 46% of cohort). Genera Coprococcus was associated with higher insulin sensitivity (ρ=0.16, P=0.003) and disposition index (ρ=0.14, P=0.009) and a lower rate of dysglycemia. Flavonifractor was associated with lower insulin sensitivity (ρ=-0.17, P=0.002) and a higher rate of dysglycemia. Eubacterium hallii was associated with insulin sensitivity (ρ=0.12, P=0.02). Analysis of 27 species from the 8 genera revealed additional associations with insulin sensitivity and disposition index, most of which displayed positive associations with these traits. These data suggest that improved insulin sensitivity and improved insulin secretion response to insulin sensitivity (i.e., disposition index) are key mechanisms whereby butyrate producing bacteria may exert metabolic protection against T2D. Disclosure J. Cui: None. M. O. Goodarzi: None. T. Zhu: None. E. T. Jensen: None. O. L. Crago: None. G. Ramesh: None. K. M. Sandow: None. Y. Chen: None. J. I. Rotter: None. J. Petrosino: None. Funding National Institutes of Health (R01DK109588)

1085-P: Defining the Role of Insulin Clearance in Dysglycemia: The Microbiome and Insulin Longitudinal Evaluation Study (MILES)

Insulin resistance and insufficient insulin secretion lead to type 2 diabetes. A role of reduced insulin clearance has been suggested, but few studies have investigated the contribution of insulin clearance while simultaneously examining insulin sensitivity and secretion. The goal of this study was to conduct such an investigation in 224 non-Hispanic White and 129 African Americans individuals from MILES (mean age 59, 62% female). Participants underwent oral glucose tolerance tests from which insulin sensitivity, insulin secretion, insulin clearance, and disposition index were calculated. Logistic regression models (controlling for age, sex, race, and BMI) examined the individual contributions of these traits separately, as well as the joint contribution of insulin sensitivity, clearance, and secretion, to early dysglycemia (prediabetes plus newly diagnosed diabetes; 46% of cohort). Models used standardized predictors such that odds ratios (OR) represent the change in odds of dysglycemia per standard deviation change. Model performance was assessed via Akaike’s Information Criterion (AIC) and area under the receiver operator characteristic curves (AUROC). In separate models, dysglycemia was associated with insulin sensitivity (OR 0.2; 0.14-0.30; P<.001), disposition index (OR 0.13; 0.08-0.20; P<.001) and insulin clearance (OR 0.66; 0.51-0.87; P<.001). In a joint model, only reduced insulin sensitivity (OR 0.04; 0.02-0.08; P<.001) and secretion (OR 0.15; 0.08-0.27; P<.001) were associated with dysglycemia. Models with insulin sensitivity (AIC=376.7; AUROC=0.82), disposition index (AIC=324.8; AUROC=0.87), or three insulin traits (AIC=303.4; AUROC=0.89) had the highest discriminative value. These results suggest that in the race groups studied, insulin resistance and compromised insulin secretion are the main independent defects leading to dysglycemia, while reduced insulin clearance may have a minor contributory role. Disclosure A. Wood: None. E. T. Jensen: None. G. Ramesh: None. Z. Arzumanyan: None. K. Lam: None. A. Bertoni: None. J. I. Rotter: None. Y. Chen: None. M. O. Goodarzi: None. Funding National Institutes of Health (R01DK109588)

Pregnancy Serum DLK1 Concentrations Are Associated With Indices of Insulin Resistance and Secretion.

ContextDelta like noncanonical notch ligand 1 (DLK1) is a paternally expressed imprinted gene that encodes an epidermal growth factor repeat-containing transmembrane protein. A bioactive, truncated DLK1 protein is present in the circulation and has roles in development and metabolism.ObjectiveWe sought to investigate links between maternal pregnancy circulating DLK1 concentrations and: (1) maternal and fetal DLK1 genotypes, (2) maternal insulin resistance and secretion, and (3) offspring size at birth.Patients, design, and settingWe measured third-trimester maternal serum DLK1 concentrations and examined their associations with parentally transmitted fetal and maternal DLK1 genotypes, indices of maternal insulin resistance and secretion derived from 75-g oral glucose tolerance tests performed around week 28 of pregnancy, and offspring size at birth in 613 pregnancies from the Cambridge Baby Growth Study.ResultsMaternal DLK1 concentrations were associated with the paternally transmitted fetal DLK1 rs12147008 allele (P = 7.8 × 10-3) but not with maternal rs12147008 genotype (P = 0.4). Maternal DLK1 concentrations were positively associated with maternal prepregnancy body mass index (P = 3.5 × 10-6), and (after adjustment for maternal body mass index) with both maternal fasting insulin resistance (Homeostatic Model Assessment of Insulin Resistance: P = 0.01) and measures of maternal insulin secretion in response to oral glucose (insulinogenic index: P = 1.2 × 10-3; insulin disposition index: P = 0.049). Further positive associations were found with offspring weight (P = 0.02) and head circumference at birth (P = 0.04).ConclusionThese results are consistent with a partial paternal or placental origin for the maternal circulating DLK1 which may lead to increased maternal circulating DLK1 concentrations, stimulation of maternal insulin resistance and compensatory hyperinsulinemia during pregnancy, and the promotion of fetal growth.

1788-P: Islet Function in Youth with Cystic Fibrosis with and without Liver Disease

Insulin deficiency largely underlies cystic fibrosis related diabetes (CFRD). CF liver disease (CFLD) is a risk factor for CFRD development, but the mechanisms linking these mortality-increasing comorbidities are unknown. This pilot study sought to characterize prandial glucose metabolism and islet function in youth across glycemia and CFLD spectrums. Glucose, insulin, c-peptide (CP) and glucagon were obtained during a 3-hr oral glucose tolerance test in youth (9M/11F, ages 12-21y) with pancreatic insufficient CF from two centers. Fasting insulin sensitivity (HOMA-IR) and insulin clearance (CP:insulin), and prandial glucose and glucagon excursion (AUC180), insulin sensitivity (Matsuda index), β-cell sensitivity to glucose, insulin secretory rates (ISR; by parametric deconvolution of CP kinetics) and disposition index (DI, composite of insulin secretion and insulin sensitivity) were calculated. CFLD status was defined using CFLD guidelines: CFLD with portal hypertension (CFLDPH), CFLD without portal hypertension (CFLD) and no liver disease (CFnoLD). CFLDPH (n=3), CFLD (n=3) CFnoLD (n=14) did not differ in age, BMI-Z, or HbA1c. CFRD was present in 2 CFLDPH, 0 CFLD, 4 CFnoLD. Fasting glucose was greater in CFLDPH vs. CFLD or CFnoLD (p<0.05). HOMA-IR and fasting CP:insulin were reduced in CFLDPH vs. CFLD and CFnoLD, but post-meal glucose-AUC180 and indices of insulin sensitivity and clearance were similar. ISR and DI tended to be lower in CFLDPH vs. CFLD (p=0.008 and p=0.077) and CFnoLD (p=0.071 and p=0.058), respectively. β-cell sensitivity was reduced in CFLDPH vs. CFLD (p<0.05). Fasting and AUC180 glucagon did not differ among groups. In this limited group of youth, reduced fasting insulin sensitivity and magnified insulin secretory defects are present in CFLDPH, the more severe form of CFLD, and may explain their heightened CFRD risk. Larger studies are warranted to define pathogenesis and inform glycemic treatment targets in individuals with severe CFLD. Disclosure M.S. Rayas: None. K.S. Hughan: Research Support; Self; Novo Nordisk Inc. R. Javaid: None. D. leung: None. D. Stefanovski: None. A. Kelly: None. M. Salehi: None. Funding Cystic Fibrosis Foundation (RAYAS16GEO, HUGHAN16GE0, MOR16CFF); National Institutes of Health (5T32DK00772923)

1836-P: Nonalcoholic Steatohepatitis (NASH) Significantly Contribute to ß-Cell Function Impairment Independently of Glucose Tolerance Status

ß-cell dysfunction is a strong risk factor for type 2 diabetes (T2D). The liver plays a central role since insulin clearance (ClearIns) is up to 80% of the insulin secretion rate (ISR). ClearIns is reduced with insulin resistance (IR) and in patients with nonalcoholic fatty liver disease (NAFLD) . Our aim was to evaluate if ISR and ß-cell function were decreased in NASH vs. NAFL thus increasing their risk of T2D and the impact of ClearIns and IR. We measured glucose, insulin and c-peptide during a 3h oral glucose tolerance test in 341 subjects with liver biopsy and evaluated ISR (from deconvolution of c-peptide), ClearIns, Matsuda insulin sensitivity index (ISI) and disposition index (DI=ISI∙ΔAUC-I/ΔAUC-G); a low DI indicates a risk to develop T2D. Subjects were grouped according to glucose tolerance, normal (NGT), impaired (IGT) or T2D, and liver histology (noNAFL, NAFL, NASH-Fibrosis F0-F1 and F2-F4). The groups had similar BMI (∼34kg/m2). Severity of NAFLD was associated with increased IR, fasting and postprandial ISR and decreased ClearIns, after adjusting for age and BMI. DI was significantly lower in NASH-F24 in each glucose tolerance group (Figure). Conclusion: Disposition index is reduced in relation to presence and severity of NASH independent of glucose tolerance status supporting an independent role of NASH in the development of T2D. Disclosure L. Vonghia: None. E. Dirinck: None. F. Carli: None. A. Verrijken: None. J. Weyler: None. P. Michielsen: None. T. Vanwolleghem: None. A. Driessen: None. L. Van Gaal: None. S. Francque: None. C. De Block: Advisory Panel; Self; A. Menarini Diagnostics, Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, MSD, Novartis AG, Novo Nordisk A/S, Sanofi. Speaker’s Bureau; Self; Novo Nordisk A/S. A. Gastaldelli: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Gilead Sciences, Inc., Inventiva Pharma, Novo Nordisk Inc. Funding Horizon2020 (634413)

Investigation of the Causal Association between Long-Chain n-6 Polyunsaturated Fatty Acid Synthesis and the Risk of Type 2 Diabetes: A Mendelian Randomization Analysis

Background: Globally, 1 in 11 adults has diabetes mellitus, and most of these cases are type 2 diabetes (T2D). The risk of T2D is influenced by many factors, including diet. The synthesis of long-chain n-6 polyunsaturated fatty acids (LC n-6 PUFA) has been posited as a risk factor for T2D; however, its causal role is uncertain. Aim: To test the causal effect of LC n-6 PUFA synthesis on insulin resistance and transgenerational T2D risk in a large cohort of men and women. Methods: Two-sample mendelian randomization (MR) was conducted to evaluate the effect of low or high levels of LC n-6 PUFA synthesis on glycemia and development of T2D in the UK Biobank (n = 463,010) and Meta-Analysis of Glucose- and Insulin-Related Traits Consortium (MAGIC; n = 5,130) cohorts. The increased likelihood of a predisposition to low or high LC n-6 PUFA synthesis and the risk of T2D was also investigated using the participants’ siblings and parents. In MR-Base, 4 genetic variants associated with LC n-6 PUFA synthesis were found (p < 10^–8). After pruning, 1 variant (rs174547) on the FADS1 gene was retained. Results: Lower LC n-6 PUFA synthesis and abundance (per % unit decrease) are associated with small reductions in the insulin disposition index (–0.038 ± 0.012 mM^–1; p = 0.002) within MAGIC. In the UK Biobank, we report negligible effects of low n-6 PUFA synthesis on the odds of T2D (OR <1%; p < 0.05). Additionally, reduced LC n-6 PUFA synthesis does not appear to be a contributor to familial T2D risk. No significant association was observed between LC n-6 PUFA synthesis and BMI. Conclusion: In a primarily white European population, LC n-6 PUFA synthesis is not a major contributor to T2D risk.

Temporal Trends in Maternal Food Intake Frequencies and Associations with Gestational Diabetes: The Cambridge Baby Growth Study.

Previous studies have suggested that in the first decade of this century the incidence of gestational diabetes (GDM) in pregnancy rose worldwide. In the Cambridge Baby Growth Study cohort we observed that this temporal trend was associated with an index of multiple deprivation and reductions in indices of insulin secretion. Deprivation level was not directly associated with GDM, suggesting that the temporal trend may relate more to other factors linked to it, such as dietary composition. In this study we investigated temporal trends in perceived food intake frequencies, derived from a qualitative, short questionnaire, in 865 pregnant Cambridge Baby Growth Study (CBGS) recruits. A number of food frequency ranks showed both temporal trends and associations with GDM, but of note is the frequency of egg consumption (negative temporal trend p = 0.03, slope = −6.2 ranks/year; negative association with GDM p = 3.0 × 10−8, slope = −0.002 increased risk/rank) as it was also positively associated with the insulin disposition index (p = 1.17 × 10−3, slope = 0.42 ranks. L/mmoL). These results are consistent with a potential protective effect of factors related to the frequency of egg consumption in pregnancy. Such factors may have contributed to the observed temporal trend in GDM risk but the overall detectable effect appears to have been small.

2432-PUB: Predictors of Imminent Glycemic Worsening in Adults with Screen-Detected Diabetes

Reliable clinical indicators of near-term risk of worsening glycemia in type 2 diabetes (T2D) could help guide individual-level interventions. Here we analyzed data from the Early Diabetes Intervention Program (EDIP) to identify predictors of near-term glycemic progression. EDIP evaluated progression of fasting blood glucose (FBG) above 140 mg/dl on consecutive quarterly measurements in individuals with screen-detected T2D and FBG below 140 at study entry (age 52.6 + 11.5 years, 41.9% male, mean entry FBG 121±14 mg/dL; mean 2-hour OGTT glucose 236±30; mean HbA1C 6.4+0.57%). We investigated accessible clinical parameters (weight, glycemia, lipids, and insulin levels) as potential near-term predictors of progression, evaluating absolute levels and yearly changes preceding progression. Variables were evaluated individually in age/sex/race-adjusted analyses and in combination in multivariable Cox progression models. Change over the preceding 1 year in fasting glucose, but not in weight or insulin levels, was predictive of glycemic progression in the subsequent year in adjusted univariate analyses (p&amp;lt;0.03). In multivariable modeling, the FBG concentration (hazard ratio HR 1.14) and the antecedent 1-year change in FBG (HR 0.90) were the strongest predictors of progression, and both retained significance in multivariable models including all specified variables (p&amp;lt; 0.0001). Adding changes in fasting insulin, HOMA-IR, or oral disposition index to the modeling did not change this result. There was a significant correlation between current FBG and the antecedent 1-year change (r=0.587; p&amp;lt;0.01), highlighting that change in FBG was contributing in part via its effect on current FBG. In the EDIP study population with screen-detected T2D, current FBG and antecedent 1-year change in FBG were the best predictors of upcoming glycemic worsening. These data underscore the value of serially monitoring fasting glucose, and suggest a similar monitoring paradigm should be evaluated in prediabetes. Disclosure R.S. Aguirre: None. T.S. Hannon: Advisory Panel; Self; Eli Lilly and Company. R. Considine: None. M. Kirkman: Research Support; Self; Bayer AG, Novo Nordisk A/S, Theracos, Inc. K.J. Mather: Advisory Panel; Self; Roche Diabetes Care. Research Support; Self; Abbott, Merck &amp; Co., Inc., Novo Nordisk A/S, Sanofi.

149-LB: The MetAP2 Inhibitor, ZGN-1061, Improves Insulin Sensitivity and Beta-Cell Function in Patients with Type 2 Diabetes

ZGN-1061 is a second-generation methionine aminopeptidase 2 (MetAP2) inhibitor in development for treatment of T2D. Full results of a Phase 2 clinical trial of ZGN-1061 vs. placebo (PBO) administered SC for 12 weeks on change from baseline in A1C in subjects with T2D are reported elsewhere. Baseline (ITT population N=175) A1C 8.6±1.1%, BMI 37±7 kg/m2, T2D duration 8±6 y. ZGN-1061 was generally well tolerated; 93% completed the trial. LS mean±SE A1C change was 0.2±0.1% for PBO vs. ±0.4±0.1% and -0.9±0.2% for 0.9 and 1.8 mg ZGN-1061 (both p&amp;lt;0.001 vs. PBO). PBO weight change was -0.6±0.3 kg vs. -1.4±0.3 kg (p=ns) and ±2.8±0.5 kg (p&amp;lt;0.001) for 0.9 and 1.8 mg ZGN-1061. This analysis included a subset of subjects who participated in a mixed-meal tolerance test (MMTT) at baseline and week 12. ZGN-1061 produced dose-dependent improvements in fasting and postprandial glucose (p&amp;lt;0.05 vs. PBO). Minimal model analysis showed improvements in insulin sensitivity (SI) and disposition index (DI_OB; a measure of β-cell compensation) from baseline to week 12 with ZGN-1061 (Table). In an exploratory combined analysis of 0.9+1.8 mg ZGN-1061, SI and DI_OB increased (p=0.02 and p=0.07). SI and DI_OB were unchanged with PBO. In patients with T2D, improved glycemic control with ZGN-1061 may be driven by changes in insulin sensitivity and β-cell function. These results support future assessments using other definitive methods. Disclosure R. Fabunmi: None. R.N. Bergman: Consultant; Self; Zafgen, Inc. F. Piccinini: None. T. Kim: Employee; Spouse/Partner; Celgene Corporation. Employee; Self; Zafgen, Inc. D. Zhuang: Employee; Self; Zafgen, Inc. K. Taylor: Employee; Self; Zafgen, Inc. D.D. Kim: Employee; Self; Zafgen, Inc. Funding Zafgen, Inc.

Temporal trends without seasonal effects on gestational diabetes incidence relate to reductions in indices of insulin secretion: the Cambridge Baby Growth Study

AimsThe incidence of gestational diabetes has been reported to have risen over the first decade of this century. Some studies have also found it to vary with seasons of the year. We investigated temporal and seasonal trends on gestational diabetes incidence in a single-centre cohort study from Cambridge, UK, and attempted to explain trends using associated risk factors.MethodsUsing a cosinor model, we tested both temporal and seasonal trends in gestational diabetes incidence in 1074 women recruited to the Cambridge Baby Growth Study in 2001–2009 who underwent oral glucose tolerance tests around week 28 of pregnancy.ResultsThere was a temporal increase in gestational diabetes incidence over the course of recruitment to this study [0.014 (0.005, 0.022) proportional increase per year, p = 2.1 × 10−3], but no seasonal effect (p = 0.7). HOMA B [− 0.015 (− 0.025, − 0.005) per year, p = 3.0 × 10−3] and the insulin disposition index [− 0.036 (− 0.060, − 0.013) per year, p = 3.0 × 10−3], unlike HOMA S, showed negative temporal trends. Risk factor analyses showed a concomitant temporal slight increase in the index of multiple deprivation [0.191 (0.138, 0.257) units per year, p = 4.6 × 10−10]. This index was positively associated with HOMA B (p = 6.1 × 10−5) but not directly with gestational diabetes (p = 0.6), HOMA S (p = 0.2) or the insulin disposition index (p = 0.4).ConclusionsIn this cohort, there were temporal, but not seasonal, increases in gestational diabetes incidence between the years 2001 and 2009, which appeared to be related more to reductions in insulin secretion than sensitivity. Possible mediators of this link include confounding factors related to deprivation.

The association between elevated serum uric acid levels and islet β-cell function indexes in newly diagnosed type 2 diabetes mellitus: a cross-sectional study.

BackgroundSerum uric acid (UA) has been reported as a risk factor for type 2 diabetes mellitus (T2DM). However, whether serum UA is associated with insulin resistance and insulin secretion, and the effect of gender on it in the case of the existed association, both remain undefined.MethodsA cross-sectional study was designed and performed, which enrolled a total of 403 newly diagnosed T2DM patients (mean age, 50.21 ± 13.34 years (62.5% males)). Clinical characteristics and islet function indexes of all participants were analyzed based on gender-specific tertiles of serum UA levels. In addition, multiple linear regression analysis was conducted to investigate covariates associated with islet function indexes.ResultsThe mean levels of serum UA were 331.05 μmol/L (interquartile range (IQR): 60.6, 400.9 μmol/L) and 267.9 μmol/L (IQR: 204.7, 331.9 μmol/L) in men and women, respectively. The values of insulin secretion indexes involving AUCins30/glu30, AUCins120/glu120 and total insulin disposition index (DI120) in females were significantly higher than those in males. Apart from the homeostasis model assessment insulin resistance of men, serum UA was positively associated with insulin secretion and insulin resistance indexes both in men and women. Multivariable linear regression analysis showed serum UA exerted an independent impact on insulin secretion in females, but not on insulin resistance. In males, islet function was simultaneously affected by serum UA age, body mass index (BMI), and serum lipids.ConclusionSerum UA harbored a positive correlation with insulin secretion and insulin resistance indexes in newly diagnosed T2DM patients, which was influenced by gender, BMI, serum lipids. Hence, serum UA may be considered as a predictor for islet function in clinical practice.

Noncovalent Strategy with Cell-Penetrating Peptides to Facilitate the Brain Delivery of Insulin through the Blood-Brain Barrier.

To overcome the difficulty in delivery of biopharmaceuticals such as peptides and proteins to the brain, several approaches combining the ligands and antibodies targeting the blood-brain barrier (BBB) have been tried. However, these are inefficient in terms of their permeability through the BBB and structural modification of bioactive drugs. In the present study, we therefore examined the usefulness of a noncovalent method using the cell-penetrating peptides (CPPs) such as octaarginine (R8) as a suitable brain delivery strategy for biopharmaceuticals. A safety examination using microvascular endothelial model bEnd.3 cells clarified that R8 was the safest among the CPPs tested in this study. The cellular uptake study demonstrated that coincubation with R8 enhanced the uptake of model peptide drug insulin by bEnd.3 cells in a concentration-dependent and a temperature-independent manner. Furthermore, an in vivo study with rats showed that the accumulation of insulin in the deeper region of the brain, i.e., hippocampus, significantly increased after the intravenous coadministration of insulin with D-R8 without altering the insulin disposition in plasma. Thus, the present study provided the first evidence suggesting that the noncovalent method with CPPs is one of the strategic options for brain delivery of biopharmaceuticals via intravenous injection.