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OBJECTIVE: To estimate risk of progression to stage 3 type 1 diabetes based on varying definition of multiple islet autoantibody positivity (mIA). RESEARCH DESIGN AND METHODS: T1DI is a combined prospective dataset of children from Finland, Germany, Sweden and USA who are at increased genetic risk for type 1 diabetes. Analysis included 16,709 infants-toddlers enrolled by age 2.5 years and comparison between groups using Kaplan-Meier survival analysis. RESULTS: Of 865 (5%) with mIA, 537 (62%) progressed to type 1 diabetes. The 15-year cumulative incidence of diabetes varied from most stringent definition (mIA/Persistent/2: ≥2 islet autoantibodies positive at the same visit with ≥2 antibodies persistent at next visit; 88%, [95% CI: 85-92%]) to least stringent (mIA/Any: positivity for two islet autoantibodies without co-occurring positivity or persistence; 18%, [5-40%]). Progression in mIA/Persistent/2 was significantly higher than all other groups (P CONCLUSIONS: The 15-year risk of progression to type 1 diabetes risk varies markedly from 18-88% based on stringency of mIA definition. While initial categorization identifies highest risk individuals, short-term follow-up over 2 years may help stratify evolving risk especially for those with less stringent definitions of mIA.

Long-chain fatty acids (LCFAs) not only are energy sources but also serve as signaling molecules. GPR120, an LCFA receptor, plays key roles in maintaining metabolic homeostasis. However, whether endogenous ligand-GPR120 circuits exist and how such circuits function in pancreatic islets are unclear. Here, we found that endogenous GPR120 activity in pancreatic δ cells modulated islet functions. At least two unsaturated LCFAs, oleic acid (OA) and linoleic acid (LA), were identified as GPR120 agonists within pancreatic islets. These two LCFAs promoted insulin secretion by inhibiting somatostatin secretion, and showed bias activation of GPR120 in a model system. Compared to OA, LA exerted higher potency in promoting insulin secretion, which is dependent on β-arrestin2 function. Moreover, GPR120 signaling was impaired in the diabetic db/db model, and replenishing OA and LA improved islet function in both the db/db- and STZ-treated diabetic models. Consistently, the administration of LA improved glucose metabolism in db/db mice. Collectively, our results reveal that endogenous LCFA-GPR120 circuits exist and modulate homeostasis in pancreatic islets. The contributions of phenotype differences caused by different LCFA-GPR120 circuits within islets highlight the roles of fine-tuned ligand–receptor signaling networks in maintaining islet homeostasis.

OBJECTIVE This study aims to evaluate the association of energy and macronutrient intake at dinner versus breakfast with disease-specific and all-cause mortality in people with diabetes. RESEARCH DESIGN AND METHODS A total of 4,699 people with diabetes who enrolled in the National Health and Nutrition Examination Survey from 2003 to 2014 were recruited for this study. Energy and macronutrient intake was measured by a 24-h dietary recall. The differences (Δ) in energy and macronutrient intake between dinner and breakfast (Δ = dinner − breakfast) were categorized into quintiles. Death information was obtained from the National Death Index until 2015. Cox proportional hazards regression models were developed to evaluate the survival relationship between Δ and diabetes, cardiovascular disease (CVD), and all-cause mortality. RESULTS Among the 4,699 participants, 913 deaths, including 269 deaths due to diabetes and 314 deaths due to CVD, were documented. After adjustment for potential confounders, compared with participants in the lowest quintile of Δ in terms of total energy and protein, participants in the highest quintile were more likely to die due to diabetes (hazard ratio [HR]Δenergy 1.92, 99% CI 1.08–3.42; HRΔprotein 1.92, 99% CI 1.06–3.49) and CVD (HRΔenergy 1.69, 99% CI 1.02–2.80; HRΔprotein 1.96, 99% CI 1.14–3.39). The highest quintile of Δtotal fat was related to CVD mortality (HR 1.67, 99% CI 1.01–2.76). Isocalorically replacing 5% of total energy at dinner with breakfast was associated with 4% and 5% lower risk of diabetes (HR 0.96, 95% CI 0.94–0.98) and CVD (HR 0.95, 95% CI 0.93–0.97) mortality, respectively. CONCLUSIONS Higher intake of energy, total fat, and protein from dinner than breakfast was associated with greater diabetes, CVD, and all-cause mortality in people with diabetes.

OBJECTIVE This randomized controlled-feeding trial aimed to determine the impact of fried meat intake on the gut microbiota and fecal cometabolites and whether such impacts influenced host glucose homoeostasis, intestinal endotoxin levels, and systemic inflammation. RESEARCH DESIGN AND METHODS A total of 117 overweight adults were randomized into two groups. Fifty-nine participants were provided fried meat four times per week, and 58 participants were restricted from fried meat intake, while holding food group and nutrient compositions constant, for 4 weeks. The gut microbiota was analyzed by 16S rRNA sequencing. Glucose and insulin concentrations at 0, 30, 60, and 120 min of an oral glucose tolerance test, fecal microbiota-host cometabolite levels, and intestinal endotoxin and inflammation serum biomarker levels were measured. The area under the curve (AUC) for insulin, insulinogenic index (IGI), and muscle insulin resistance index (MIRI) were calculated. RESULTS The participants who consumed fried meat had lower IGI values than the control subjects, but they had higher MIRI and AUC values of insulin and lipopolysaccharide (LPS), TNF-α, IL-10, and IL-1β levels (P < 0.05). Fried meat intake lowered microbial community richness and decreased Lachnospiraceae and Flavonifractor abundances while increasing Dialister, Dorea, and Veillonella abundances (P FDR CONCLUSIONS Fried meat intake impaired glucose homoeostasis and increased intestinal endotoxin and systemic inflammation levels by influencing the gut microbiota and microbial-host cometabolites.

Objective: Nonalcoholic fatty liver disease has been associated with the development of gestational diabetes (GDM). We sought to determine whether abnormal liver enzyme levels and indices of hepatic steatosis and fibrosis in an entire pregnant population are associated with GDM development. Methods: A retrospective cohort study was conducted on adult women (≥18 years) who delivered at 2 teaching hospitals in Sydney Australia from January 2016 to December 2017. Liver enzymes (aspartate aminotransaminase (AST), alanine aminotransaminase (ALT), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), albumin (ALB) and bilirubin (BIL)) obtained 12 months pre-gravid, or during pregnancy but prior to GDM screening, were extracted from the hospital pathology database and linked with oral glucose tolerance test results. The Fibrosis-4 (FIB-4) and Hepatic Steatosis Index (HSI) were calculated. Univariate analysis was undertaken to determine the association between deranged liver enzymes, FIB-4, HSI and GDM. Multiple logistic regression, with adjustment for age, ethnicity, pre-gravid body mass index (BMI), parity, prior GDM and family history of diabetes, was conducted to determine if any of these were independent predictors of GDM. Results: Over 2 years, 1429 women had liver enzymes collected. As per IADPSG (2010) criteria, 255 had diagnosed GDM, of which 82 (32.2%) were obese (BMI >30kg/m2), 243 (82.4%) were multiparous, and 223 (87.5%) had prior GDM. Elevated GGT (>35IU/L, p=0.006) and HSI (p=0.005) were associated with development of GDM, whilst low ALB (110IU/L), ALT (>35IU/L), AST (>35IU/L), BIL (>19umol/L) and FIB-4 were not. On adjustment for confounders, elevated GGT (AOR 1.1, 95% CI 0.32-3.8, p=0.88) and HSI (AOR 0.6, 95% CI 0.26-1.3, p=0.21) were not independent predictors of GDM. Conclusions: Our results indicate deranged liver enzymes or clinical indices of hepatic steatosis and fibrosis were not associated with GDM. Disclosure T. Y. L. Chai: None. D. Pasupathy: None. J. George: None. N. Cheung: None.

Brown adipose tissue (BAT) is a key organ that produces heat and dissipates energy, and may be clinically relevant to the treatment of obesity and diabetes. Tetrahydrobiopterin (BH4) is an essential co-factor of tyrosine hydroxylase, a rate-limiting enzyme of catecholamine biosynthesis including that of norepinephrine (NA) and nitric oxide (NO) synthase. Although both NA and NO are well-known factors in BAT differentiation, the role of BH4 in the differentiation of BAT is poorly understood. We investigated the role of BH4 in differentiation of BAT using a mouse model of BH4 deficiency, the Hph-1 mouse. Hph-1 neonatal mice exhibit dysplasia of BAT as well as attenuated thermogenesis-related gene expressions (UCP1, Dio2, Pgc1a) compared with control mice. As differentiation capacity is considered to be at maximum during late gestation, we administered BH4 to fetal Hph-1 mice via placental transfer using intraperitoneal injection to pregnant Hph-1 mice for 6 days just before birth. Maternal BH4 supplementation ameliorated dysplasia of neonatal BAT and restored thermogenesis-related genes expression. Intriguingly, offspring of the maternal BH4-supplementation group showed less weight gain, ameliorated glucose intolerance, and improved cold tolerance after growth under high fat chow diet. We then evaluated the direct effect of BH4 on brown adipocyte differentiation using brown pre-adipocytes isolated from control and Hph-1 mice. Compared with control mice, brown pre-adipocytes from Hph-1 mice showed reduced differentiation capacity, while BH4 supplementation in brown pre-adipocytes from Hph-1 mice ameliorated differentiation capacity nitric oxide-dependently. Taking these findings together, BH4 plays an integral role in the differentiation of BAT, especially in the fetal period, and may represent a novel target for prevention of metabolic disorders such as obesity and diabetes. Disclosure H. Minamino: None. Y. Fujita: None. Y. Oguri: None. T. Goto: None. A. Ohashi: None. F. Furuya: None. N. Isomura: None. T. Kohei: None. Y. Li: None. S. Kawarasaki: None. T. Kawada: None. H. Hasegawa: None. N. Inagaki: Research Support; Self; Astellas Pharma Inc., Drawbridge Health, Japan Tobacco Inc., Kissei Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Life Scan Japan, Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Novo Nordisk Pharma Ltd.,, Sanofi K.K., Sanwa Kagaku Kenkyusho, Terumo Medical Corporation. Speaker’s Bureau; Self; Astellas Pharma Inc., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited.

OBJECTIVE We aimed to evaluate whether xanthine oxidase (XO), a key enzyme in uric acid (UA) metabolism and a major source of reactive oxygen species, plays a causal and important role in the development of type 2 diabetes mellitus (T2DM) in a large prospective cohort study. RESEARCH DESIGN AND METHODS A total of 4,412 diabetes-free adults (2,071 women and 2,341 men) aged 30–65 years at baseline in 2008 were involved. Participants were followed for incident change of glucose metabolism during an average of 4.7 years. At baseline, serum XO and UA, serum lipids, and glucose homeostasis indexes including fasting blood glucose (FBG), 2-h blood glucose (PBG), glycosylated hemoglobin A1c (HbA1c), and fasting insulin were tested for analysis. RESULTS During an average follow-up period of 4.7 years, 249 women and 360 men developed new-onset T2DM. Serum XO activity was positively associated with UA concentration (all P values CONCLUSIONS Elevated serum XO activity, but not UA concentration, was associated with an increased risk of developing T2DM in women and men with mutual adjustment for XO and UA. Further studies are needed to examine the underlying mechanisms.

Clinical islet transplantation (CIT) is a potential therapy for type 1 diabetes. Allorejection mediated by the host CD4 T cells is a major hurdle for successful CIT, despite potent systemic immunosuppression (SI). To address these issues, we engineered PLGA microparticles (PLGA-MPs) that allow the localized delivery of TGF-β1 for regulatory T cells (TRegs) induction at the transplant site. TGF-β1 is an immunoregulatory agent that promotes the TRegs differentiation from naïve CD4 cells by inducing FoxP3 expression while suppressing inflammatory Th1 and Th2 responses. To date, we have (i) fabricated TGF-β1 loaded PLGA particles by double emulsion (PVA(aq)- CH2Cl2- PVA(aq)) with characterization in size (45±26 μm), TGF-β1 encapsulation efficiency (49.1±0.1%), and release kinetics (durable biphasic release for 14 days); (ii) proved effective TRegs conversion in OVA-OTII antigen-specific murine model (Fig.1); and (iii) shown efficacy for in vivo Treg conversion by MPs in rodent islet allografts, where accepted grafts showed improved insulin production and elevated TRegs. Future studies exploring the competency of PLGA-MPs to provide durable allograft protection in rodent models is on-going. Based on these promising preliminary results, TGF-β1 PLGA-MPs could provide a translational therapeutic strategy to minimize islet graft rejection and the dependency on SI. Disclosure Y. Li: None. A. Frei: Employee; Self; Medline Industries, Inc.. S.D. Barash: None. C.L. Stabler: None.

Strong associations between HLA alleles and infectious and autoimmune diseases are well established. Although obesity is also associated with these diseases, the relationship between HLA and obesity has not been systematically investigated in a large cohort. In the current study, we analyzed the association of HLA alleles with BMI using data from 1.3 million healthy adult donors from the Chinese Marrow Donor Program (CMDP). We found 23 HLA alleles, including 12 low-resolution and 11 high-resolution alleles, were significantly associated with BMI after correction for multiple testing. Alleles associated with high BMI were enriched in haplotypes that were common in both Chinese and European populations, whereas the alleles associated with low BMI were enriched in haplotypes common only in Asians. Alleles B*07, DRB1*07, DRB1*12, and C*03:02 provided the strongest associations with BMI (P = 6.89 × 10−10, 1.32 × 10−9, 1.52 × 10−9, and 4.45 × 10−8, respectively), where B*07 and DRB1*07 also had evidence for sex-specific effects (Pheterogeneity = 0.0067 and 0.00058, respectively). These results, which identify associations between alleles of HLA-B, DRB1, and C with BMI in Chinese young adults, implicate a novel biological connection between HLA alleles and obesity.

Insulin and adrenergic stimulation are two divergent regulatory systems that may interact under certain pathophysiological circumstances. Here, we characterized a complex consisting of insulin receptor (IR) and β2-adrenergic receptor (β2AR) in the heart. The IR/β2AR complex undergoes dynamic dissociation under diverse conditions such as Langendorff perfusions of hearts with insulin or after euglycemic-hyperinsulinemic clamps in vivo. Activation of IR with insulin induces protein kinase A (PKA) and G-protein receptor kinase 2 (GRK2) phosphorylation of the β2AR, which promotes β2AR coupling to the inhibitory G-protein, Gi. The insulin-induced phosphorylation of β2AR is dependent on IRS1 and IRS2. After insulin pretreatment, the activated β2AR-Gi signaling effectively attenuates cAMP/PKA activity after β-adrenergic stimulation in cardiomyocytes and consequently inhibits PKA phosphorylation of phospholamban and contractile responses in myocytes in vitro and in Langendorff perfused hearts. These data indicate that increased IR signaling, as occurs in hyperinsulinemic states, may directly impair βAR-regulated cardiac contractility. This β2AR-dependent IR and βAR signaling cross-talk offers a molecular basis for the broad interaction between these signaling cascades in the heart and other tissues or organs that may contribute to the pathophysiology of metabolic and cardiovascular dysfunction in insulin-resistant states.

Elevated serum free fatty acids (FFAs) levels play an important role in the development of insulin resistance (IR) and diabetes. We investigated the dynamic changes and the underlying regulatory mechanism of postprandial FFA profile in hyperlipidemia (HLP) and their relation with insulin sensitivity in both humans and mice. We found that serum stearic acid (SA) is the only fatty acid that is increased dramatically in the postprandial state. The elevation of SA is due to increased insulin-stimulated de novo synthesis mediated by sterol regulatory element–binding protein-1c (SREBP-1c)/acetyl-CoA carboxylase/fatty acid synthase/elongation of long-chain fatty acid family member 6 (ELOVL6) and the elongation of palmitic acid (PA) catalyzed by ELOVL6. Downregulation of SREBP-1c or ELOVL6 by small interfering RNA can reduce SA synthesis in liver and serum SA level, followed by amelioration of IR in HLP mice. However, inhibition of SREBP-1c is more effective in improving IR than suppression of ELOVL6, which resulted in accumulation of PA. In summary, increased postprandial SA is caused by the insulin-stimulated SREBP-1c pathway and elongation of PA in HLP. Reduction of postprandial SA is a good candidate for improving IR, and SREBP-1c is potentially a better target to prevent IR and diabetes by decreasing SA.

OBJECTIVE Hyperglycemia induces reactive oxygen species (ROS) and apoptosis in cardiomyocytes, which contributes to diabetic cardiomyopathy. The present study was to investigate the role of Rac1 in ROS production and cardiomyocyte apoptosis during hyperglycemia. RESEARCH DESIGN AND METHODS Mice with cardiomyocyte-specific Rac1 knockout (Rac1-ko) were generated. Hyperglycemia was induced in Rac1-ko mice and their wild-type littermates by injection of streptozotocin (STZ). In cultured adult rat cardiomyocytes, apoptosis was induced by high glucose. RESULTS The results showed a mouse model of STZ-induced diabetes, 7 days of hyperglycemia-upregulated Rac1 and NADPH oxidase activation, elevated ROS production, and induced apoptosis in the heart. These effects of hyperglycemia were significantly decreased in Rac1-ko mice or wild-type mice treated with apocynin. Interestingly, deficiency of Rac1 or apocynin treatment significantly reduced hyperglycemia-induced mitochondrial ROS production in the heart. Deficiency of Rac1 also attenuated myocardial dysfunction after 2 months of STZ injection. In cultured cardiomyocytes, high glucose upregulated Rac1 and NADPH oxidase activity and induced apoptotic cell death, which were blocked by overexpression of a dominant negative mutant of Rac1, knockdown of gp91phox or p47phox, or NADPH oxidase inhibitor. In type 2 diabetic db/db mice, administration of Rac1 inhibitor, NSC23766, significantly inhibited NADPH oxidase activity and apoptosis and slightly improved myocardial function. CONCLUSIONS Rac1 is pivotal in hyperglycemia-induced apoptosis in cardiomyocytes. The role of Rac1 is mediated through NADPH oxidase activation and associated with mitochondrial ROS generation. Our study suggests that Rac1 may serve as a potential therapeutic target for cardiac complications of diabetes.