FLAT RATE Shipping on all US orders, no minimum! 

The Influence of Type 1 Diabetes Genetic Susceptibility Regions, Age, Sex, and Family History on the Progression From Multiple Autoantibodies to Type 1 Diabetes: A TEDDY Study Report

Diabetes - Tue, 11/21/2017 - 13:01

This article seeks to determine whether factors related to autoimmunity risk remain significant after the initiation of two or more diabetes-related autoantibodies and continue to contribute to type 1 diabetes (T1D) risk among autoantibody-positive children in The Environmental Determinants of Diabetes in the Young (TEDDY) study. Characteristics included are age at multiple autoantibody positivity, sex, selected high-risk HLA-DR-DQ genotypes, relationship to a family member with T1D, autoantibody at seroconversion, INS gene (rs1004446_A), and non-HLA gene polymorphisms identified by the Type 1 Diabetes Genetics Consortium (T1DGC). The risk of progression to T1D was not different among those with or without a family history of T1D (P = 0.39) or HLA-DR-DQ genotypes (P = 0.74). Age at developing multiple autoantibodies (hazard ratio = 0.96 per 1-month increase in age; 95% CI 0.95, 0.97; P < 0.001) and the type of first autoantibody (when more than a single autoantibody was the first-appearing indication of seroconversion [P = 0.006]) were statistically significant. Female sex was also a significant risk factor (P = 0.03). Three single nucleotide polymorphisms were associated with increased diabetes risk (rs10517086_A [P = 0.03], rs1534422_G [P = 0.006], and rs2327832_G [P = 0.03] in TNFAIP3) and one with decreased risk (rs1004446_A in INS [P = 0.006]). The TEDDY data suggest that non-HLA gene polymorphisms may play a different role in the initiation of autoimmunity than they do in progression to T1D once autoimmunity has appeared. The strength of these associations may be related to the age of the population and the high-risk HLA-DR-DQ subtypes studied.

Categories: Diabetes

Genetically Determined Plasma Lipid Levels and Risk of Diabetic Retinopathy: A Mendelian Randomization Study

Diabetes - Tue, 11/21/2017 - 13:01

Results from observational studies examining dyslipidemia as a risk factor for diabetic retinopathy (DR) have been inconsistent. We evaluated the causal relationship between plasma lipids and DR using a Mendelian randomization approach. We pooled genome-wide association studies summary statistics from 18 studies for two DR phenotypes: any DR (N = 2,969 case and 4,096 control subjects) and severe DR (N = 1,277 case and 3,980 control subjects). Previously identified lipid-associated single nucleotide polymorphisms served as instrumental variables. Meta-analysis to combine the Mendelian randomization estimates from different cohorts was conducted. There was no statistically significant change in odds ratios of having any DR or severe DR for any of the lipid fractions in the primary analysis that used single nucleotide polymorphisms that did not have a pleiotropic effect on another lipid fraction. Similarly, there was no significant association in the Caucasian and Chinese subgroup analyses. This study did not show evidence of a causal role of the four lipid fractions on DR. However, the study had limited power to detect odds ratios less than 1.23 per SD in genetically induced increase in plasma lipid levels, thus we cannot exclude that causal relationships with more modest effect sizes exist.

Categories: Diabetes

Issues and Events

Diabetes - Tue, 11/21/2017 - 13:01
Categories: Diabetes

In This Issue of Diabetes

Diabetes - Mon, 10/23/2017 - 13:00
Categories: Diabetes

The Gastrointestinal Tract as an Integrator of Mechanical and Hormonal Response to Nutrient Ingestion

Diabetes - Mon, 10/23/2017 - 13:00

Glucose tolerance after meal ingestion in vivo is the result of multiple processes that occur in parallel. Insulin secretion together with reciprocal inhibition of glucagon secretion contributes to glucose tolerance. However, other factors beyond glucose effectiveness and insulin action require consideration. The absorption of ingested nutrients and their subsequent systemic rate of appearance largely depend on the rate of delivery of nutrients to the proximal small intestine. This is determined by the integrated response of the upper gastrointestinal tract to a meal. While gastric emptying is probably the most significant component, other factors need to be considered. This review will examine all processes that could potentially alter the fraction and rate of appearance of ingested nutrients in the peripheral circulation. Several of these processes may be potential therapeutic targets for the prevention and treatment of diabetes. Indeed, there is increased interest in gastrointestinal contributions to nutritional homeostasis, as demonstrated by the advent of antidiabetes therapies that alter gastrointestinal motility, the effect of bariatric surgery on diabetes remission, and the potential of the intestinal microbiome as a modulator of human metabolism. The overall goal of this review is to examine current knowledge of the gastrointestinal contributions to metabolic control.

Categories: Diabetes

Give GWAS a Chance

Diabetes - Mon, 10/23/2017 - 13:00
Categories: Diabetes

Fatty Acid Metabolic Remodeling During Type 2 Diabetes Remission After Bariatric Surgery

Diabetes - Mon, 10/23/2017 - 13:00

Hypertrophic remodeling of white adipose tissues is associated with overexposure of lean organs to circulating triglycerides (TGs) and nonesterified fatty acids (NEFAs), ultimately leading to insulin resistance. Bariatric surgery promotes type 2 diabetes (T2D) remission through a succession of weight loss–dependent and –independent mechanisms. However, the longitudinal contribution of adipocyte size reduction and fatty acid metabolic handling remain unknown. Here we show that severely obese participants with T2D display hypertriglyceridemia and excessive systemic lipolysis during intravenous lipid overload. Three days after biliopancreatic diversion with duodenal switch (DS), whole-body glycerol turnover was normalized and associated with lower HOMA–insulin resistance index. A mean excess weight loss of 84% was achieved 12 months after DS. The smaller subcutaneous adipocyte size predicted better glycemic control in T2D. TG disposal and acylcarnitine production during lipid overload, along with muscle insulin sensitivity, improved with weight loss. Nevertheless, systemic NEFA fluxes and NEFA spillover remained similar, suggesting that increased NEFA storage capacity per volume of adipose tissue exactly compensated for the decrease in fat mass during weight loss. In conclusion, T2D remission after DS is mainly associated with greater circulating TG disposal, lower systemic lipolysis, and better fatty acid handling by lean tissues.

Categories: Diabetes

Downregulation of Insulin Sensitivity After Oral Glucose Administration: Evidence for the Anti-Incretin Effect

Diabetes - Mon, 10/23/2017 - 13:00

Intestinal nutrients stimulate insulin secretion more potently than intravenous (IV) glucose administration under similar plasma glucose levels (incretin effect). According to the anti-incretin theory, intestinal nutrients should also cause a reduction of insulin sensitivity and/or secretion (anti-incretin effect) to defend against hyperinsulinemia-hypoglycemia. An exaggerated anti-incretin effect could contribute to insulin resistance/type 2 diabetes, whereas reduction of anti-incretin signals might explain diabetes improvement after bariatric surgery. In this study, we tested some of the predictions made by the anti-incretin theory. Eight healthy volunteers and eight severely obese subjects with insulin resistance were studied. Insulin secretion, insulin sensitivity, Ra, and disposition index were measured after oral glucose tolerance test and isoglycemic IV glucose injection (IGIV). Obese subjects were studied before and after intestinal bypass surgery (biliopancreatic diversion [BPD]). The d-xylose test and lactulose-to-rhamnose ratio were used to test for possible malabsorption of glucose after surgery. Monte Carlo mathematical simulations were used to test whether insulin secretion induced by oral glucose could cause hypoglycemia when coupled with the levels of insulin sensitivity measured during IGIV. Despite isoglycemic conditions, insulin sensitivity was lower during oral than during IV glucose administration. This difference was amplified in obese subjects and reduced to normal after BPD. No evidence of glucose malabsorption was found. Mathematical simulations showed that hypoglycemia would occur if insulin sensitivity were not reduced by oral glucose stimulation. This study demonstrates an anti-incretin effect of intestinal glucose stimulation, which downregulates insulin sensitivity. The findings support a new model for how foodborne factors can induce insulin-resistance and provide a possible explanation for the improvement of insulin resistance/diabetes after gastrointestinal bypass surgery.

Categories: Diabetes

Opioid Receptor Activation Impairs Hypoglycemic Counterregulation in Humans

Diabetes - Mon, 10/23/2017 - 13:00

Although intensive glycemic control improves outcomes in type 1 diabetes mellitus (T1DM), iatrogenic hypoglycemia limits its attainment. Recurrent and/or antecedent hypoglycemia causes blunting of protective counterregulatory responses, known as hypoglycemia-associated autonomic failure (HAAF). To determine whether and how opioid receptor activation induces HAAF in humans, 12 healthy subjects without diabetes (7 men, age 32.3 ± 2.2 years, BMI 25.1 ± 1.0 kg/m2) participated in two study protocols in random order over two consecutive days. On day 1, subjects received two 120-min infusions of either saline or morphine (0.1 μg/kg/min), separated by a 120-min break (all euglycemic). On day 2, subjects underwent stepped hypoglycemic clamps (nadir 60 mg/dL) with evaluation of counterregulatory hormonal responses, endogenous glucose production (EGP, using 6,6-D2-glucose), and hypoglycemic symptoms. Morphine induced an ~30% reduction in plasma epinephrine response together with reduced EGP and hypoglycemia-associated symptoms on day 2. Therefore, we report the first studies in humans demonstrating that pharmacologic opioid receptor activation induces some of the clinical and biochemical features of HAAF, thus elucidating the individual roles of various receptors involved in HAAF’s development and suggesting novel pharmacologic approaches for safer intensive glycemic control in T1DM.

Categories: Diabetes

Growth Differentiation Factor 15 Mediates Systemic Glucose Regulatory Action of T-Helper Type 2 Cytokines

Diabetes - Mon, 10/23/2017 - 13:00

T-helper type 2 (Th2) cytokines, including interleukin (IL)-13 and IL-4, produced in adipose tissue, are critical regulators of intra-adipose and systemic lipid and glucose metabolism. Furthermore, IL-13 is a potential therapy for insulin resistance in obese mouse models. Here, we examined mediators produced by adipocytes that are responsible for regulating systemic glucose homeostasis in response to Th2 cytokines. We used RNA sequencing data analysis of cultured adipocytes to screen factors secreted in response to recombinant IL-13. Recombinant IL-13 induced expression of growth differentiation factor 15 (GDF15) via the Janus kinase-activated STAT6 pathway. In vivo administration of α-galactosylceramide or IL-33 increased IL-4 and IL-13 production, thereby increasing GDF15 levels in adipose tissue and in plasma of mice; however, these responses were abrogated in STAT6 knockout mice. Moreover, administration of recombinant IL-13 to wild-type mice fed a high-fat diet (HFD) improved glucose intolerance; this was not the case for GDF15 knockout mice fed the HFD. Taken together, these data suggest that GDF15 is required for IL-13–induced improvement of glucose intolerance in mice fed an HFD. Thus, beneficial effects of Th2 cytokines on systemic glucose metabolism and insulin sensitivity are mediated by GDF15. These findings open up a potential pharmacological route for reversing insulin resistance associated with obesity.

Categories: Diabetes

Hepatic GALE Regulates Whole-Body Glucose Homeostasis by Modulating Tff3 Expression

Diabetes - Mon, 10/23/2017 - 13:00

Transcripts of key enzymes in the Leloir pathway of galactose metabolism in mouse livers are significantly increased after chronic high-fat/high-sucrose feeding. UDP-galactose-4-epimerase (GALE) is the last enzyme in this pathway that converts UDP-galactose to UDP-glucose and was previously identified as a downstream target of the endoplasmic reticulum (ER) stress effector spliced X-box binding protein 1, suggesting an interesting cross talk between galactose and glucose metabolism in the context of hepatic ER stress and whole-body metabolic fitness. However, its specific role in glucose metabolism is not established. Using an inducible and tissue-specific mouse model, we report that hepatic overexpression of Gale increases gluconeogenesis from pyruvate and impairs glucose tolerance. Conversely, genetic reduction of Gale in liver improves glucose tolerance. Transcriptional profiling identifies trefoil factor 3 (Tff3) as one of the downstream targets of GALE. Restoration of Tff3 expression corrects glucose intolerance in Gale-overexpressing mice. These studies reveal a new link between hepatic GALE activity and whole-body glucose homeostasis via regulation of hepatic Tff3 expression.

Categories: Diabetes

Hypoxia in Combination With Muscle Contraction Improves Insulin Action and Glucose Metabolism in Human Skeletal Muscle via the HIF-1{alpha} Pathway

Diabetes - Mon, 10/23/2017 - 13:00

Skeletal muscle insulin resistance is the hallmark of type 2 diabetes and develops long before the onset of the disease. It is well accepted that physical activity improves glycemic control, but the knowledge on underlying mechanisms mediating the beneficial effects remains incomplete. Exercise is accompanied by a decrease in intramuscular oxygen levels, resulting in induction of HIF-1α. HIF-1α is a master regulator of gene expression and might play an important role in skeletal muscle function and metabolism. Here we show that HIF-1α is important for glucose metabolism and insulin action in skeletal muscle. By using a genome-wide gene expression profiling approach, we identified RAB20 and TXNIP as two novel exercise/HIF-1α–regulated genes in skeletal muscle. Loss of Rab20 impairs insulin-stimulated glucose uptake in human and mouse skeletal muscle by blocking the translocation of GLUT4 to the cell surface. In addition, exercise/HIF-1α downregulates the expression of TXNIP, a well-known negative regulator of insulin action. In conclusion, we are the first to demonstrate that HIF-1α is a key regulator of glucose metabolism in skeletal muscle by directly controlling the transcription of RAB20 and TXNIP. These results hint toward a novel function of HIF-1α as a potential pharmacological target to improve skeletal muscle insulin sensitivity.

Categories: Diabetes

Endothelial SHIP2 Suppresses Nox2 NADPH Oxidase-Dependent Vascular Oxidative Stress, Endothelial Dysfunction, and Systemic Insulin Resistance

Diabetes - Mon, 10/23/2017 - 13:00

Shc homology 2–containing inositol 5' phosphatase-2 (SHIP2) is a lipid phosphatase that inhibits insulin signaling downstream of phosphatidylinositol 3-kinase (PI3K); its role in vascular function is poorly understood. To examine its role in endothelial cell (EC) biology, we generated mice with catalytic inactivation of one SHIP2 allele selectively in ECs (ECSHIP2/+). Hyperinsulinemic-euglycemic clamping studies revealed that ECSHIP2/+ was resistant to insulin-stimulated glucose uptake in adipose tissue and skeletal muscle compared with littermate controls. ECs from ECSHIP2/+ mice had increased basal expression and activation of PI3K downstream targets, including Akt and endothelial nitric oxide synthase, although incremental activation by insulin and shear stress was impaired. Insulin-mediated vasodilation was blunted in ECSHIP2/+ mice, as was aortic nitric oxide bioavailability. Acetylcholine-induced vasodilation was also impaired in ECSHIP2/+ mice, which was exaggerated in the presence of a superoxide dismutase/catalase mimetic. Superoxide abundance was elevated in ECSHIP2/+ ECs and was suppressed by PI3K and NADPH oxidase 2 inhibitors. These findings were phenocopied in healthy human ECs after SHIP2 silencing. Our data suggest that endothelial SHIP2 is required to maintain normal systemic glucose homeostasis and prevent oxidative stress-induced endothelial dysfunction.

Categories: Diabetes

Pages