GLP-1 Response to Oral Glucose Is Reduced in Prediabetes, Screen-Detected Type 2 Diabetes, and Obesity and Influenced by Sex: The ADDITION-PRO Study

The role of glucose-stimulated release of GLP-1 in the development of obesity and type 2 diabetes is unclear. We assessed GLP-1 response to oral glucose in a large study population of lean and obese men and women with normal and impaired glucose regulation. Circulating concentrations of glucose, insulin, and GLP-1 during an oral glucose tolerance test (OGTT) were analyzed in individuals with normal glucose tolerance (NGT) (n = 774), prediabetes (n = 525), or screen-detected type 2 diabetes (n = 163) who attended the Danish ADDITION-PRO study (n = 1,462). Compared with individuals with NGT, women with prediabetes or type 2 diabetes had 25% lower GLP-1 response to an OGTT, and both men and women with prediabetes or type 2 diabetes had 16–21% lower 120-min GLP-1 concentrations independent of age and obesity. Obese and overweight individuals had up to 20% reduced GLP-1 response to oral glucose compared with normal weight individuals independent of glucose tolerance status. Higher GLP-1 responses were associated with better insulin sensitivity and β-cell function, older age, and lesser degree of obesity. Our findings indicate that a reduction in GLP-1 response to oral glucose occurs prior to the development of type 2 diabetes and obesity, which can have consequences for early prevention strategies for diabetes.

Source Diabetes Pathophysiology http://ift.tt/1LjXyNd

Cellular Stress, Excessive Apoptosis, and the Effect of Metformin in a Mouse Model of Type 2 Diabetic Embryopathy

Increasing prevalence of type 2 diabetes in women of childbearing age has led to a higher incidence of diabetes-associated birth defects. We established a model of type 2 diabetic embryopathy by feeding 4-week-old female mice a high-fat diet (HFD) (60% fat). After 15 weeks on HFD, the mice showed characteristics of type 2 diabetes mellitus (DM) and were mated with lean male mice. During pregnancy, control dams fed a normal diet (10% fat) were maintained on either normal diet or HFD, serving as a control group with elevated circulating free fatty acids. DM dams produced offspring at a rate of 11.3% for neural tube defect (NTD) formation, whereas no embryos in the control groups developed NTDs. Elevated markers of oxidative stress, endoplasmic reticulum stress, caspase activation, and neuroepithelial cell apoptosis (causal events in type 1 diabetic embryopathy) were observed in embryos of DM dams. DM dams treated with 200 mg/kg metformin in drinking water ameliorated fasting hyperglycemia, glucose intolerance, and insulin resistance with consequent reduction of cellular stress, apoptosis, and NTDs in their embryos. We conclude that cellular stress and apoptosis occur and that metformin effectively reduces type 2 diabetic embryopathy in a useful rodent model.

Source Diabetes Pathophysiology http://ift.tt/1LzF88T

GLP-1R Agonists Modulate Enteric Immune Responses Through the Intestinal Intraepithelial Lymphocyte GLP-1R

Obesity and diabetes are characterized by increased inflammation reflecting disordered control of innate immunity. We reveal a local intestinal intraepithelial lymphocyte (IEL)-GLP-1 receptor (GLP-1R) signaling network that controls mucosal immune responses. Glp1r expression was enriched in intestinal IEL preparations and copurified with markers of Tαβ and T IELs, the two main subsets of intestinal IELs. Exendin-4 increased cAMP accumulation in purified IELs and reduced the production of cytokines from activated IELs but not from splenocytes ex vivo. These actions were mimicked by forskolin, absent in IELs from Glp1r^–/– mice, and attenuated by the GLP-1R agonist exendin (9-39) consistent with a GLP-1R–dependent mechanism of action. Furthermore, Glp1r^–/– mice exhibited dysregulated intestinal gene expression, an abnormal representation of microbial species in feces, and enhanced sensitivity to intestinal injury following administration of dextran sodium sulfate. Bone marrow transplantation using wild-type C57BL/6 donors normalized expression of multiple genes regulating immune function and epithelial integrity in Glp1r^–/– recipient mice, whereas acute exendin-4 administration robustly induced the expression of genes encoding cytokines and chemokines in normal and injured intestine. Taken together, these findings define a local enteroendocrine-IEL axis linking energy availability, host microbial responses, and mucosal integrity to the control of innate immunity.

Source Diabetes Pathophysiology http://ift.tt/1LjXwVi

Adaptation of {beta}-Cell and Endothelial Function to Carbohydrate Loading: Influence of Insulin Resistance

High-carbohydrate diets have been associated with β-cell strain, dyslipidemia, and endothelial dysfunction. We examined how β-cell and endothelial function adapt to carbohydrate overloading and the influence of insulin resistance. On sequential days in randomized order, nondiabetic subjects (classified as insulin-sensitive [IS] [n = 64] or insulin-resistant [IR] [n = 79] by euglycemic clamp) received four mixed meals over 14 h with either standard (300 kcal) or double carbohydrate content. β-Cell function was reconstructed by mathematical modeling; brachial artery flow-mediated dilation (FMD) was measured before and after each meal. Compared with IS, IR subjects showed higher glycemia and insulin hypersecretion due to greater β-cell glucose and rate sensitivity; potentiation of insulin secretion, however, was impaired. Circulating free fatty acids (FFAs) were less suppressed in IR than IS subjects. Baseline FMD was reduced in IR, and postprandial FMD attenuation occurred after each meal, particularly with high carbohydrate, similarly in IR and IS. Throughout the two study days, higher FFA levels were significantly associated with lower (incretin-induced) potentiation and impaired FMD. In nondiabetic individuals, enhanced glucose sensitivity and potentiation upregulate the insulin secretory response to carbohydrate overloading. With insulin resistance, this adaptation is impaired. Defective suppression of endogenous FFA is one common link between impaired potentiation and vascular endothelial dysfunction.

Source Diabetes Pathophysiology http://ift.tt/1LjXwEZ