• 1)the role of reduced GIP & GLP-1 levels in mediating postprandial insulin secretion in diabetic subjects; 2)the role of endogenous GLP-1 to stimulate insulin secretion in diabetic subjects; 3)the role of hyperglycemia to impair the incretin effect
  

The objective of this project is to understand defects in insulin secretion that contribute to abnormal glucose metabolism in patients with diabetes. Diabetes is a major problem for patients receiving care at VA medical centers among whom 20% are affected. Specifically, this project will seek to determine the mechanism(s) by which the incretin effect is impaired in diabetic patients. The incretin effect refers to the action of GI hormones and neural stimuli to increase insulin secretion after food intake, and accounts for approximately 50% of postprandial insulin secretion in nondiabetic humans. There are several studies indicating that this response is severely impaired in patients with type 2 diabetes. The mechanism(s) by which this occurs has not been explained. There is some evidence to suggest that secretion of the important incretins, glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), may be impaired in diabetic individuals. There is also some data to suggest that the β-cells in persons with diabetes are insensitive to the incretins. The problem with the current state of knowledge in this area is that previous work has involved small numbers of diabetic subjects, and did not directly test mechanisms by which the incretin effect is altered in diabetes.

In this project we will: 1) determine the role of reduced GIP and GLP-1 levels in mediating postprandial insulin secretion in diabetic subjects. Subjects with type 2 diabetes and nondiabetic controls will have the incretin effect measured on separate occasions using test meals that cause different levels of circulating incretins. This will allow the role of reduced incretin levels in diabetes to be assessed; 2) determine the role of endogenous GLP-1 to stimulate insulin secretion in diabetic subjects. Subjects with type 2 diabetes and nondiabetic controls will have the incretin effect measured on two occasions, with and without infusion of a GLP-1 receptor antagonist. This study will compare the role of GLP-1 signaling to stimulate postprandial insulin secretion in diabetic and nondiabetic humans; 3) determine the role of hyperglycemia to impair the incretin effect. Groups of type 2 diabetic subjects will have the incretin effect measured before and after intensified diabetes treatment. This study will test the effect of chronic hyperglycemia on incretin mediated insulin secretion. In all studies, the incretin effect will be measured before and after these interventions using studies with a within subjects design. A combined glucose clamp/meal tolerance test protocol will be used to quantify the incretin effect.

These studies will allow the role of incretin secretion, incretin action, and overall metabolic milieu, on postprandial insulin secretion to be defined. The results of these studies will add important new information for understanding abnormal β-cell function in diabetes. By identifying the sites where the incretin effect is impaired this project will provide the basis for new approaches to treat diabetic patients. This is especially relevant with the recent availability of new medications that target the incretin pathways to lower blood glucose.

The blood samples will be drawn and processed in the GCRC. The samples will be frozen and stored in Building 15, Room 401. Samples will be shipped to the Genome Research Institute by staff trained in IATA shipping procedures.