7- Abstract The intestinal incretin GLP-1 is a potent glucose-mediated insulin secretagogue. Patients with type 2 diabetes (DM2) have a blunted incretin effect on insulin secretion but the administration of GLP-1 is able to restore ?-cell sensitivity to glucose in DM. Patients who experienced DM2 remission after gastric bypass surgery (GBP) have rapid (within weeks), and sustained (years), exaggerated post-prandial GLP-1 release, with normalization of the incretin effect on insulin secretion. In vitro and/or rodent studies show that GLP-1 can stimulate ?-cell growth and differentiation. Whether the sustained enhanced GLP-1 release after GBP results in greater ?-cell function is unknown. In this proposal we will examine 1) The role of endogenous GLP-1 in the recovery of ?-cell function in response to oral glucose, by using exendin 9-39, a GLP- 1 receptor antagonist;2) The change of maximal ?-cell response to glucose infusion and arginine administration after GBP;3) Insulin sensitivity and body composition, in patients with severe obesity and DM2, before and up to 2 years after GBP;4) Determinants of DM2 remission after GBP. Understanding the mechanisms of DM2 remission, or lack of, after GBP will help identify predictors of outcome as well as develop medical alternatives for the treatment of severe obesity and DM2.
The increased prevalence of obesity and type 2 diabetes (DM2) has resulted in a surge in the number of patients seeking surgical weight loss. Gastric bypass surgery (GBP) results in 30-40% body weight loss with resolution of DM2 in 40-80% of cases. The mechanisms by which DM2 improves after GBP are unclear. Glycemic control occurs long before significant weight loss, suggesting that the nature of the procedure, rather than the weight loss, is responsible for the DM2 improvement. Recent data have singled out the role of the gut hormones known as incretins in diabetes improvement after GBP. Our proposal will study 1) whether the short and long term change in the gut hormone incretins after GBP results in improved insulin secretion in response to the administration of oral and IV glucose, in patients with diabetes undergoing GBP surgery;2) the factors responsible for diabetes remission - or lack of - after GBP. We wish to apply our finding to define better surgical outcome on diabetes.