This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.The overall goal of this project is to understand the mechanisms by which gastric bypass surgery improves glucose metabolism. Type 2 diabetes is one of the major co-morbidities of obesity and contributes to the increase in cardiovascular morbidity and mortality suffered by obese people. Significant and sustained weight loss with gastric bypass, such as Roux-en-Y gastric bypass (RYGB), has been well documented. In addition, it has been amply reported that abnormalities in glucose metabolism- from mild impairments to frank diabetes- are rapidly and substantially improved following surgery. Metabolic benefit(s) of surgery occurs rapidly, appearing within days of the procedure and before substantial weight loss, which is consistent with an endocrine mechanism of action and there is accumulating information in the literature supporting GI hormones, mainly GLP-1, in mediating this effect. This hypothesis has not been rigorously tested, so that the effects of bariatric surgery to correct abnormal glucose metabolism remain unexplained. However this is a very important area for investigation since better understanding of the metabolic benefits of bariatric surgery could lead to surgical refinements to improve results and provide important new clues for predicting surgical outcomes. In addition, understanding the physiologic mechanisms whereby RYGB improves glucose metabolism would have important application to the treatment of diabetes more generally. In this proposal we describe a systematic characterization of insulin secretion and glucose tolerance before and at several points after gastric bypass surgery. The central hypothesis guiding this project is that the reconfiguration of intestinal transit with the Roux-en-Y will increase the release of insulinotropic GI hormones, termed incretins that improve insulin secretion and glucose metabolism. The study is divided into two specific aims. 1. To test the hypothesis that insulin secretion, insulin sensitivity, and hepatic glucose production are improved faster and to a greater extent in diabetic patients who have gastric bypass surgery compared with those subjects who have gastric restrictive surgery. 2. To determine the role of incretin hormones on insulin secretion and glucose tolerance in non-diabetic patients undergoing gastric bypass surgery using intravenous-oral hyperglycemic clamp. 3. To measure insulin secretion and GI hormone levels in persons suffering from hypoglycemia following gastric bypass using meal tolerance test.
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