Grant: Operating Grant

Glucose tolerance reverts toward normal within 3 to 6 days after bilio-pancreatic diversion (BPD) in obese subjects with type 2 diabetes (T2D) even before any significant weight loss. The mechanisms for this dramatic improvement, however, are not understood. We have previously shown that impaired fat tolerance (i.e. increased circulating fat upon intravenous infusion of fat) occurs before development of T2D in subjects at high-risk of this disease, is present in subjects with T2D, and is reverted with weight loss after BPD. We propose that improvement of glucose metabolism following BPD may involve rapid reversal of impaired fat tolerance in T2D. Subjects without or with T2D who undergo either gastric restrictive (gastric banding) or intestinal bypass surgery for treatment of obesity will be studied before and 5-7 days, and 3 and 18 months after surgery. Two out of three metabolic protocols will be performed on each occasion, the first one to measure intravenous glucose tolerance and insulin secretion, the second to measure circulating fat metabolism and intravenous tolerance, insulin resistance, and adipose tissue function, and the third one to measure glucose and lipid tolerance and metabolism, and hormone secretion after a mixed meal. The present study will determine some mechanisms underlying the profound improvement of glucose homeostasis after bariatric surgery, a very successful treatment approach for some patients with T2D that is now becoming more widely available. The proposed studies will provide novel and unique information on the potential role of gut endocrine regulation of adipose tissue function after bariatric surgery. As this work will be performed in human subjects, results will directly identify relevant pathophysiological mechanisms that will become prime targets for the development of preventive and therapeutic interventions for T2D.