The Effects of Duodenal-jejunal Bypass on Glucose Homeostasis

Roux-en-y gastric bypass (RYGB) is a bariatric surgery used for the treatment of morbid obesity that involves the creation of a small gastric pouch with partial gastric and proximal small bowel exclusion and expedited distal small bowel nutrient delivery. Evidence exists that RYGB is among the most effective bariatric procedures in treating type 2 diabetes with the rate of diabetes resolution well exceeding that which can be explained by weight loss. Although the mechanisms for the weight-independent restoration of euglycemia have yet to be established, the surgical diversion of nutrients away from the duodenum appears to play an important role. The incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1), are secreted from the gastrointestinal tract in response to enteral nutrients and augment glucose-mediated insulin secretion from the pancreas. We hypothesized in this thesis that an important aspect of the resolution of type 2 diabetes after RYGB involves altered incretin secretion after duodenal-jejunal bypass (DJB) with enhanced GLP-1 and decreased GIP secretion.;To test this hypothesis, we first needed to determine if DJB decreases gastrointestinal GIP secretion. We used lymphatic sampling to study nutrient-induced incretin secretion two weeks after DJB or Sham surgery in Wistar rats. We found that DJB did not improve glucose tolerance or alter meal-stimulated GIP secretion. The second aim tested the hypothesis that DJB increases GLP-1 secretion and thus improves glucose tolerance in type 2 diabetes. We first characterized the lymphatic incretin response to different nutrients in type 2 diabetic, Goto-Kakizaki (GK) rats. We found that GK rats have a defect in glucose-mediated secretion of both incretins to a glucose-containing meal. We subsequently compared DJB and ileal interposition (IT) in GK rats to determine if duodenal bypass offers an independent mechanism to improve glucose tolerance. We found that both DJB and IT equally and modestly improved oral glucose tolerance suggesting a mechanism mediated by enhanced distal small bowel nutrient stimulation. DJB increased GLP-1 secretion, and systemic GLP-1 receptor antagonism reversed the small improvement noted in glucose tolerance. This study was the first to our knowledge to document a cause and effect relationship between duodenal bypass, an enhancement in GLP-1 receptor signaling, and the improvement in glucose tolerance. Finally, we tested the hypothesis that DJB improves insulin resistance independent of weight loss by performing DJB or Sham surgery in high-fat fed Wistar and Long-Evans rats. We found that DJB did not affect body weight or oral glucose tolerance. Formal tests of insulin sensitivity via a hyperinsulinemic-euglycemic clamp found no improvement in insulin resistance with DJB.;In summary, the magnificent reversal of glucose intolerance and insulin sensitivity seen in type 2 diabetic patients after RYGB can not be solely explained by duodenal bypass. This work supports that gastric exclusion of the neuro-endocrine stomach may be the most important contributing component beyond weight loss mediating a significant metabolic improvement after bariatric surgery. Further, animal and clinical studies are needed to determine how gastric exclusion or resection alters post-prandial glucose homeostasis.