1838-P: Vertical Sleeve Gastrectomy Improves Glycemia Independent of Caloric Restriction through a Coordinated Regulation of Incretin Secretion, Insulin Sensitivity, and Islet Function

Abstract

Vertical sleeve gastrectomy (VSG) alleviates diabetes in 40-50% of patients, however the degree to which weight loss drives this phenomenon is unclear. To address this question, we compared key factors for glucose regulation for 90d between mice with a VSG and sham-operated controls (PF-Sham)that were pair-fed to match caloric restriction between groups. Animals received separate mixed meal, intraperitoneal glucose, and insulin tolerance tests (MMTT, IPGTT, ITT) within 14d of surgery, and again 70-80d postoperatively. After the 90d observation period, pancreatic islets were isolated and measurements of glucose-stimulated insulin secretion (GSIS) and Ca2+ oscillations were performed using ex vivo perifusion. Over 90 days the mean body weight of the VSG and PF-Sham mice did not differ presumably due to the pair-feeding regimen. Glucose clearance and insulin secretion during MMTTs were greater in VSG mice compared to controls at both 12 and 80d, as were prandial GLP-1, GIP, and glucagon levels. Notably, the MMTT blood glucose rose in the PF-Sham group from day 12 to 80, but improved further in the VSG group during the same time period despite similar body weight gain. Glucose disposal and insulin secretion were enhanced during IPGTTs at both 10 and 70d in the VSG group, while islets isolated from VSG mice displayed elevated GSIS and glucose-stimulated Ca2+ oscillations ex vivo. Insulin sensitivity was enhanced in the VSG group at 75d following surgery, but not 14d. Our data suggest a multifactorial model for the improvement in glucose metabolism after VSG in which insulin secretion is rapidly enhanced after surgery due in part to enhanced incretin secretion and islet glucose sensitivity. Prandial incretin levels dampen over time, while enhanced to islet function persist chronically after surgery. Insulin sensitivity improves after VSG independent of BW, but only at later time points as incretin levels wane. Disclosure J.D. Douros: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (F32DK115031-01)