2095-P: ß-Cell Glucose-Dependent Insulinotropic Polypeptide Receptors Are Necessary for Improved Islet Function following Sleeve Gastrectomy

Abstract

Bariatric surgeries improve glucose control in part by enhancing the glucose sensitivity of insulin secretion. In a mouse model of sleeve gastrectomy (SG), prandial secretion of the incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are increased and positively correlated with ex vivo insulin secretion. However, several previous studies suggest that GLP-1 action is dispensable for the effects of SG on glucose homeostasis. Therefore, we hypothesized that improved glucose control and islet function after SG require β-cell GIP receptors (GIPR). We tested this hypothesis using an inducible, β-cell specific GIPR knockout mouse line (GIPRβcell-/-). Within two weeks of surgery control mice with SG have reductions of bodyweight and glucose excursion during either a mixed-meal (MMTT) or intraperitoneal glucose tolerance test (IPGTT) compared to sham-operated animals. Islets isolated from control SG mice have enhanced glucose stimulated insulin secretion (GSIS) compared to islets from sham-operated controls in perifusion experiments, similar to our previous reports. While GIPRβcell-/- mice given SG evince improvements in bodyweight and MMTT glucose disposal compared to sham operated GIPRβcell-/- animals, they do not display the postoperative improvement of IP glucose tolerance seen in control mice given SG. Moreover, islets from GIPRβcell-/- SG mice do not have the improved GSIS typical of this surgery. These data indicate that changes in bodyweight and prandial glucose homeostasis after SG are not dependent on GIPR signaling. However, β-cell GIPR are necessary for enhancing intrinsic islet function after SG. These results support enteroendocrine signaling as a mediator for one of the key components of metabolic improvement after bariatric surgery. Disclosure J.D. Douros: None. J. Campbell: Research Support; Self; Eli Lilly and Company, Novo Nordisk Inc. Speaker’s Bureau; Self; Merck Sharp & Dohme Corp. J. Tong: None. D. D’Alessio: Advisory Panel; Self; Eli Lilly and Company. Consultant; Self; Intarcia Therapeutics. Research Support; Self; Ansh Labs, Eli Lilly and Company, Merck Sharp & Dohme Corp. Other Relationship; Self; Novo Nordisk A/S. Funding 1F32DK115031-01