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

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 improvedGSIS 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 GIPRare 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