Differential Importance of Glucose-Dependent Insulinotropic Polypeptide vs Glucagon-Like Peptide 1 Receptor Signaling for Beta Cell Survival in Mice

Abstract

Background & Aims: Glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) activate pathways involved in beta cell survival and proliferation in vitro; we compared the relative importance of exogenous and endogenous GIP receptor (GIPR) and GLP-1 receptor (GLP-1R) activation for beta cell cytoprotection in mice. Methods: The effects of incretin hormone receptor signaling on beta cell regeneration and survival were assessed in mice following administration of streptozotocin in the absence or presence of the GIPR agonist [D-Ala2]-GIP (D-GIP), the GLP-1R agonist exendin-4, or the dipeptidyl peptidase-4 inhibitor sitagliptin. Beta cell survival was assessed in Gipr-/- mice given streptozotocin and by gene expression profiling of RNA from islets isolated from Glp1r-/- and Gipr-/- mice. The antiapoptotic actions of sitagliptin were assessed in wild-type and dual incretin receptor knockout (DIRKO) mice. Results: Administration of exendin-4 for 7 or 60 days improved blood glucose and insulin levels, reduced islet cell apoptosis, and increased pancreatic insulin content and beta cell mass. In contrast, D-GIP was less effective at improving these parameters under identical experimental conditions. Furthermore, Gipr-/- mice did not exhibit increased sensitivity to streptozotocin-induced diabetes. Sitagliptin reduced hemoglobin A1c levels and increased plasma and pancreatic levels of insulin after streptozotocin administration to wild-type mice. Sitagliptin reduced the levels of activated caspase-3 in wild-type islets but not in beta cells from DIRKO mice. Conclusions: There are functionally important differences in the pharmacologic and physiologic roles of incretin receptors in beta cells. GLP-1R signaling exerts more robust control of beta cell survival, relative to GIPR activation or dipeptidylpeptidase-4 inhibition in mice in vivo. © 2009 AGA Institute.