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

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 A_1c 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.

Abbreviations used in this paper: AUC, area under the curve, D-GIP, [D-Ala²] glucose-dependent insulinotropic polypeptide, DIRKO, dual incretin receptor knockout, DPP-4, dipeptidylpeptidase-4, EGFR, epidermal growth factor receptor, Ex-4, exendin-4, GIP, glucose-dependent insulinotropic polypeptide, GIPR, glucose-dependent insulinotropic polypeptide receptor, GLP-1, glucagon-like peptide 1, GLP-1R, glucagon-like peptide 1 receptor, PARP, poly(adenosine diphosphate ribose) polymerase, S-GLP-1, [Ser⁸] GLP-1(7-36)NH₂, STZ, streptozotocin