Glucose-dependent insulinotropic polypeptide is a growth factor for β (INS-1) cells by pleiotropic signaling

Activation of the G-protein-coupled receptor for glucose-dependent insulinotropic polypeptide facilitates insulin-release from pancreatic beta -cells. In the present study, we examined whether glucose-dependent insulinotropic polypeptide also acts as a growth factor for the beta -cell line INS-1. Here, we show that glucose-dependent insulinotropic polypeptide induced cellular proliferation synergistically with glucose between 2.5 mm and 15 mm by pleiotropic activation of signaling pathways. Glucose-dependent insulinotropic polypeptide stimulated the signaling modules of PKA/cAMP regulatory element binder, MAPK, and PI3K/protein kinase B in a glucose- and dose-dependent manner. Janus kinase 2 and signal transducer and activators of transcription 5/6 pathways were not stimulated by glucose-dependent insulinotropic polypeptide. Activation of PI3K by glucose-dependent insulinotropic polypeptide and glucose was associated with insulin receptor substrate isoforms insulin receptor substrate-2 and growth factor bound-2 associated binder-1 and PI3K isoforms p85 alpha, p110 alpha, p110 beta, and p110 gamma. Downstream of PI3K, glucose-dependent insulinotropic polypeptide-stimulated protein kinase beta alpha and protein kinase B beta isoforms and phosphorylated glycogen synthase kinase-3, forkhead transcription factor FKHR, and p70(S6K). These data indicate that glucose-dependent insulinotropic polypeptide functions synergistically with glucose as a pleiotropic growth factor for insulin-producing beta -cells, which may play a role for metabolic adaptations of insulin-producing cells during type II diabetes.