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Glucose-Dependent Insulinotropic Polypeptide Is a Growth Factor for ß (INS-1) Cells by Pleiotropic Signaling

Department of Internal Medicine (A.T., K.T., H.T., R.A., D.H.), Division of Gastroenterology and Metabolism, Philipps-University, Marburg, Germany D-35033; and Department of Medicine II (B.G.), Ludwig Maximilians University, Munich, Germany D-81377

Address all correspondence and requests for reprints to: Dieter Hörsch, M.D., Department of Internal Medicine, Division of Gastroenterology and Metabolism, Philipps-University, Baldingerstrasse, D-35033 Marburg, Germany. E-mail: hoerschd{at}post.med.uni-marburg.de

Activation of the G-protein-coupled receptor for glucose-dependent insulinotropic polypeptide facilitates insulin-release from pancreatic ß-cells. In the present study, we examined whether glucose-dependent insulinotropic polypeptide also acts as a growth factor for the ß-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, p110, p110ß, and p110. Downstream of PI3K, glucose-dependent insulinotropic polypeptide-stimulated protein kinase B and protein kinase Bß 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 ß-cells, which may play a role for metabolic adaptations of insulin-producing cells during type II diabetes.

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