Noncanonical Activation of Akt/Protein Kinase B in β-Cells by the Incretin Hormone Glucose-dependent Insulinotropic Polypeptide

• Published in: The Journal of biological chemistry Vol. 284; no. 16; p. 10764
• Main Authors: Scott B. Widenmaier, Arthur V. Sampaio, T. Michael Underhill, Christopher H. S. McIntosh
• Format: Journal Article
• Language: English
• Published: American Society for Biochemistry and Molecular Biology 17.04.2009
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M809116200

Therapeutics based on the actions of the incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), have recently been introduced for the treatment of type 2 diabetes mellitus. The serine/threonine kinase Akt is a major mediator of incretin action on the pancreatic islet, increasing β-cell mass and function and promoting β-cell survival. The mechanisms underlying incretin activation of Akt are thought to involve an essential phosphoinositide 3-kinase-mediated phosphorylation of threonine 308, similar to the prototypical Akt activator, insulin-like growth factor-I (IGF-I). In this study, using activity assays on immunoprecipitated Akt, we discovered that GIP and GLP-1 were capable of stimulating Akt in the INS-1 β-cell line and isolated mouse islets via a mechanism that did not require phosphoinositide 3-kinase or phosphorylation of Thr 308 and Ser 473 , and this pathway involved the production of cAMP. Furthermore, we found that GIP stimulated anti-apoptotic signaling via this alternate mode of Akt activation. We conclude that incretins can activate Akt via a novel noncanonical mechanism that may provide an alternative therapeutic target for the treatment of type 2 diabetes mellitus and have broader implications for Akt physiology in human health and disease.