Noncanonical activation of Akt/protein kinase B in {beta}-cells by the incretin hormone glucose-dependent insulinotropic polypeptide.
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 beta-cell mass and function and promoting beta-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 beta-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.
Widenmaier
Scott B
SB
Department of Cellular and Physiological Sciences and the Diabetes Research Group, Life Sciences Institute, University of British Columbia, Vancouver V6T 1Z3, Canada.
Sampaio
Arthur V
AV
Underhill
T Michael
TM
McIntosh
Christopher H S
CH
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D005576:Colforsin / Q000378:metabolism; D004789:Enzyme Activation; D005749:Gastric Inhibitory Polypeptide / Q000235:genetics / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1 / Q000235:genetics / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006801:Humans; D054795:Incretins / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D051381:Rats
D054795:Incretins; D007328:Insulin; D005576:Colforsin; D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D000262:Adenylyl Cyclases; D005947:Glucose