title: Glucose promotes pancreatic islet beta-cell survival through a PI 3-kinase/Akt-signaling pathway.
abstract: The concentration of glucose in plasma is an important determinant of pancreatic beta-cell mass, whereas the relative contributions of hypertrophy, proliferation, and cell survival to this process are unclear. Glucose results in depolarization and subsequent calcium influx into islet beta-cells. Because depolarization and calcium (Ca(2+)) influx promote survival of neuronal cells, we hypothesized that glucose might alter survival of islet beta-cells through a similar mechanism. In the present studies, cultured mouse islet beta-cells showed a threefold decrease in apoptosis under conditions of 15 mM glucose compared with 2 mM glucose (P < 0.05). MIN6 insulinoma cells incubated in 25 mM glucose for 24 h showed a threefold decrease in apoptosis compared with cells in 5 mM glucose (1.7 +/- 0.2 vs. 6.3 +/- 1%, respectively, P < 0.001). High glucose (25 mM) enhanced survival-required depolarization and Ca(2+) influx and was blocked by phosphatidylinositol (PI) 3-kinase inhibitors. Glucose activation of the protein kinase Akt was demonstrated in both insulinoma cells and cultured mouse islets by means of an antibody specific for Ser(473) phospho-Akt and by an in vitro Akt kinase assay. Akt phosphorylation was dependent on PI 3-kinase but not on MAPK. Transfection of insulinoma cells with an Akt kinase-dead plasmid (Akt-K179M) resulted in loss of glucose-mediated protection, whereas transfection with a constitutively active Akt enhanced survival in glucose-deprived insulinoma cells. The results of these studies defined a novel pathway for glucose-mediated activation of a PI 3-kinase/Akt survival-signaling pathway in islet beta-cells. This pathway may provide important targets for therapeutic intervention.
authors.affiliation: Division of Gastroenterology, Diabetes and Metabolism, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA. ssriniva@im.wustl.edu
authors.forename: Shanthi
authors.initials: S
authors.lastname: Srinivasan
authors.forename: Ernesto
authors.initials: E
authors.lastname: Bernal-Mizrachi
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Ohsugi
authors.forename: Marshall Alan
authors.initials: MA
authors.lastname: Permutt
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000494:pharmacology*; D007340:Insulinoma; D007515:Islets of Langerhans / Q000166:cytology* / Q000201:enzymology*; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D009336:Necrosis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D012313:RNA / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014407:Tumor Cells, Cultured
chemical_list: D002118:Calcium; D005947:Glucose; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D012313:RNA