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Articles in PresS, published online ahead of print June 25, 2002
Am J Physiol Endocrinol Metab, 10.1152/ajpendo.00177.2002
Submitted on April 29, 2002
Accepted on June 17, 2002
1 Internal Medicine, Washington University School of Medicine, Saint Louis, Missouri, USA
* To whom correspondence should be addressed. E-mail: ssriniva{at}im.wustl.edu.
The concentration of glucose in plasma is an important determinant of pancreatic ß-cell mass, while the relative contributions of hypertrophy, proliferation, and cell survival to this process are unclear. Glucose results in depolarization and subsequent calcium influx into islet -cells. Since depolarization and calcium (Ca++) influx promote survival of neuronal cells, we hypothesized that glucose might alter survival of islet ß-cells through a similar mechanism. In the current studies, cultured mouse islet ß-cells showed a three-fold decrease in apoptosis under conditions of 15mM glucose compared to 2 mM glucose (p<0.05). MIN6 insulinoma cells incubated in 25mM glucose for 24 hours showed a three-fold decrease in apoptosis compared to cells in 5mM glucose (1.7 ± 0.2% vs. 6.3 ± 1% respectively, p<0.001). High glucose (25mM) enhanced survival required depolarization and Ca++ influx, and was blocked by phosphotidylinositol-3-kinase (PI 3-kinase) inhibitors. Glucose activation of the protein kinase Akt was demonstrated in both insulinoma cells and cultured mouse islets using an antibody specific for Ser473 phospho-Akt, and by an in vitro Akt kinase assay. Akt phosphorylation was dependent on PI 3-K, but not MAPK. Transfection of insulinoma cells with an Akt kinase-dead plasmid (Akt-K179M) resulted in loss of glucose-mediated protection, while 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 ß-cells. This pathway may provide important targets for therapeutic intervention.
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