Affiliation:
1. Divisions of Gastroenterology and
2. Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110
Abstract
The concentration of glucose in plasma is an important determinant of pancreatic β-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 β-cells. Because depolarization and calcium (Ca2+) influx promote survival of neuronal cells, we hypothesized that glucose might alter survival of islet β-cells through a similar mechanism. In the present studies, cultured mouse islet β-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 Ca2+ 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 Ser473 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 β-cells. This pathway may provide important targets for therapeutic intervention.
Publisher
American Physiological Society
Subject
Physiology (medical),Physiology,Endocrinology, Diabetes and Metabolism
Cited by
103 articles.
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