Glucose promotes pancreatic islet β-cell survival through a PI 3-kinase/Akt-signaling pathway

Shanthi Srinivasan, Ernesto Bernal-Mizrachi, Mitsuru Ohsugi, Marshall Alan Permutt

Research output: Contribution to journalArticle

92 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)E784-E793
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume283
Issue number4 46-4
DOIs
StatePublished - Oct 2002

Keywords

  • Apoptosis
  • Depolarization
  • Islet β-cell mass
  • Phosphatidylinositol 3-kinase

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)

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