Phosphatidylinositol 3-kinase suppresses glucose-stimulated insulin secretion by affecting post-cytosolic [Ca(2+)] elevation signals

Diabetes. 2002 Jan;51(1):87-97. doi: 10.2337/diabetes.51.1.87.

Abstract

The role of phosphatidylinositol (PI) 3-kinase in the regulation of pancreatic beta-cell function was investigated. PI 3-kinase activity in p85 alpha regulatory subunit-deficient (p85 alpha(-/-)) islets was decreased to approximately 20% of that in wild-type controls. Insulin content and mass of rough endoplasmic reticula were decreased in beta-cells from p85 alpha(-/-) mice with increased insulin sensitivity. However, p85 alpha(-/-) beta-cells exhibited a marked increase in the insulin secretory response to higher concentrations of glucose. When PI 3-kinase in wild-type islets was suppressed by wortmannin or LY294002, the secretion was also substantially potentiated. Wortmannin's potentiating effect was not due to augmentation in glucose metabolism or cytosolic [Ca(2+)] elevation. Results of p85 alpha(-/-) islets and wortmannin-treated wild-type islets stimulated with diazoxide and KCl showed that inhibition of PI 3-kinase activity exerted its effect on secretion, at least in part, distal to a cytosolic [Ca(2+)] elevation. These results suggest that PI 3-kinase activity normally plays a crucial role in the suppression of glucose-stimulated insulin secretion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androstadienes
  • Animals
  • Calcium / metabolism*
  • Chromones / pharmacology
  • Cytosol / metabolism
  • Endoplasmic Reticulum / genetics
  • Endoplasmic Reticulum / ultrastructure
  • Enzyme Inhibitors / pharmacology
  • Glucose / pharmacology*
  • Insulin / metabolism*
  • Insulin Secretion
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / enzymology
  • Islets of Langerhans / metabolism*
  • Mice
  • Mice, Knockout
  • Morpholines / pharmacology
  • Phosphatidylinositol 3-Kinases / deficiency
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Protein Subunits
  • Wortmannin

Substances

  • Androstadienes
  • Chromones
  • Enzyme Inhibitors
  • Insulin
  • Morpholines
  • Protein Subunits
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Phosphatidylinositol 3-Kinases
  • Glucose
  • Calcium
  • Wortmannin