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© 2002 by the American Diabetes Association, Inc.
Phosphatidylinositol 3-Kinase Suppresses Glucose-Stimulated Insulin Secretion by Affecting Post-Cytosolic [Ca2+] Elevation Signals
1 Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
2 Department of Pharmacology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
3 Third Department of Internal Medicine, Yokohama City University, Yokohama, Japan
The role of phosphatidylinositol (PI) 3-kinase in the regulation of pancreatic ß-cell function was investigated. PI 3-kinase activity in p85
regulatory subunit–deficient (p85-/-) islets was decreased to 
20% of that in wild-type controls. Insulin content and mass of rough endoplasmic reticula were decreased in ß-cells from p85-/- mice with increased insulin sensitivity. However, p85-/- ß-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 [Ca2+] elevation. Results of p85-/- 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 [Ca2+] elevation. These results suggest that PI 3-kinase activity normally plays a crucial role in the suppression of glucose-stimulated insulin secretion.
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