Cholesterol regulates glucose-stimulated insulin secretion through phosphatidylinositol 4,5-bisphosphate.
Membrane cholesterol modulates the ability of glucose to stimulate insulin secretion from pancreatic beta-cells. The molecular mechanism by which this occurs is not understood. Here, we show that in cultured beta-cells, cholesterol acts through phosphatidylinositol 4,5-bisphosphate (PIP(2)) to regulate actin dynamics, plasma membrane potential, and glucose-stimulated insulin secretion. Cholesterol-overloaded beta-cells exhibited decreased PIP(2) hydrolysis, with diminished glucose-induced actin reorganization, membrane depolarization, and insulin secretion. The converse findings were observed in cholesterol-depleted cells. These results support a model in which cholesterol depletion is coupled through PIP(2) to enhance both plasma membrane Ca2+ influx from the extracellular space, as well as inositol 1,4,5-triphosphate-stimulated Ca2+ efflux from intracellular stores. The inability to increase cytosolic Ca2+ may be the main underlying factor to account for impaired glucose-stimulated insulin secretion in cholesterol-overloaded beta-cells.
Hao
Mingming
M
Section of Endocrinology and Metabolism, Department of Internal Medicine, Yale University, P.O. Box 208020, New Haven, CT 06520-8020, USA. mingming.hao@yale.edu
Bogan
Jonathan S
JS
D000199:Actins / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism* / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008954:Models, Biological; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism*; D013549:Sweetening Agents / Q000378:metabolism / Q000494:pharmacology
D000199:Actins; D007328:Insulin; D019269:Phosphatidylinositol 4,5-Diphosphate; D013549:Sweetening Agents; D002784:Cholesterol; D005947:Glucose; D002118:Calcium