Metabolic cycling in control of glucose-stimulated insulin secretion.

Journal Article (Journal Article;Review)

Glucose-stimulated insulin secretion (GSIS) is central to normal control of metabolic fuel homeostasis, and its impairment is a key element of beta-cell failure in type 2 diabetes. Glucose exerts its effects on insulin secretion via its metabolism in beta-cells to generate stimulus/secretion coupling factors, including a rise in the ATP/ADP ratio, which serves to suppress ATP-sensitive K(+) (K(ATP)) channels and activate voltage-gated Ca(2+) channels, leading to stimulation of insulin granule exocytosis. Whereas this K(ATP) channel-dependent mechanism of GSIS has been broadly accepted for more than 30 years, it has become increasingly apparent that it does not fully describe the effects of glucose on insulin secretion. More recent studies have demonstrated an important role for cyclic pathways of pyruvate metabolism in control of insulin secretion. Three cycles occur in islet beta-cells: the pyruvate/malate, pyruvate/citrate, and pyruvate/isocitrate cycles. This review discusses recent work on the role of each of these pathways in control of insulin secretion and builds a case for the particular relevance of byproducts of the pyruvate/isocitrate cycle, NADPH and alpha-ketoglutarate, in control of GSIS.

Full Text

Duke Authors

Cited Authors

  • Jensen, MV; Joseph, JW; Ronnebaum, SM; Burgess, SC; Sherry, AD; Newgard, CB

Published Date

  • December 2008

Published In

Volume / Issue

  • 295 / 6

Start / End Page

  • E1287 - E1297

PubMed ID

  • 18728221

Pubmed Central ID

  • PMC2603555

International Standard Serial Number (ISSN)

  • 0193-1849

Digital Object Identifier (DOI)

  • 10.1152/ajpendo.90604.2008


  • eng

Conference Location

  • United States