Metabolic cycling in control of glucose-stimulated insulin secretion

Jensen MV, Joseph JW, Ronnebaum SM, Burgess SC, Sherry AD, Newgard CB. Metabolic cycling in control of glucose-stimulated insulin secretion. Am J Physiol Endocrinol Metab 295: E1287-E1297, 2008. First published August 26, 2008; doi:10.1152/ajpendo.90604.2008. - 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 Ca2+ 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.