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Am J Physiol Endocrinol Metab 295: E1287-E1297, 2008. First published August 26, 2008; doi:10.1152/ajpendo.90604.2008
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REVIEWS

Metabolic cycling in control of glucose-stimulated insulin secretion

Mette V. Jensen,1 Jamie W. Joseph,2 Sarah M. Ronnebaum,1 Shawn C. Burgess,3 A. Dean Sherry,3 and Christopher B. Newgard1

1Sarah W. Stedman Nutrition and Metabolism Center, Department of Pharmacology and Cancer Biology, and Department of Medicine, Duke University Medical Center, Durham, North Carolina; 2School of Pharmacy, University of Waterloo, Waterloo, Ontario, Canada; and 3Ralph and Mary Nell Rogers NMR Center and Advanced Imaging Research Center, Departments of Radiology and Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas

Submitted 21 February 2008 ; accepted in final form 19 August 2008

ABSTRACT

Glucose-stimulated insulin secretion (GSIS) is central to normal control of metabolic fuel homeostasis, and its impairment is a key element of β-cell failure in type 2 diabetes. Glucose exerts its effects on insulin secretion via its metabolism in β-cells to generate stimulus/secretion coupling factors, including a rise in the ATP/ADP ratio, which serves to suppress ATP-sensitive K+ (KATP) channels and activate voltage-gated Ca2+ channels, leading to stimulation of insulin granule exocytosis. Whereas this KATP 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 β-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.


Address for reprint requests and other correspondence: C. B. Newgard, Sarah W. Stedman Nutrition and Metabolism Center, Duke Univ. Medical Center, Duke Independence Park Facility, 4321 Medical Park Dr., Suite 200, Durham, NC 27704 (E-mail: newga002{at}mc.duke.edu)




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