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J. Biol. Chem., Vol. 277, Issue 14, 11746-11755, April 5, 2002
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From the The precise metabolic steps that couple glucose
catabolism to insulin secretion in the pancreatic beta cell are
incompletely understood. ATP generated from glycolytic metabolism in
the cytosol, from mitochondrial metabolism, and/or from the hydrogen
shuttles operating between cytosolic and mitochondrial compartments has been implicated as an important coupling factor. To identify the importance of each of these metabolic pathways, we have compared the
fates of four fuel secretagogues (glucose, pyruvate, dihydroxyacetone, and glycerol) in the INS1-E beta cell line. Two of these fuels, dihydroxyacetone and glycerol, are normally ineffective as
secretagogues but are enabled by adenovirus-mediated expression of
glycerol kinase. Comparison of these two particular fuels allows the
effect of redox state on insulin secretion to be evaluated since the phosphorylated products dihydroxyacetone phosphate and glycerol phosphate lie on opposite sides of the NADH-consuming glycerophosphate dehydrogenase reaction. Based upon measurements of glycolytic metabolites, mitochondrial oxidation, mitochondrial matrix calcium, and
mitochondrial membrane potential, we find that insulin secretion most
tightly correlates with mitochondrial metabolism for each of the four
fuels. In the case of glucose stimulation, the high control strength of
glucose phosphorylation sets the pace of glucose metabolism and thus
the rate of insulin secretion. However, bypassing this reaction with
pyruvate, dihydroxyacetone, or glycerol uncovers constraints imposed by
mitochondrial metabolism, each of which attains a similar maximal
limit of insulin secretion. More specifically, we found that the
hyperpolarization of the mitochondrial membrane, related to the proton
export from the mitochondrial matrix, correlates well with insulin
secretion. Based on these findings, we propose that fuel-stimulated
secretion is in fact limited by the inherent thermodynamic
constraints of proton gradient formation.
Mitochondrial Metabolism Sets the Maximal Limit of
Fuel-stimulated Insulin Secretion in a Model Pancreatic Beta Cell
A SURVEY OF FOUR FUEL SECRETAGOGUES*
§,,
Division of Clinical Biochemistry and
Experimental Diabetology, Department of Internal Medicine, University
Medical Center, CH-1211 Geneva 4, Switzerland and from the
¶ Touchstone Center for Diabetes Research, Departments of
Biochemistry and Internal Medicine, University of Texas
Southwestern Medical Center, Dallas, Texas 75390
*
This study was supported by Grant 32-49755.96 from the Swiss
National Science Foundation (to C. B. W.) and by a European Union Network Grant (through the Swiss Federal Office for Education and
Science).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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