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J. Biol. Chem., Vol. 279, Issue 26, 27263-27271, June 25, 2004

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Biochemical Mechanism of Lipid-induced Impairment of Glucose-stimulated Insulin Secretion and Reversal with a Malate Analogue^*

Anne Boucher, Danhong Lu, Shawn C. Burgess¶, Sabine Telemaque-Potts||, Mette V. Jensen, Hindrik Mulder**, May-Yun Wang, Roger H. Unger, A. Dean Sherry¶, and Christopher B. Newgard

From the Sarah W. Stedman Nutrition and Metabolism Center and Departments of Pharmacology and Cancer Biology, Medicine, and Biochemistry, Duke University Medical Center, Durham, North Carolina 27710, ^¶Mary Nell and Ralph Rogers Magnetic Resonance Center and Touchstone Center for Diabetes Research, University of Texas Southwestern Medical Center, Dallas, Texas 75390, the ^||Department of Internal Medicine, Wayne State University, Detroit, Michigan 48201, and ^**Department of Cell and Molecular Biology, Lund University, Lund, Sweden

Hyperlipidemia appears to play an integral role in loss of glucose-stimulated insulin secretion (GSIS) in type 2 diabetes. This impairment can be simulated in vitro by chronic culture of 832/13 insulinoma cells with high concentrations of free fatty acids, or by study of lipid-laden islets from Zucker diabetic fatty rats. Here we show that impaired GSIS is not a simple result of saturation of lipid storage pathways, as adenovirus-mediated overexpression of a cytosolically localized variant of malonyl-CoA decarboxylase in either cellular model results in dramatic lowering of cellular triglyceride stores but no improvement in GSIS. Instead, the glucose-induced increment in "pyruvate cycling" activity (pyruvate exchange with tricarboxylic acid cycle intermediates measured by ¹³C NMR), previously shown to play an important role in GSIS, is completely ablated in concert with profound suppression of GSIS in lipid-cultured 832/13 cells, whereas glucose oxidation is unaffected. Moreover, GSIS is partially restored in both lipid-cultured 832/13 cells and islets from Zucker diabetic fatty rats by addition of a membrane permeant ester of a pyruvate cycling intermediate (dimethyl malate). We conclude that chronic exposure of islet -cells to fatty acids grossly alters a mitochondrial pathway of pyruvate metabolism that is important for normal GSIS.

Received for publication, February 2, 2004 , and in revised form, March 24, 2004.

^* This work was supported by National Institutes of Health Grants RO1-DK-42582 (to C. B. N.), PO1-DK-58398 (to C. B. N. and A. D. S.), and HL-34557 (to A. D. S.), a grant from the Donald Reynolds Foundation (to C. B. N.), and a sponsored research agreement with Takeda Chemicals LTD, Osaka, Japan (to C. B. N.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to this work.

To whom correspondence should be addressed: Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Independence Park Facility, 4321 Medical Park Dr., Ste. 200, Durham, NC 27704. Tel.: 919-668-6059; Fax: 919-477-0632; E-mail: Newga002{at}mc.duke.edu.

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