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J. Biol. Chem., Vol. 281, Issue 47, 35624-35632, November 24, 2006

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The Mitochondrial Citrate/Isocitrate Carrier Plays a Regulatory Role in Glucose-stimulated Insulin Secretion^*

Jamie W. Joseph, Mette V. Jensen, Olga Ilkayeva, Ferdinando Palmieri, Cristina Alárcon^¶, Christopher J. Rhodes^¶, and Christopher B. Newgard¹

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 27704, the Department of Pharmaco-Biology, Laboratory of Biochemistry and Molecular Biology, and National Research Council Institute of Biomembranes and Bioenergetics, University of Bari, 70125 Bari, Italy, and the ^¶Department of Medicine, Diabetes Center and Endocrine Division, University of Chicago, Chicago, Illinois 60637

Glucose-stimulated insulin secretion (GSIS) is mediated in part by glucose metabolism-driven increases in ATP/ADP ratio, but by-products of mitochondrial glucose metabolism also play an important role. Here we investigate the role of the mitochondrial citrate/isocitrate carrier (CIC) in regulation of GSIS. Inhibition of CIC activity in INS-1-derived 832/13 cells or primary rat islets by the substrate analogue 1,2,3-benzenetricarboxylate (BTC) resulted in potent inhibition of GSIS, involving both first and second phase secretion. A recombinant adenovirus containing a CIC-specific siRNA (Ad-siCIC) dose-dependently reduced CIC expression in 832/13 cells and caused parallel inhibitory effects on citrate accumulation in the cytosol. Ad-siCIC treatment did not affect glucose utilization, glucose oxidation, or ATP/ADP ratio but did inhibit glucose incorporation into fatty acids and glucose-induced increases in NADPH/NADP⁺ ratio relative to cells treated with a control siRNA virus (Ad-siControl). Ad-siCIC also inhibited GSIS in 832/13 cells, whereas overexpression of CIC enhanced GSIS and raised cytosolic citrate levels. In normal rat islets, Ad-siCIC treatment also suppressed CIC mRNA levels and inhibited GSIS. We conclude that export of citrate and/or isocitrate from the mitochondria to the cytosol is an important step in control of GSIS.

Received for publication, March 20, 2006 , and in revised form, August 23, 2006.

^* This work was supported by a Canadian Institute of Health research fellowship (to J. W. J.), National Institutes of Health Grants DK42583 and DK58398 (to C. B. N.) and DK51610 (to C. J. R.), a grant from the Ministero dell'Istruzione, Universita e Ricerca (to F. P.), and a sponsored research agreement with Takeda Pharmaceuticals (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.

¹ To whom correspondence should be addressed: Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Independence Park Facility, 4321 Medical Park Dr., Suite 200, Durham, NC 27704. Tel.: 919-668-6059; Fax: 919-477-0632; E-mail: newga002{at}mc.duke.edu.

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