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J. Biol. Chem., Vol. 279, Issue 53, 55659-55666, December 31, 2004

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The Malate-Aspartate NADH Shuttle Member Aralar1 Determines Glucose Metabolic Fate, Mitochondrial Activity, and Insulin Secretion in Beta Cells^*

Blanca Rubi, Araceli del Arco, Clarissa Bartley, Jorgina Satrustegui¶, and Pierre Maechler||

From the Department of Cell Physiology and Metabolism, University Medical Centre, 1211 Geneva, Switzerland, the ^¶Departamento de Biología Molecular, Universidad Autónoma de Madrid, Centro de Biología Molecular Severo Ochoa, 28049 Madrid, Spain, and the Facultad de Ciencias del Medio Ambiente, Universidad de Castilla-La Mancha, 45071 Toledo, Spain

The NADH shuttle system, which transports reducing equivalents from the cytosol to the mitochondria, is essential for the coupling of glucose metabolism to insulin secretion in pancreatic beta cells. Aralar1 and citrin are two isoforms of the mitochondrial aspartate/glutamate carrier, one key constituent of the malateaspartate NADH shuttle. Here, the effects of Aralar1 overexpression in INS-1E beta cells and isolated rat islets were investigated for the first time. We prepared a recombinant adenovirus encoding for human Aralar1 (AdCA-Aralar1), tagged with the small FLAG epitope. Transduction of INS-1E cells and isolated rat islets with AdCA-Aralar1 increased aralar1 protein levels and immunostaining revealed mitochondrial localization. Compared with control INS-1E cells, overexpression of Aralar1 potentiated metabolism secretion coupling stimulated by 15 mM glucose. In particular, there was an increase of NAD(P)H generation, of mitochondrial membrane hyperpolarization, ATP levels, glucose oxidation, and insulin secretion (+45%, p < 0.01). Remarkably, this was accompanied by reduced lactate production. Rat islets overexpressing Aralar1 secreted more insulin at 16.7 mM glucose (+65%, p < 0.05) compared with controls. These results show that aspartate-glutamate carrier capacity limits glucose-stimulated insulin secretion and that Aralar1 overexpression enhances mitochondrial metabolism.

Received for publication, August 13, 2004 , and in revised form, October 18, 2004.

^* This work was supported by Swiss National Science Foundation Grant 31-67023.01, the Roche Research Foundation, the European Foundation for the Study of Diabetes/Johnson & Johnson, and Dr. Max Cloetta Foundation (Zurich) (to P. M.), and the Spanish Ministerio de Ciencia y Tecnología (to J. S.) and the Fundación Ramón Areces to the Centro de Biología Molecular Severo Ochoa. This study was part of the Geneva Programme for Metabolic Disorders. 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.

^|| To whom correspondence should be addressed: Dept. of Cell Physiology and Metabolism, University Medical Centre, 1 rue Michel-Servet, CH-1211 Geneva 4, Switzerland. Tel.: 41-22-379-55-54; Fax: 41-22-379-55-43; E-mail: Pierre.Maechler{at}medecine.unige.ch.

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