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J. Biol. Chem., Vol. 282, Issue 44, 31835-31843, November 2, 2007

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Glucose Regulates Diacylglycerol Intracellular Levels and Protein Kinase C Activity by Modulating Diacylglycerol Kinase Subcellular Localization^*

Claudia Miele¹, Flora Paturzo¹, Raffaele Teperino, Fumio Sakane, Francesca Fiory, Francesco Oriente, Paola Ungaro, Rossella Valentino, Francesco Beguinot, and Pietro Formisano²

From the Dipartimento di Biologia e Patologia Cellulare e Molecolare & Istituto di Endocrinologia ed Oncologia Sperimentale del CNR, Federico II University of Naples, Via Pansini 5, Naples 80131, Italy and the Department of Biochemistry, Sapporo Medical University School of Medicine, South-1, West-17, Chuo-ku, Sapporo 060-8556, Japan

Although chronic hyperglycemia reduces insulin sensitivity and leads to impaired glucose utilization, short term exposure to high glucose causes cellular responses positively regulating its own metabolism. We show that exposure of L6 myotubes overexpressing human insulin receptors to 25 mM glucose for 5 min decreased the intracellular levels of diacylglycerol (DAG). This was paralleled by transient activation of diacylglycerol kinase (DGK) and of insulin receptor signaling. Following 30-min exposure, however, both DAG levels and DGK activity returned close to basal levels. Moreover, the acute effect of glucose on DAG removal was inhibited by >85% by the DGK inhibitor R59949. [GenBank] DGK inhibition was also accompanied by increased protein kinase C- (PKC) activity, reduced glucose-induced insulin receptor activation, and GLUT4 translocation. Glucose exposure transiently redistributed DGK isoforms and , from the prevalent cytosolic localization to the plasma membrane fraction. However, antisense silencing of DGK, but not of DGK expression, was sufficient to prevent the effect of high glucose on PKC activity, insulin receptor signaling, and glucose uptake. Thus, the short term exposure of skeletal muscle cells to glucose causes a rapid induction of DGK, followed by a reduction of PKC activity and transactivation of the insulin receptor signaling. The latter may mediate, at least in part, glucose induction of its own metabolism.

Received for publication, March 22, 2007 , and in revised form, August 1, 2007.

^* This work was supported by the European Community's FP6 EUGENE2 (Grant LSHM-CT-2004-512013), by grants from the Associazione Italiana per la Ricerca sul Cancro (to F. B. and P. F.), by the Ministero dell'Università e della Ricerca Scientifica (Grant FIRB RBNE0155LB to F. B. and P. F.), and by Telethon-Italy. 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 Both authors contributed equally to this work.

² To whom correspondence should be addressed. Tel.: 39-081-746-3608; Fax: 39-081-746-3235; E-mail: fpietro{at}unina.it.

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