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J. Biol. Chem., Vol. 278, Issue 48, 47376-47387, November 28, 2003

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Human Glycated Albumin Affects Glucose Metabolism in L6 Skeletal Muscle Cells by Impairing Insulin-induced Insulin Receptor Substrate (IRS) Signaling through a Protein Kinase C-mediated Mechanism^*

Claudia Miele¶, Audrey Riboulet¶||, Maria Alessandra Maitan**, Francesco Oriente, Chiara Romano, Pietro Formisano, Jean Giudicelli, Francesco Beguinot, and Emmanuel Van Obberghen

From the Dipartimento di Biologia e Patologia Cellulare e Molecolare & Centro di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale delle Ricerche, Università di Napoli Federico II, Via S. Pansini, 5, 80131 Naples, Italy and INSERM Unité 145, Faculté de Médecine 28, Avenue de Valombrose 06107 Nice Cedex 2, France

Nonenzymatic glycation is increased in diabetes and leads to increased levels of glycated proteins. Most studies have focused on the role of glycation products in vascular complications. Here, we have investigated the action of human glycated albumin (HGA) on insulin signaling in L6 skeletal muscle cells. Exposure of these cells to HGA inhibited insulin-stimulated glucose uptake and glycogen synthase activity by 95 and 80%, respectively. These effects were time- and dose-dependent, reaching a maximum after 12 h incubation with 0.1 mg/ml HGA. In contrast, exposure of the cells to HGA had no effect on thymidine incorporation. Further, HGA reduced insulin-stimulated serine phosphorylation of PKB and GSK3, but did not alter ERK1/2 activation. HGA did not affect either insulin receptor kinase activity or insulin-induced Shc phosphorylation on tyrosine. In contrast, insulin-dependent IRS-1 and IRS-2 tyrosine phosphorylation was severely reduced in cells preincubated with HGA for 24 h. Insulin-stimulated association of PI3K with IRS-1 and IRS-2, and PI3K activity were reduced by HGA in parallel with the changes in IRS tyrosine phosphorylation, while Grb2-IRS association was unchanged. In L6 myotubes, exposure to HGA increased PKC activity by 2-fold resulting in a similar increase in Ser/Thr phosphorylation of IRS-1 and IRS-2. These phosphorylations were blocked by the PKC inhibitor bisindolylmaleimide (BDM). BDM also blocked the action of HGA on insulin-stimulated PKB and GSK3. Simultaneously, BDM rescued insulin-stimulation of glucose uptake and glycogen synthase activity in cells exposed to HGA. The use of antibodies specific to PKC isoforms shows that this effect appears to be mediated by activated PKC, independent of reactive oxygen species production. In summary, in L6 skeletal muscle cells, exposure to HGA leads to insulin resistance selectively in glucose metabolism with no effect on growth-related pathways regulated by the hormone.

Received for publication, January 31, 2003 , and in revised form, September 10, 2003.

^* The research performed in INSERM Unit 145 (Nice, France) was supported by INSERM, Région PACA, Université de Nice-Sophia Antipolis, and by grants from the European Community (N°QLG1-CT-1999-00674 "Eurodiabetesgenes" and QLK3-CT-2000-01038), and from Merck Santé (Lyon, France) and Aventis (Frankfurt, Germany). The work performed in the Dipartimento di Biologia e Patologia Cellulare e Molecolare (Naples, Italy) was supported in part by the European Community (Grant QLRT-1999-00674 "Eurodiabetesgenes" (to F. B.), grants from the Associazione Italiana per la Ricerca sul Cancro (AIRC) (to F. B. and P. F.), the Ministero dell'Università e della Ricerca Scientifica (to F. B.), and Telethon-Italy (Grant no. 0896 (to F. B.)). 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.

^|| Supported by a Fellowship from the Région Provence-Alpes-Côte d'Azur and Bayer-Diagnostics France.

^** Recipient of a fellowship of the Federazione Italiana per la Ricerca sul Cancero (FIRC).

To whom correspondence should be addressed: INSERM Unité 145, Faculté de Médecine, 28, Avenue de Valombrose 06107 Nice Cedex 2, France. Tel.: 33-4-93-81-54-47; Fax: 33-4-93-81-54-32; E-mail: vanobbeg{at}unice.fr.

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