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Methylglyoxal Impairs the Insulin Signaling Pathways Independently of the Formation of Intracellular Reactive Oxygen Species

Institut National de la Santé et de la Recherche Médicale (INSERM), Nice, France

Address correspondence and reprint requests to Jean Giudicelli, INSERM U145, IFR50, Faculty of Medicine, 06107 Nice Cedex 2, France. E-mail: jean.giudicelli{at}unice.fr

Abbreviations: AGE, advanced glycation end product; CM-DCF, chloro-methyl-2'7'-dichlorofluorescein diacetate; DMEM, Dulbecco’s modified Eagle’s medium; EGF, epidermal growth factor; ERK, extracellular-regulated kinase; [³H]SP, [³H]succinimidyl propionate; IRS, insulin receptor substrate; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide; PDTC, pyrrolidonedithiocarbamate; PI3K, phosphatidylinositol-3 kinase; p85, p85 regulatory subunit of PI3K; PKB, protein kinase B; PKC, protein kinase C; ROS, reactive oxygen species

Nonenzymatic glycation is increased in diabetes and leads to elevated levels of advanced glycation end products (AGEs), which link hyperglycemia to the induction of insulin resistance. In hyperglycemic conditions, intracellularly formed -ketoaldehydes, such as methylglyoxal, are an essential source of intracellular AGEs, and the abnormal accumulation of methylglyoxal is related to the development of diabetes complications in various tissues and organs. We have previously shown in skeletal muscle that AGEs induce insulin resistance at the level of metabolic responses. Therefore, it was important to extend our work to intermediates of the biosynthetic pathway leading to AGEs. Hence, we asked the question whether the reactive -ketoaldehyde methylglyoxal has deleterious effects on insulin action similar to AGEs. We analyzed the impact of methylglyoxal on insulin-induced signaling in L6 muscle cells. We demonstrate that a short exposure to methylglyoxal induces an inhibition of insulin-stimulated phosphorylation of protein kinase B and extracellular-regulated kinase 1/2, without affecting insulin receptor tyrosine phosphorylation. Importantly, these deleterious effects of methylglyoxal are independent of reactive oxygen species produced by methylglyoxal but appear to be the direct consequence of an impairment of insulin-induced insulin receptor substrate-1 tyrosine phosphorylation subsequent to the binding of methylglyoxal to these proteins. Our data suggest that an increase in intracellular methylglyoxal content hampers a key molecule, thereby leading to inhibition of insulin-induced signaling. By such a mechanism, methylglyoxal may not only induce the debilitating complications of diabetes but may also contribute to the pathophysiology of diabetes in general.

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