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Serine Phosphorylation of Insulin Receptor Substrate-1: A Novel Target for the Reversal of Insulin Resistance

Department of Biochemistry, School of Medicine, University of Patras, 26110 Patras, Greece

Address all correspondence and requests for reprints to: Athanasios G. Papavassiliou, M.D., Ph.D., Professor and Chairman, Department of Biochemistry, School of Medicine, University of Patras, GR-26110 Patras, Greece. E-mail: papavas{at}med.upatras.gr

ABSTRACT

Insulin resistance, the failure to respond to normal circulating concentrations of insulin, is a common state associated with obesity, aging, and a sedentary lifestyle. Compelling evidence implicates TNF as the cause and link between obesity and insulin resistance. Serine phosphorylation of insulin receptor substrate-1 seems prominent among the mechanisms of TNF-induced insulin resistance. Recent advances indicate that serine kinases may phosphorylate and thus inhibit the tyrosine phosphorylation of insulin receptor substrate-1, revealing an integration point of TNF and insulin signaling pathways. Selective targeting of the molecular scenery whereby this key phosphorylation occurs/operates represents a rich area for the development of rationally designed new antidiabetic drugs. In relation to efficacy and side effects, this prospect should permit a more precise and perhaps individualized approach to therapeutic intervention, allowing clinicians to focus the attack where the problem lies.

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