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J. Biol. Chem., Vol. 280, Issue 41, 34389-34392, October 14, 2005

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Attenuation of Insulin-stimulated Insulin Receptor Substrate-1 Serine 307 Phosphorylation in Insulin Resistance of Type 2 Diabetes^*

From the Department of Cell Biology and Diabetes Research Centre, Linköping University, SE58185 Linköping, Sweden

Insulin resistance is a primary characteristic of type 2 diabetes and likely causally related to the pathogenesis of the disease. It is a result of defects in signal transduction from the cell surface receptor of insulin to target effects. We found that insulin-stimulated phosphorylation of serine 307 (corresponding to serine 302 in the murine sequence) in the immediate downstream mediator protein of the insulin receptor, insulin receptor substrate-1 (IRS1), is required for efficient insulin signaling and that this phosphorylation is attenuated in adipocytes from patients with type 2 diabetes. Inhibition of serine 307 phosphorylation by rapamycin mimicked type 2 diabetes and reduced the sensitivity of IRS1 tyrosine phosphorylation in response to insulin, while stimulation of the phosphorylation by okadaic acid, in cells from patients with type 2 diabetes, rescued cells from insulin resistance. EC₅₀ for insulin-stimulated phosphorylation of serine 307 was about 0.2 nM with a t_1/2 of about 2 min. The amount of IRS1 was similar in cells from non-diabetic and diabetic subjects. These findings identify a molecular mechanism for insulin resistance in non-selected patients with type 2 diabetes.

Received for publication, June 3, 2005 , and in revised form, August 16, 2005.

^* This work was supported by the Östergötland County Council, the Swedish Diabetes Association, and the Swedish Research Council. 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 To whom correspondence should be addressed. Tel.: 46-13-224315; Fax: 46-13-224314; E-mail: peter.stralfors{at}ibk.liu.se.

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