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J. Biol. Chem., Vol. 280, Issue 20, 20010-20020, May 20, 2005

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An Insulin-response Element-binding Protein That Ameliorates Hyperglycemia in Diabetes^*

Betty C. Villafuerte and Elizabeth N. Kaytor¶||

From the Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky 40202 and the ^¶Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30322

Insulin modulates glucose homeostasis, but the role of insulin-responsive transcription factors in such actions is not well understood. Recently, we have identified the insulin-response element-binding protein-1 (IRE-BP1) as a transcription factor that appears to mediate insulin action on multiple target genes. To examine the possibility that IRE-BP1 is an insulin-responsive glucoregulatory factor involved in the metabolic actions of insulin, we investigated the effect of adenoviral overexpression of hepatic IRE-BP1 on the glycemic control of insulin-resistant diabetic rats. Adenoviral IRE-BP1 lowered both fasting and postprandial glucose levels, and microarray of hepatic RNA revealed modulation of the expression of genes involved in gluconeogenesis, lipogenesis, and fatty acid oxidation. The insulin mimetic effects of IRE-BP1 were also confirmed in L6 myocytes; stable constitutive expressions of IRE-BP1 enhanced glucose transporter expression, glucose uptake, and glycogen accumulation in these cells. These findings showed physiologic sufficiency of IRE-BP1 as the transcriptional mediator of the metabolic action of insulin. Understanding IRE-BP1 action should constitute a useful probe into the mechanisms of metabolic regulation and an important target to develop therapeutic agents that mimic or enhance insulin action.

Received for publication, September 20, 2004 , and in revised form, March 4, 2005.

^* This work was supported by EmTech Biotechnology Development Inc., Georgia Institute of Technology Faculty Research Commercialization Program, and by the Walter F. and Avis Jacobs Foundation (to B. C. V.). 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.

The on-line version of this article (available at http://www.jbc.org) contains Supplement A.

^|| Present address: Fish & Richardson PC, 60 South 6th St., 3300 Dain Rauscher Plaza, Minneapolis, MN 55402.

To whom correspondence should be addressed: Dept. of Medicine, Division of Endocrinology, University of Louisville School of Medicine, 570 S. Preston St., Donald Baxter Bldg., Rm. 221E, Louisville, KY 40202. Tel.: 502-852-4048; Fax: 502-852-2492; E-mail: bcvill01{at}louisville.edu.

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