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Regulation of Insulin-Response Element Binding Protein-1 in Obesity and Diabetes: Potential Role in Impaired Insulin-Induced Gene Transcription

Department of Medicine, Division of Endocrinology and Metabolism (J.C., C.-C.C., Y.S., B.C.V.), Division of Nephrology (M.J.R., M.T.B.), Department of Anatomical Sciences and Neurobiology (J.P.M.), University of Louisville School of Medicine, Louisville, Kentucky 40202

Address all correspondence and requests for reprints to: Betty C. Villafuerte, M.D., Department of Medicine, Division of Endocrinology & Metabolism, 580 South Preston Street, Delia Baxter Building, Room 119E, Louisville, Kentucky 40202. E-mail: bcvill01{at}louisville.edu.

One of the major mechanisms by which insulin modulates glucose homeostasis is through regulation of gene expression. Therefore, reduced expression of transcription factors that are required for insulin-regulated gene expression may contribute to insulin resistance. We recently identified insulin response element-binding protein-1 (IRE-BP1) as a transcription factor that binds and transactivates multiple insulin-responsive genes, but the regulation of IRE-BP1 in vivo is largely unknown. In this study, we show that IRE-BP1 interacts with the insulin response sequence of the IGF-I, IGFBP-1, and IGFBP-3 genes using chromatin immunoprecipitation assay. Furthermore, activation by IRE-BP1 is sequence specific and mimics that of the insulin effect on gene transcription. Tissue expression of IRE-BP1 is 50- to 200-fold higher in classical insulin target compared with nontarget tissues in lean animals, with a significantly reduced level of expression in the skeletal muscle and adipose tissue in obese and diabetic animals. In the liver, IRE-BP1 is localized to the nucleus in lean rats but is sequestered to the cytoplasm in obese and diabetic animals. Cytoplasmic sequestration appears to be related to inhibition of insulin-mediated phosphatidylinositol-3 kinase signaling. Therefore, in diabetes and obesity, the mechanisms involved in reducing the transactivation of the insulin response sequence by IRE-BP1 include decreased gene transcription and nuclear exclusion to prevent DNA binding. Our study supports the notion that IRE-BP1 may be relevant to the action of insulin in vivo and may play a role in the development of insulin resistance and diabetes.

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