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Transgenic Expression of Insulin-Response Element Binding Protein-1 in β-Cells Reproduces Type 2 Diabetes

Department of Medicine, Divisions of Endocrinology & Metabolism (B.C.V., Y.S., J.P.M., J.P.) and Nephrology (M.T.B.), Departments of Anatomical Sciences and Neurobiology (J.P.M.) and Pediatrics, Kosair Children’s Hospital Research Institute (P.N.E.), 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.

Recent evidence supports the idea that insulin signaling through the insulin receptor substrate/phosphatidyl-inositol 3-kinase/Akt pathway is involved in the maintenance of β-cell mass and function. We previously identified the insulin-response element binding protein-1 (IRE-BP1) as an effector of insulin-induced Akt signaling in the liver, and showed that the 50-kDa carboxyl fragment confers the transcriptional activity of this factor. In this investigation we found that IRE-BP1 is expressed in the , β, and -cells of the islets of Langerhans, and is localized to the cytoplasm in β-cells in normal rats, but is reduced and redistributed to the islet cell nuclei in obese Zucker rats. To test whether IRE-BP1 modulates β-cell function and insulin secretion, we used the rat insulin II promoter to drive expression of the carboxyl fragment in β-cells. Transgenic expression of IRE-BP1 in FVB mice increases nuclear IRE-BP1 expression, and produces a phenotype similar to that of type 2 diabetes, with hyperinsulinemia, hyperglycemia, and increased body weight. IRE-BP1 increased islet type I IGF receptor expression, potentially contributing to the development of islet hypertrophy. Our findings suggest that increased gene transcription mediated through IRE-BP1 may contribute to β-cell dysfunction in insulin resistance, and allow for the hypothesis that IRE-BP1 plays a role in the pathophysiology of type 2 diabetes.