title: Transgenic expression of insulin-response element binding protein-1 in beta-cells reproduces type 2 diabetes.
abstract: 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 beta-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 alpha, beta, and delta-cells of the islets of Langerhans, and is localized to the cytoplasm in beta-cells in normal rats, but is reduced and redistributed to the islet cell nuclei in obese Zucker rats. To test whether IRE-BP1 modulates beta-cell function and insulin secretion, we used the rat insulin II promoter to drive expression of the carboxyl fragment in beta-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 beta-cell dysfunction in insulin resistance, and allow for the hypothesis that IRE-BP1 plays a role in the pathophysiology of type 2 diabetes.
authors.affiliation: Department of Medicine, Division of Endocrinology & Metabolism, University of Louisville School of Medicine, Louisville, Kentucky 40202, USA. bcvill01@louisville.edu
authors.forename: Betty C
authors.initials: BC
authors.lastname: Villafuerte
authors.forename: Michelle T
authors.initials: MT
authors.lastname: Barati
authors.forename: Ying
authors.initials: Y
authors.lastname: Song
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Moore
authors.forename: Paul N
authors.initials: PN
authors.lastname: Epstein
authors.forename: Jessica
authors.initials: J
authors.lastname: Portillo
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D005934:Glucagon / Q000378:metabolism; D050416:Glucagon-Secreting Cells / Q000378:metabolism / Q000473:pathology; D005947:Glucose / Q000378:metabolism; D006946:Hyperinsulinism / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D035941:Iron Regulatory Protein 1 / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009765:Obesity / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D010641:Phenotype; D051381:Rats; D011924:Rats, Zucker; D019864:Somatostatin-Secreting Cells / Q000378:metabolism / Q000473:pathology
chemical_list: D007328:Insulin; D005934:Glucagon; D035941:Iron Regulatory Protein 1; D005947:Glucose