31 Okada, T. Liew, C. W. Hu, J. Hinault, C. Michael, M. D. Krtzfeldt, J. Yin, C. Holzenberger, M. Stoffel, M. Kulkarni, R. N. 2007 Proc Natl Acad Sci U S A 104 21 8977-82 May 22 0027-8424 (Print) 17416680 Insulin-Secreting Cells/*metabolism/*pathology *Insulin Resistance Hyperplasia/chemically induced/genetics/metabolism/pathology Homeostasis Glucose/metabolism Gene Expression Regulation Forkhead Transcription Factors/metabolism Fats/pharmacology Cell Proliferation Animals Animal Feed Active Transport, Cell Nucleus Signal Transduction Receptor, Insulin/deficiency/genetics/*metabolism Mice, Knockout Mice Liver/metabolism Receptor Knockout Active Transport Cell Nucleus Insulin/deficiency/genetics/*metabolism Insulin and insulin-like growth factor 1 (IGF1) are ubiquitous growth factors that regulate proliferation in most mammalian tissues including pancreatic islets. To explore the specificity of insulin receptors in compensatory beta-cell growth, we examined two models of insulin resistance. In the first model, we used liver-specific insulin receptor knockout (LIRKO) mice, which exhibit hyperinsulinemia without developing diabetes due to a compensatory increase in beta-cell mass. LIRKO mice, also lacking functional insulin receptors in beta-cells (beta IRKO/LIRKO), exhibited severe glucose intolerance but failed to develop compensatory islet hyperplasia, together leading to early death. In the second model, we examined the relative significance of insulin versus IGF1 receptors in islet growth by feeding high-fat diets to beta IRKO and beta-cell-specific IGF1 receptor knockout (beta IGFRKO) mice. Although both groups on the high-fat diet developed insulin resistance, beta IRKO, but not beta IGFRKO, mice exhibited poor islet growth consistent with insulin-stimulated phosphorylation, nuclear exclusion of FoxO1, and reduced expression of Pdx-1. Together these data provide direct genetic evidence that insulin/FoxO1/Pdx-1 signaling is one pathway that is crucial for islet compensatory growth response to insulin resistance. P30 DK36836/DK/NIDDK NIH HHS/United StatesR01 DK55033/DK/NIDDK NIH HHS/United StatesR01 DK67536/DK/NIDDK NIH HHS/United StatesR01 DK68721/DK/NIDDK NIH HHS/United StatesU10DK42502/DK/NIDDK NIH HHS/United StatesJournal ArticleResearch Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov'tUnited States http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17416680