Insulin receptors in β-cells are critical for islet compensatory growth response to insulin resistance

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 104; no. 21; pp. 8977 - 8982
• Main Authors: Okada, Terumasa, Liew, Chong Wee, Hu, Jiang, Hinault, Charlotte, Michael, M. Dodson, Krtzfeldt, Jan, Yin, Catherine, Holzenberger, Martin, Stoffel, Markus, Kulkarni, Rohit N
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 22-05-2007; National Acad Sciences
• Series: From the Cover
• Subjects: Active Transport, Cell Nucleus; Animal Feed; Animals; Antibodies; Biological Sciences; Cell Proliferation; Diabetes; Fats - pharmacology; Forkhead Box Protein O1; Forkhead Transcription Factors - metabolism; Gene Expression Regulation; Glucose - metabolism; High fat diet; Homeostasis; Hyperglycemia; Hyperplasia; Hyperplasia - chemically induced; Hyperplasia - genetics; Hyperplasia - metabolism; Hyperplasia - pathology; Insulin; Insulin Resistance; Insulin-Secreting Cells - metabolism; Insulin-Secreting Cells - pathology; Liver - metabolism; Mice; Mice, Knockout; Pancreas; Receptor, Insulin - deficiency; Receptor, Insulin - genetics; Receptor, Insulin - metabolism; Receptors; Signal Transduction; Type 2 diabetes mellitus
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0608703104

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 β-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 β-cell mass. LIRKO mice, also lacking functional insulin receptors in β-cells (βIRKO/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 βIRKO and β-cell-specific IGF1 receptor knockout (βIGFRKO) mice. Although both groups on the high-fat diet developed insulin resistance, βIRKO, but not βIGFRKO, 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.