Reconstitution of Insulin Action in Muscle, White Adipose Tissue, and Brain of Insulin Receptor Knock-out Mice Fails to Rescue Diabetes

• Published in: The Journal of biological chemistry Vol. 286; no. 11; pp. 9797 - 9804
• Main Authors: Lin, Hua V., Accili, Domenico
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18.03.2011; American Society for Biochemistry and Molecular Biology
• Subjects: Adipose Tissue, White - metabolism; Adipose Tissue, White - pathology; Animals; Brain - metabolism; Brain - pathology; Carbohydrate Metabolism; Cell Surface Receptor; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - pathology; Diabetes Mellitus, Type 2 - therapy; Fatty Acid Metabolism; Gene Knock-out; Glucose Transporter Type 4 - genetics; Glucose Transporter Type 4 - metabolism; Insulin - genetics; Insulin - metabolism; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells - metabolism; Insulin-Secreting Cells - pathology; Metabolism; Mice; Mice, Knockout; Mouse Genetics; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Receptor, Insulin - genetics; Receptor, Insulin - metabolism; Signal Transduction; Carbohydrate Metabolism; Gene Knock-out; Insulin Resistance; Fatty Acid Metabolism; Mouse Genetics; Brain Metabolism; Cell Surface Receptor; Insulin Secretion
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M110.210807

Type 2 diabetes results from an impairment of insulin action. The first demonstrable abnormality of insulin signaling is a decrease of insulin-dependent glucose disposal followed by an increase in hepatic glucose production. In an attempt to dissect the relative importance of these two changes in disease progression, we have employed genetic knock-outs/knock-ins of the insulin receptor. Previously, we demonstrated that insulin receptor knock-out mice (Insr−/−) could be rescued from diabetes by reconstitution of insulin signaling in liver, brain, and pancreatic β cells (L1 mice). In this study, we used a similar approach to reconstitute insulin signaling in tissues that display insulin-dependent glucose uptake. Using GLUT4-Cre mice, we restored InsR expression in muscle, fat, and brain of Insr−/− mice (GIRKI (Glut4-insulin receptor knock-in line 1) mice). Unlike L1 mice, GIRKI mice failed to thrive and developed diabetes, although their survival was modestly extended when compared with Insr−/−. The data underscore the role of developmental factors in the presentation of murine diabetes. The broader implication of our findings is that diabetes treatment should not necessarily target the same tissues that are responsible for disease pathogenesis.