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

Hua V Lin,Domenico Accili

doi:10.1074/jbc.m110.210807

Abstract

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.

Highlights

To analyze the contribution of individual organs and cell types to the integrated physiology of insulin action, we and others have used gene targeting by homologous recombination to carry out gain- and loss-of-function experiments affecting insulin signaling [2]
We generated mice in which insulin receptor (InsR) expression was restricted to muscle, fat, and brain
Western blot analyses showed reconstitution of InsR expression in skeletal muscle of GIRKI-1 and GIRKI-2 mice, whereas only GIRKI-1 mice displayed InsR reconstitution in white adipose tissue (WAT) (Fig. 1A)

Summary

Introduction

To analyze the contribution of individual organs and cell types to the integrated physiology of insulin action, we and others have used gene targeting by homologous recombination to carry out gain- and loss-of-function experiments affecting insulin signaling [2]. We have previously shown that InsrϪ/Ϫ mice can be rescued from neonatal diabetic ketoacidosis by restoring InsR expression in liver, brain, and pancreatic ␤ cells [4, 5]. We generated InsR knock-in mice in which insulin action was selectively restored in muscle, adipocytes, and Glut4-expressing brain cells.

Results

Conclusion