Diabetes in Mice With Selective Impairment of Insulin Action in Glut4-Expressing Tissues

OBJECTIVE—Impaired insulin-dependent glucose disposal in muscle and fat is a harbinger of type 2 diabetes, but murine models of selective insulin resistance at these two sites are conspicuous by their failure to cause hyperglycemia. A defining feature of muscle and fat vis-à-vis insulin signaling is that they both express the insulin-sensitive glucose transporter Glut4. We hypothesized that diabetes is the result of impaired insulin sig-naling in all Glut4-expressing tissues. RESEARCH DESIGN AND METHODS—To test the hypoth-esis, we generated mice lacking insulin receptors at these sites (“GIRKO ” mice), including muscle, fat, and a subset of Glut4-positive neurons scattered throughout the central nervous system. RESULTS—GIRKO mice develop diabetes with high frequency because of reduced glucose uptake in peripheral organs, exces