To investigate the role of glucose transporter expression in whole-body glucose homeostasis, we have created transgenic mice that have a 2.0- to 3.5-fold increase in GLUT4 glucose transporter level in skeletal muscle and heart. This increase is sufficient to significantly improve insulin action and to reduce basal blood glucose levels in transgenic streptozotocin-induced diabetic mice. These results provide the first evidence of a direct causality between skeletal muscle GLUT4 transporter level and overall insulin responsiveness.