We have described mouse models in which the expression levels of GLUT4 in skeletal muscle have been modified. GLUT4 null mice, which lack skeletal-muscle GLUT4, are insulin-resistant. In contrast, MLC-GLUT4 mice, which overexpress GLUT4 specifically in the skeletal muscle, exhibit an increase in insulin-sensitivity and glucose disposal. Restoring GLUT4 expression specifically in the skeletal muscle of the GLUT4 null mice by mating with MLC-GLUT4 transgenic mice normalizes the reduced glucose uptake and glucose metabolism of the skeletal muscle of the MLC-GLUT4 null mouse. These models represent unique agents to dissect the mechanism for insulin signalling and GLUT4 translocation in skeletal muscle that expresses varying levels of GLUT4.