Skeletal muscle plays an essential role in the regulation of whole-body glucose homeostasis. Glucose is transported into the muscle cells via protein-mediated transport that requires sarcolemmal glucose transporters (GLUT). Translocation of GLUT-4 to the plasma membranes is the most potent factor stimulating glucose uptake by myocytes. Relocation of GLUT-4 from an intracellular pool(s) to the plasma membranes is activated by either insulin (associated with activation of kinase PI3K), or physical activity (associated with activation of kinase AMPK). Recent studies have shown that the signaling protein known as AS160 is involved in the directed GLUT-4 intramyocellular redistribution. AS160 protein appears to be activated by the insulin pathway as well as by AMPK. Moreover, in human skeletal muscles that are insulin-resistant, insulin-stimulated phosphorylation of AS160 is significantly impaired. Therefore, decreased insulin-induced AS160 phosphorylation that results in diminished GLUT-4 redistribution to the plasma membrane may play an important role in insulin resistance in vivo.