In skeletal muscle, insulin resistance may be caused by defects in glucose transport, which may be in the translocation, fusion, or exposure and activation of GLUT-4 glucose transporters which may be due to defects in intracellular signaling. These defects may be inherent or may be due to circulating or paracrine factors such as hyperglycemia (glucose toxicity) or increased serum free fatty acids or TNF- . Drugs such as metformin and thiazolidinediones improve insulin sensitivity. the impairment in insulin-stimulated glucose transport can be bypassed by other stimuli, such as exercise and hypoxia, which increase GLUT-4 translocation and lead to the treatment of insulin resistance.