Insulin resistance can result from a variety of insults, including exposure to glucocorticoids, TNF-a glucosamine, high glucose, and osmotic shock. To date, there has been little data to suggest that there may be a common mechanism underlying the decrease in insulin sensitivity associated with these agents. Using two of these models (TNF- a and glucocorticoid exposure), we have identified the induction of reactive oxygen species as a common pathway that may mediate cellular insulin resistance. We are now using pharmacological and genetic tests to clarify the role played by ROS in cultured cells, animals, and humans with insulin resistance. This project is performed in collaboration with Eric Lander's group at the Whitehead Institute Center for Genome Research.