The major objectives of this research proposal are to define the mechanisms of insulin resistance in various altered physiologic states in man and to elucidate the relationship between measurements of in vivo and in vitro insulin action. We propose to apply this combined approach to the insulin resistance of human obesity, noninsulin-dependent diabetes mellitus and aging. Additionally, we will assess the affects of high carbohydrate feedings and treatment with oral sulfonylurea agents. With this approach, we will determine under what conditions insulin resistance is directly related to decreased insulin receptors and under what conditions postreceptor defects are implicated. In vivo studies will be carried out by use of the glucose clamp technique. In vitro studies will involve measurements of insulin binding to receptors on isolated adipocytes, monocytes and erythrocytes. In addition, in vitro measurements of glucose transport by isolated adipocytes will be performed and studies of insulin binding and glucose transport in cultured fibroblasts will also be carried out. It is expected that the studies proposed will provide information and test hypotheses which should elucidate the causes of insulin resistance in various human disease states. Clearly, a better understanding of the mechanisms of insulin resistance can potentially lead to a more rational design and understanding of therapeutic approaches.