Epinephrine is known to produce insulin resistance, but the exact molecular mechanism involved is unknown. In the present study we have examined the levels and phosphorylation state of the insulin receptor and of insulin receptor substrate 1 (IRS-1), as well as the association between IRS-1 and phosphatidylinositol 3-kinase (PI 3-kinase) in the liver and muscle of rats treated with epinephrine. The results demonstrate a decrease in insulin-stimulated receptor and IRS-1 phosphorylation levels which was accompanied by a reduction in the association of IRS-1 with PI 3-kinase in vivo in liver and muscle of epinephrine treated rats. These data suggest that molecular post-receptor defects may explain some aspects of the insulin resistance induced by catecholamines.310755759