The mechanisms responsible for glucocorticoid-induced insulin resistance remain unclear. Glucocorticoids show several interactions with the sympatho-adrenal system which may contribute to this decrease in insulin sensitivity: they enhance the synthesis and actions of catecholamines, but abolish insulin-induced activation of muscle sympathetic nerve activity. The present study was performed in order to investigate the effects of the interactions between glucocorticoids and the sympatho-adrenal system on insulin sensitivity. Basal and insulin-stimulated glucose metabolism was measured in healthy human subjects during four 2-h clamp studies as follows: control (C); after taking oral dexamethasone (2 mg daily) for 2 days (D); after taking oral ephedrine sulphate (40 mg daily) for 2 days (E); and after taking dexamethasone+ephedrine (D+E). Glucose uptake, production and oxidation were calculated from plasma 13C glucose and exhaled 13CO2 during constant tracer infusion of U-13C glucose. Basal glucose production, utilization and oxidation were similar in all four studies. During hyperinsulinaemia, glucose uptake was reduced by 51.5% with treatment D, by 25.9% with treatment E, and by 49.6% with D+E. Glucose oxidation was reduced by 54.0% with treatment D, by 24.0% with treatment E, and by 57.2% with D+E. Hepatic glucose production was completely suppressed in all four studies. It is concluded that both dexamethasone and ephedrine decrease insulin-mediated glucose uptake and oxidation. Co-administration of ephedrine does not suppress the glucocorticoid-induced alterations of glucose metabolism. This indicates that glucocorticoid-induced insulin resistance is not related to the inhibition of muscle sympathetic nerve activity. These results suggest instead that glucocorticoids and sympathomimetic agents may impair glucose metabolism by common actions.