Insulin was found to decrease the concentration of serum dehydroepiandrosterone (DHEA) and DHEA-sulphate (DHEAS) and recent data suggest that an increase in the metabolic clearance rate of DHEA (MCRDHEA) may be involved. In this study, we have investigated the effects of insulin on DHEA metabolism in men. A total of 10 men were enrolled into the study, and all subjects completed the study. Subjects were healthy, non-obese, and 20-30 years old. DHEA was administered intravenously to subjects, alone or in combination with insulin. A hyperinsulinaemic-euglycaemic clamp was initiated for subjects with the insulin infusion and euglycaemia was maintained by checking blood glucose and adjusting the rate of a 25% dextrose infusion as needed. Serum was collected before DHEA infusion, during DHEA infusion after attaining steady state (3.5-4 h), and during DHEA plus insulin infusion (6-6.5 h) (steady state) and then assayed for DHEA, DHEA metabolites, and DHEA acylation by LCAT. Results showed rapid transformation of DHEA into androst-5-ene-3 beta, 17 beta-diol, DHEA fatty-acid esters (DHEA-FA), androstenedione and 5 alpha-androstan-3 alpha-ol-17-one glucuronide (androsterone glucuronide) whereas DHEAS, testosterone, androstane-3 alpha, 17 beta-diol glucuronide and oestradiol serum levels were not affected. When insulin was simultaneously infused once steady-state DHEA levels had been attained, we observed a decline only in DHEA, DHEA-FA and DHEAS levels, with no effect on other steroids examined. Although serum DHEA esterification was not affected by DHEA, a stimulation by insulin was observed. These results suggest that insulin increases the DHEA metabolic clearance rate by stimulating its conversion to DHEA-FA and by enhancing uptake of DHEA-FA by peripheral tissues.