To determine the role insulin resistance may play in the catabolic effect of high-dose prednisone therapy, healthy volunteers were studied on four occasions with the hormone-clamp technique at two insulin infusion rates. Subjects were studied after 5 days of prednisone (60 mg/day) or no steroid treatment and were infused with somatostatin, glucagon, growth hormone, [3H]glucose, [14C]leucine, and insulin (0.1 or 0.2 mU.kg-1.min-1). At each rate of insulin infusion, the rate of leucine oxidation was increased (P less than .001) after steroid treatment. Leucine flux, an indicator of whole-body proteolysis, was similar in the presence or absence of steroid treatment (2.26 +/- 0.08 vs. 2.13 +/- 0.04 mumol.kg-1.min-1, respectively) at the lower rate of insulin infusion but was higher during steroid treatment (2.18 +/- 0.06 vs. 1.84 +/- 0.13 mumol.kg-1.min-1) at the 0.2-mU.kg-1.min-1 insulin infusion. Steroid pretreatment had no significant effect on the nonoxidative rates of leucine disappearance. These data provide strong evidence that the protein wasting associated with glucocorticosteroid therapy is in part the result of steroid-induced resistance to the antiproteolytic effect of insulin and an increase in the oxidation (and thus wasting) of one essential amino acid, leucine.