In order to study the effect of corticosteroids on energy metabolism in immunosuppressed patients after kidney transplantation, we have examined glucose utilization, energy expenditure, and lean body mass in 10 kidney-transplanted patients receiving steroids (methylprednisolone 8.2 +/- 1.5 mg/day) and in 10 healthy age- and weight-matched control subjects. Glucose utilization was measured during euglycemic insulin clamp in combination with indirect calorimetry and infusion of [3H-3]-glucose, while beta-cell function was measured during a hyperglycemic clamp. The kidney-transplanted patients were resistant to the glucoregulatory effect of insulin, as demonstrated by a 25% reduction in total glucose disposal compared to control subjects. This defect was almost completely accounted for by a defect in storage of glucose as glycogen (3.3 +/- 0.5 vs. 5.0 +/- 0.5 mg/kg LBM min; P less than 0.05). The reduction in nonoxidative glucose disposal was associated with reduced lean body mass and incapacity to release energy as heat after infusion of insulin, i.e. thermogenic defect. In contrast, oxidation of glucose and lipids was not influenced by steroid therapy. Furthermore, suppression of hepatic glucose production was normal, and insulin secretion was normally enhanced in relation to the degree of insulin resistance in the steroid-treated patients. In conclusion, steroid-induced insulin resistance in kidney-transplanted patients is due to alterations in the nonoxidative pathway of glucose metabolism. These findings raise the question of whether steroid therapy directly influences glycogen synthase in man.