A recent report suggested that the glucose-free fatty acid (FFA) cycle may contribute to steroid-induced insulin resistance in rats, and that glucose tolerance could be restored to normal when FFA levels were lowered with nicotinic acid. To test this hypothesis in man, we measured insulin sensitivity (by euglycemic insulin clamp in combination with indirect calorimetry and infusion of tritiated glucose) before and after short-term administration of a nicotinic-acid derivative (Acipimox) in 10 steroid-treated, kidney transplant patients with insulin resistance. Thirty-five healthy subjects served as controls. Six of them received Acipimox. Total body glucose metabolism was reduced in steroid-treated patients compared with control subjects (41.7 +/- 3.3 v 50.0 +/- 2.2 mumol/kg lean body mass [LBM].min, P less than .05). The reduction in insulin-stimulated glucose uptake was mainly due to an impairment in nonoxidative glucose metabolism (primarily glucose storage as glycogen) (18.3 +/- 2.8 v 27.2 +/- 2.2 mumol/kg LBM.min, P less than .01). Acipimox lowered basal FFA concentrations (from 672 +/- 63 to 114 +/- 11 mumol/L, P less than .05) and the rate of lipid oxidation measured in the basal state (1.5 +/- 0.2 to 0.6 +/- 0.1 mumol/kg LBM.min, P less than .01) and during the clamp (0.7 +/- 0.2 to 0.03 +/- 0.2 mumol/kg LBM.min, P less than .05). In addition, Acipimox administration normalized total glucose disposal (to 54.4 +/- 4.4 mumol/kg LBM.min), mainly due to enhanced nonoxidative glucose metabolism (to 28.9 +/- 3.9 mumol/kg LBM.min) in steroid-treated patients (both P less than .05 v before Acipimox).(ABSTRACT TRUNCATED AT 250 WORDS)