Reversal of steroid-induced insulin resistance by a nicotinic-acid derivative in man

Abstract

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 reveived Acipimox. Total body glucose metabolism was reduced in steroid-treated patients compared with control subjects (41.7 ± 3.3 v 50.0 ± 2.2 μmol/kg lean body mass [LBM] · min, P < .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 μmol/kg LBM · min, P < .01). Acipimox lowered basal FFA concentrations (from 672 ± 63 to 114 ± 11 μmol/L, P < .05) and the rate of lipid oxidation measured in the basal state (1.5 ± 0.2 to 0.6 ± 0.1 μmol/kg LBM · min, P < .01) and during the clamp (0.7 ± 0.2 to 0.03 ± 0.2 μmol/kg LBM · min, P < .05). In addition, Acipimox administration normalized total glucose disposal (to 54.4 ± 4.4 μmol/kg LBM · min), mainly due to enhanced nonoxidative glucose metabolism (to 28.9 ± 3.9 μmol/kg LBM · min) in steroid-treated patients (both P < .05 v before Acipimox). In keeping with these findings, Acipimox also enhanced nonoxidative glucose metabolism by 28% in six control subjects ( P < .05). Therefore, the improvement in nonoxidative glucose metabolism after Acipimox was unrelated to the degree of insulin resistance. We conclude that corticosteroids cause insulin resistance primarily by affecting glucose storage. Although there is no evidence that an operative glucose-FFA cycle would contribute to this defect, short-term lowering of FFAs by a nicotinic-acid derivative, Acipimox, restored glucose storage to normal. This effect may be unrelated to the FFA-lowering effect of the drug.