RU-486 PREVENTS THE ACUTE EFFECTS OF CORTISOL ON GLUCOSE AND LEUCINE METABOLISM

Glucocorticoids have deleterious effects on glucose and protein metabo lism. RU 486 is an antiprogestin with antiglucocorticoid activity, whi ch could be used to prevent the undesirable metabolic effects of gluco corticoids. A randomized, controlled, double blind study was performed in eight healthy male volunteers who were tested four times: during t he iv infusion of cortisol (2 mu g/kg.min for 5 h) after the oral inge stion of RU 486 (600 mg) or a placebo, and during the infusion of a no rmal saline solution with placebo or RU 486 ingestion. During each tes t, a primed continuous iv infusion of D-[6,6-2H]glucose and [1-C-13-]l eucine was given for the calculation of hepatic glucose production and plasma leucine appearance rate. (CO2)-C-13 enrichment in breath was m easured for the calculation of leucine oxidation. Plasma concentration s of cortisol, ACTH, insulin, C-peptide, glucagon, and GH were measure d at regular intervals. Compared to saline, cortisol infusion increase d plasma glucose (5.5 +/- 0.6 us. 4.1 +/- 0.4 mmol/L; P < 0.01) and le ucine (179 +/- 35 us. 155 +/- 35 mu mol/L; P < 0.01) concentrations as well as the leucine appearance rate (2.24 +/- 0.3 vs. 2.0 +/- 0.28 mu mol/kg.min; P < 0.05) and oxidation (0.51 +/- 0.22 vs. 0.39 +/- 0.06 mu mol/kg.min; P < 0.01), and there was no change in hepatic glucose p roduction. None of the metabolic changes induced by cortisol were seen when cortisol was administered after the ingestion of RU 486. When RU 486 was given before normal saline infusion, plasma glucose concentra tions were transiently lower than those after placebo ingestion, as wa s the hepatic glucose production. No change in insulin, C-peptide, or glucagon was seen between tests. GH concentrations were higher during cortisol infusion, but not when cortisol was administered after the in gestion of RU 486. The following conclusions were reached. 1) RU 486 c an suppress the effects of acute hypercortisolemia on glucose and prot ein metabolism and GH secretion in man. Long term studies are warrante d to explore the potential of antiglucocorticoid molecules as preventi ve agents of the deleterious effects of chronic glucocorticoid adminis tration. 2) RU 486 is useful molecule for studying the metabolic effec ts of cortisol in man.