RU 486 prevents the acute effects of cortisol on glucose and leucine metabolism

Abstract

Glucocorticoids have deleterious effects on glucose and protein metabolism. RU 486 is an antiprogestin with antiglucocorticoid activity, which could be used to prevent the undesirable metabolic effects of glucocorticoids. A randomized, controlled, double blind study was performed in eight healthy male volunteers who were tested four times: during the iv infusion of cortisol (2 micrograms/kg.min for 5 h) after the oral ingestion of RU 486 (600 mg) or a placebo, and during the infusion of a normal saline solution with placebo or RU 486 ingestion. During each test, a primed continuous iv infusion of D-[6,6-2H]glucose and [1-13C-]leucine was given for the calculation of hepatic glucose production and plasma leucine appearance rate. 13CO2 enrichment in breath was measured for the calculation of leucine oxidation. Plasma concentrations of cortisol, ACTH, insulin, C-peptide, glucagon, and GH were measured at regular intervals. Compared to saline, cortisol infusion increased plasma glucose 5.5 +/- 0.6 vs. 4.7 +/- 0.4 mmol/L; P < 0.01) and leucine (179 +/- 35 vs. 155 +/- 35 mumol/L; P < 0.01) concentrations as well as the leucine appearance rate (2.24 +/- 0.3 vs. 2.0 +/- 0.28 mumol/kg.min; P < 0.05) and oxidation (0.51 +/- 0.22 vs. 0.39 +/- 0.06 mumol/kg.min; P < 0.01), and there was no change in hepatic glucose production. 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 concentrations were transiently lower than those after placebo ingestion, as was 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 ingestion of RU 486. The following conclusions were reached. 1) RU 486 can suppress the effects of acute hypercortisolemia on glucose and protein metabolism and GH secretion in man. Long term studies are warranted to explore the potential of antiglucocorticoid molecules as preventive agents of the deleterious effects of chronic glucocorticoid administration. 2) RU 486 is useful molecule for studying the metabolic effects of cortisol in man.

PIP: In Montreal, Quebec, a randomized, double blind study was conducted in eight healthy men at Hotel-Dieu Hospital during administration of cortisol (2 mcg/kg per minute for 5 h) with RU-486 (600 mg), during cortisol administration with a placebo, during 0.9% saline administration with RU-486, and during normal saline administration with a placebo. Clinicians administered a primed continuous infusion of D-[6,6-2H]glucose and [1-13C-]leucine during each test to determine hepatic glucose production and plasma leucine appearance rate. Continuous infusion of labeled bicarbonate in four men was also conducted to calculate the recovery factor of carbon dioxide in their breath. Researchers wanted to examine glucose and protein metabolism during hypercortisolemia with or without RU-486 and the effects of RU-486 on the metabolic effects of acute cortisol deficiency. Among men receiving the placebo, plasma glucose levels were higher during cortisol infusion than saline infusion (5.5 vs. 4.7 mmol/l; p 0.01). The leucine appearance rate was also higher during cortisol infusion than saline infusion (2.24 vs. 2 mcmol/kg per min; p 0.05) as well as leucine oxidation (0.51 vs. 0.31 mcmol/kg; p 0.01). Hepatic glucose production did not change in either placebo group. Cortisol did not induce the same metabolic changes when it was administered after RU-486. Normal saline infusion after RU-486 induced a short-term lower plasma glucose level and hepatic glucose production. Insulin, C-peptide, or glucagon did not change. Cortisol induced increased growth hormone (GH) levels (e.g., at 240 min, 5.9 vs. 1.7 mcg/l; p 0.01) while GH levels did not change when cortisol was administered after RU-486. These findings show that RU-486 suppresses the effects of acute hypercortisolemia on glucose and protein metabolism and GH secretion in males. Long-term studies could reveal the potential of RU-486 to prevent the adverse effects of chronic glucocorticoid administration. RU-486 allows researchers to study the metabolic effects of cortisol in males.