Glucocorticoids antagonize insulin's antiproteolytic action on skeletal muscle in humans.
Although chronic glucocorticoid elevations cause net skeletal muscle protein loss in man, the kinetic mechanisms responsible for this catabolic effect and the capacity of insulin to overcome it remain unclear. To examine this issue, we measured basal and insulin-stimulated rates of protein synthesis and breakdown in muscle using the phenylalanine forearm kinetic method in eight normal volunteers studied postabsorptively and after 4 days of dexamethasone treatment (8 mg/day). To avoid the confounding effects of systemic insulinization, local forearm insulin levels were raised by approximately 430 pmol/L using a 150-min brachial arterial infusion of insulin (0.251 pmol/kg.min). Postabsorptively, dexamethasone produced mild hyperglycemia (P < 0.003) and a 3-fold rise in plasma insulin (P < 0.001), but no change in forearm phenylalanine balance or kinetics. Before dexamethasone treatment, local hyperinsulinemia increased forearm glucose uptake 2.5-fold and caused a positive net balance of phenylalanine due to a marked 40% inhibition of proteolysis. After dexamethasone treatment, forearm glucose uptake was modestly reduced. However, forearm net phenylalanine balance remained negative due to a striking reduction in insulin's inhibitory effect on proteolysis. We conclude that 1) the effects of glucocorticoid on basal muscle protein turnover are minimized by compensatory hyperinsulinemia, and 2) glucocorticoids cause muscle resistance to insulin's antiproteolytic action.
Yale General Clinical Research Center, Yale University School of Medicine, New Haven, Connecticut 06510.
R J
RJ
Louard
R
R
Bhushan
R A
RA
Gelfand
E J
EJ
Barrett
R S
RS
Sherwin
D000293:Adolescent; D000328:Adult; D000596:Amino Acids / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D005260:Female; D005542:Forearm / Q000098:blood supply; D005934:Glucagon / Q000097:blood; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007328:Insulin / Q000097:blood / Q000494:pharmacology*; D007329:Insulin Antagonists / Q000494:pharmacology*; D007700:Kinetics; D007773:Lactates / Q000097:blood; D019344:Lactic Acid; D008297:Male; D009124:Muscle Proteins / Q000378:metabolism*; D009132:Muscles / Q000187:drug effects* / Q000378:metabolism; D010649:Phenylalanine / Q000097:blood; D011480:Protease Inhibitors / Q000494:pharmacology*
D000596:Amino Acids; D001786:Blood Glucose; D007328:Insulin; D007329:Insulin Antagonists; D007773:Lactates; D009124:Muscle Proteins; D011480:Protease Inhibitors; D019344:Lactic Acid; D010649:Phenylalanine; D003907:Dexamethasone; D005934:Glucagon; D006854:Hydrocortisone