Hydrocortisone was infused overnight into nine normal healthy adults on three occasions at 0, 80, and 200 micrograms.kg-1.h-1, producing plasma cortisol concentrations of 10.6 +/- 1.2, 34.0 +/- 2.0, and 64.9 +/- 4.3 micrograms/dl, respectively. L-[1-13C]leucine, L-[phenyl-2H5]phenylalanine, and L-[2-15N]glutamine were infused during the last 7 h of hypercortisolemia to measure amino acid kinetics. During the last 3.5 h, somatostatin, glucagon, and insulin were infused to reduce the cortisol-induced elevation in plasma insulin to basal. Hypercortisolemia increased plasma glucose, free fatty acid (FFA), and insulin concentrations. Institution of the somatostatin clamp returned insulin to basal but increased glucose and FFA. Acute hypercortisolemia increased protein breakdown 5-20%, as measured by increases in leucine and phenylalanine appearance rates. Normalizing insulin during hypercortisolemia did not alter phenylalanine flux but enhanced leucine appearance rate, the latter result indicating that insulin was affecting leucine metabolism during hypercortisolemia. The fraction of the leucine flux that was oxidized was not significantly increased with hypercortisolemia, but disposal by the nonoxidative route of leucine uptake for protein synthesis was increased. Hypercortisolemia increased cycling of amino acids by increasing protein breakdown and synthesis, but the increase in this process could have increased resting energy expenditure (REE) only 1-2%. Hypercortisolemia increased glutamine flux in a dose-dependent fashion through an increase in de novo synthesis, which presumably reflects increased release from skeletal muscle. Hypercortisolemia increased REE 9-15% at the 80 and 200 micrograms.kg-1.h-1 infusion rates. Respiratory quotient did not rise with cortisol infusion but tended to decrease, suggesting that the increase in REE was fueled by increased oxidation of fat. These data demonstrate that hypercortisolemia increases metabolic rate and may be in part responsible for the hypermetabolic state in injury.