To examine the insulin antagonistic effects of growth hormone (GH), seven healthy subjects underwent, in random order, two 5-h euglycemic clamp studies with moderate hyperinsulinemia. A GH infusion (45 ng.kg-1.min-1) was given throughout one of the studies. GH inhibited the insulin-stimulated glucose disposal by 27% from 4.4 +/- 0.7 to 3.3 +/- 0.4 mg.kg-1.min-1 (P less than 0.02) and raised the nonprotein energy expenditures (NPEE) from 18.7 +/- 0.5 to 20.5 +/- 0.3 kcal.kg-1.24 h-1 (P less than 0.03). Lipid oxidation contributed 71.7 +/- 5.6% of NPEE during the GH infusion as compared with 48.7 +/- 5.2% during the control clamp (P less than 0.02). In skeletal muscle biopsies, insulin binding to wheat germ agglutinin-purified insulin receptors and insulin receptor kinase activity were unaffected by GH infusion. Glycogen synthase activation by insulin was inhibited by 41% during the GH clamp (fractional velocity 14.1 +/- 2.5 vs. 8.3 +/- 1.4%, P less than 0.03). In conclusion, GH 1) increases energy expenditures and inhibits glucose oxidation in favor of an increased lipid oxidation, and 2) inhibits insulin-mediated activation of the glycogen synthase in skeletal muscle biopsies by a mechanism distal to insulin receptor binding and kinase activity.