Recent data demonstrate that recombinant human insulin-like growth factor I (rhIGF-I) has GH-like effects on protein metabolism, selectively stimulating whole body protein synthesis. Additionally, recent studies suggest that the combination of recombinant human GH (rhGH) and rhIGF-I might be more anabolic than either compound alone when administered to calorically deprived subjects. To investigate whether the same is true in normally fed healthy individuals, seven healthy subjects (mean age, 26 +/- 1 yr) fed a normal weight maintenance diet (approximately 33 Cal/kg.day) with approximately 1.4 g/kg.day protein were given rhGH (0.025 mg/kg.day) and rhIGF-I (100 micrograms/kg bid daily) sc for 5 days. Whole body leucine kinetics were studied using primed 4-h infusions of [14C]leucine before and after treatment and measuring the specific activity of 14C-labeled alpha-ketoisocaproic acid and 14CO2 in plasma and breath, respectively. These data were compared with those from six additional subjects treated only with rhGH as well as with those from previously reported subjects given rhIGF-I alone. Subjects receiving combination treatment had a significant increase in plasma IGF-I concentrations (123 +/- 9 to 709 +/- 29 micrograms/L; P = 0.001). As expected, there was a significant decrease in leucine oxidation in subjects given combination therapy (P = 0.03) as well as a significant increase in leucine turnover (P = 0.018); hence the nonoxidative leucine disposal, a measure of whole body protein synthesis, was significantly increased (P = 0.018). However, when the absolute changes in all three parameters of leucine kinetics were compared in the three treatment groups (rhGH alone, rhIGF-I alone, and combined rhGH and rhIGF-I), there was no additive effect of combination treatment on whole body protein anabolism (P > 0.05, by analysis of variance). We conclude that, contrary to the calorically deprived model, in normally fed individuals, the coadministration of rhIGF-I and rhGH at these doses is not more anabolic on whole body protein than either compound given alone. This difference in observed effects in the fed and partly fasted state may be related to the difference in total insulin output and suggests a saturable capacity of the body to accumulate protein during normal substrate availability while the body is exposed to individual anabolic hormones. These data suggest a common pathway for GH and IGF-I to enhance whole body protein anabolism in the normally fed state.