There is evidence of a metabolic role for IGF-I in type 1 diabetes, but it is unclear whether IGF-I acts indirectly by reducing GH secretion or has direct effects. Using stable isotopes we have investigated, on three separate occasions, the effect of a pulse of recombinant human GH, a sc injection of recombinant human IGF-I, and a placebo on glucose, lipid, and protein metabolism in subjects with type 1 diabetes during a basal insulin infusion and a hyperinsulinemic euglycemic clamp. Endogenous GH secretion was suppressed with octreotide. IGF-I reduced the hepatic glucose production rate (Ra), increased peripheral glucose uptake, and reduced protein breakdown during the basal insulin infusion (P < 0.05, P < 0.005, and P < 0.05, respectively, vs. placebo) and the hyperinsulinemic euglycemic clamp (P < 0.05, P < 0.005, and P < 0.05, respectively, vs. placebo). IGF-I had no effect on glycerol Ra, an index of lipolysis. GH increased glucose and glycerol Ra during the basal insulin infusion (P < 0.005 vs. placebo study), but the effects were no different from placebo during the clamp. In conclusion, IGF-I had a direct effect on glucose and protein metabolism, which was maintained during the hyperinsulinemic euglycemic clamp. This suggests that IGF-I acts in concert with insulin and may have an important role in maintaining glucose homeostasis and protein metabolism in type 1 diabetes.