In vivo effects of 300-min infusions of recombinant insulinlike growth factor I (IGF-I) and IGF-II on glucose and protein metabolism have been investigated in awake, fasted lambs. Two doses of recombinant human (rh) IGF-I were infused: 6.7 nmol/kg.h, which induced hypoglycemia, and 2.0 nmol/kg.h, which did not. The effects were compared with an insulin infusion (0.17 nmol/kg.h) that had the same hypoglycemic potential as the high dose rhIGF-I infusion. rhIGF-II was infused at a rate of 6.7 nmol/kg.h. Primed constant infusions of isotopically labeled glucose, urea and leucine tracers were used to determine glucose and protein kinetics. rhIGF-I lowered blood glucose by increasing the rate of glucose clearance (P less than 0.01), in contrast to insulin, which both increased clearance and reduced glucose production. Net protein loss was reduced after infusion of low and high dose rhIGF-I and insulin by 11% (P less than 0.05), 15% (P less than 0.01), and 12% (P less than 0.05), respectively. rhIGF-II infusion did not alter the rate of net protein loss. In contrast to insulin, high dose rhIGF-I infusion increased the rate of protein synthesis in skeletal (P less than 0.05) and cardiac muscle (P less than 0.01) and in hepatic tissue (P less than 0.05). We conclude that (a) protein metabolism is more sensitive than glucose metabolism to rhIGF-I infusion, as protein loss was reduced by an rhIGF-I infusion that did not alter glucose kinetics; (b) protein synthesis is increased by rhIGF-I infusion but not by insulin infusion; and (c) rhIGF-II is a less effective anabolic agent than rhIGF-I. We speculate that the effects of rhIGF-I on protein metabolism are not mediated by insulin receptors.