Fetal nutritional stress may result in intrauterine growth restriction and postnatal insulin resistance. To determine whether insulin resistance can begin in utero, we subjected late gestation (130-135 days) ewes to 120 hours of complete fasting and compared the results to our previous work in fed ewes(38). We determined the effect of insulin and/or recombinant human (rh)IGF-I infusion on ovine fetal phenylalanine kinetics, protein synthesis, and phenylalanine accretion.. Experimental infusates were 1) saline, 2)rhIGF-I plus a replacement dose of insulin (40 nmol IGF-I/h and 16 mIU insulin/h), 3)insulin (890 mIU/h), and 4) IGF-I plus insulin (40 nmolIGF-I/h and 890 mIU insulin/h). During hormone infusion, both glucose and amino acid concentrations were clamped at basal concentrations. Amino acid infusion was required during infusion of either hormone to maintain plasma concentrations constant. However, the amount required during insulin infusion was less than during IGF-I infusion, and 40% less than the amount required during identical studies in non-fasted animals. Phenylalanine used for protein synthesis and accretion was increased compared to control animals, but again less so than in the non-fasted animals. In contrast to non-fasted animals, neither hormone increased the fractional synthetic rate of skeletal muscle protein nor that of plasma albumin. These results indicate that a short but severe nutritional stress can significantly alter the fetal anabolic response to insulin, even when both glucose and amino acid substrate supplies are restored. Therefore, adaptive responses characterized by insulin resistance begin in utero when the fetus is subjected to sufficient nutritional stress.