Fetal sensitivity to insulin and glucose was investigated during fetal hyperinsulinemic-euglycemic (HI-euG, n=18) and hyperglycemic-euinsulinemic (HG-euI, n=12) clamps. Singleton bearing adolescent ewes were fed high (H) or control (C) nutrient intakes to induce compromised or normal placental/fetal size, respectively. Catheters were inserted into the umbilical vein (v), fetal artery (a) and veins, and studies conducted between day 126 and 133 of gestation. Umbilical blood flow (UmBF) was determined by the steady- state transplacental diffusion technique using 3H2O, and glucose fluxes quantified by the Fick principle. For the HI-euG study, fetal glucose utilisation was measured at spontaneously occurring fetal insulin concentrations and two additional higher levels, while fetal glucose was clamped at the initial baseline level. For the HG-euI study, fetal insulin was suppressed by somatostatin infusion and fetal glucose utilisation determined at baseline (before somatostatin) glucose concentrations, and at 150 and 200% of this value. Placentome weight (219 vs. 395g), fetal weight (2965 vs. 4373g) and UmBF (519 vs. 794 ml/min) were lower (P<0.001) in H than in C groups. Relative to control fetuses, glucose extraction (G[v-a]/G[v] x 100) in the non-perturbed state was higher (21.7 vs.15.9%) in growth- restricted fetuses despite lower glucose (0.78 vs. 1.05µmol/ml) and insulin (8.5 vs. 16.9 µU/ml) concentrations (all P<0.001). During the HI-euG study, total fetal glucose utilisation rate increased in response to higher insulin concentrations (65 and 64% in H and C groups). Similarly during the HG-euI study a two- fold increase in glucose supply increased fetal glucose utilisation by 41 and 44% in H and C groups. Throughout both studies, absolute total fetal glucose utilisation rates were reduced in H vs. C groups (P<0.01), but were similar when expressed per kg fetus (HI-euG: 34.7, 49.5 and 57.5 in H vs. 34.7, 51.2 and 56.1µmol/min/kg in C, HG-euI: 28.7, 35.7 and 40.8 in H vs. 32.9, 34.5 and 43.8µmol/min/kg in C). These normal body weight specific metabolic responses to short term experimental increases in plasma insulin and glucose in response to chronic IUGR indicate maintained mechanisms of insulin action and glucose uptake/utilisation capacity, which, if persistent, might predispose such IUGR offspring to excessive energy deposition in later life.