Ontogeny of Insulin Effect in Fetal Sheep

Abstract

Compared with fetuses near term, midgestation fetal sheep at about 75 d of gestation have higher weight-specific glucose uptake rates, higher plasma glucose concentrations, lower plasma insulin concentrations, higher red blood cell insulin receptor concentrations and affinity, and a lower proportion of body weight accounted for by potentially insulin-sensitive skeletal muscle. Based on these observations, we measured the net rate of glucose uptake by the fetus from the uteroplacenta under basal and hyperinsulinemic conditions in eight fetal sheep at 76 d of gestation and eight fetal sheep at 132 d of gestation (term approximately 150 d). Hyperinsulinemia (414 +/- 90 pM) in the 76-d fetal sheep decreased plasma glucose concentration by 0.20 +/- 0.03 mM (-13%, p < 0.01) and increased the net rate of glucose uptake (8.4 +/- 2.2 mumol/min/kg, +21.3%, p < 0.05) and glucose clearance (11.4 +/- 2.6 mL/min/kg, +39%, p < 0.01). In the 132-d fetuses, a comparable hyperinsulinemia (306 +/- 36 pM) decreased plasma glucose concentration (-0.31 +/- 0.02 mM, -26%, p < 0.05) and increased glucose clearance (16.7 +/- 1.8 mL/min/kg, +73.6%, p < 0.05) to a greater extent than in the 76-d fetuses (p < 0.05 and p < 0.01, respectively). Net glucose uptake rate increased significantly in the 132-d fetuses (6.7 +/- 1.1 mumol/min/kg, +27.5%, p < 0.05), but not differently from the 76-d fetuses (p = 0.21). These data define brisk and significant effects of insulin on glucose metabolism in fetal sheep, even as early as approximately 50% of gestation. The midgestation fetal sheep, particularly in relation to its larger fractional content of body water and smaller fractional content of insulin-sensitive tissues, demonstrates glucose metabolic responses to insulin at least as great as those that occur near term.