Effects of Insulin and Glucose Concentrations on Glucose Utilization in Fetal Sheep

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Abstract
Glucose and insulin clamp experiments were performed in vivo in chronically catheterized, late-gestation fetal lambs to quantify the effects of glucose and insulin on fetal glucose metabolism. Fetal glucose uptake from the placenta via the umbilical circulation (umbilical glucose uptake) was measured by application of the Fick principle, and fetal glucose utilization rate (GUR) was measured using [U-14C]glucose tracer. Fetal plasma insulin concentrations ranged from 2 to 119 μU·ml−1 and fetal blood glucose concentrations ranged from 7.3 to 62.6 mg·dl−1. GUR varied from 2.82 to 15.12 mg/min/kg and the exogenous glucose entry rate (umbilical glucose uptake + glucose infusion) varied from 2.46 to 13.95 mg/min/kg. The mean GUR [6.53 ± 0.28 (SEM) mg/kg/min] was not different from the mean exogenous glucose entry rate [6.29 ± 0.30 (SEM) mg/kg/min]. Multiple linear regression analysis on a glucose-by-insulin surface demonstrated a best-fit model of fetal glucose utilization following the quadratic equation: GUR = −0.322 + [0.289 (glucose)] + [0.108 (insulin)] - [0.00319 (glucose)2] - [0.000673 (insulin)2], r = 0.883 (all terms significant at p < 0.02). This model predicted a GURmax of 10.56 mg/min/kg at blood glucose concentration = 45.3 mg/dl and plasma insulin concentration = 80 μU/ml and Km values for blood glucose concentration and plasma insulin concentration of 20.6 mg/dl and 10 μU/ml, respectively. According to this model, the glucose and insulin effects were additive. Furthermore, change in GUR was not proportionate to change in glucose concentration, accounting for a decreasing metabolic clearance rate at higher glucose concentrations. These results demonstrate the three-dimensional nature of the simultaneous additive effects of glucose and insulin on glucose utilization. These results also serve to emphasize that comparative studies of insulin and glucose metabolism in fetal lambs must be conducted at similar concentrations of glucose to avoid inaccurate estimates of the magnitude of insulin effect on glucose metabolism.