Abstract 354 Poster Session I, Saturday, 5/1 (poster 138)

To study the independent effect of insulin on amino acid (AA) utilization in the ovine fetus we studied 17 late gestation fetal sheep before (control period, C) and at the end of a 4-hour hyperinsulinemic-euglycemic-euaminoacidemic clamp (study period, S). During hyperinsulinemia (fetal arterial insulin concentration 14 ± 2 and 84 ± 12 µU/mL, mean ± sem, in C vs S, p<0.0001 by unpaired t-test), euglycemia was maintained by a glucose clamp (fetal arterial glucose concentration 21.5 ± 0.7 and 21.5 ± 0.8 mg/dL in C vs S). Simultaneously, euaminoacidemia was achieved by novel application of a rapid measurement of fetal lysine concentration to adjust the infusion rate of a mixed amino acid solution (Trophamine™) to maintain exact control period concentration for lysine and approximate control concentrations of other AA's. Umbilical blood flow and fetal arterial lysine concentration were not different between the two periods. Umbilical AA uptakes were not different in the two periods, but in the study period there was a significant increase in AA utilization (defined as umbilical AA uptake plus AA uptake from Trophamine infusion) for all essential AA: VAL (+45%), LEU (+45%), LEU (+69%), ILE (+76%), PHE (+53%), THR (+54%), MET (+97%), LYS (+83%), HIS (+76%) and for the non-essential AA: ASP (+10-fold), PRO (+119%), GLY (+39%), ALA (+58%), ARG (+76%). Mean fetal total nitrogen uptake increased 59% with insulin infusion (from 0.91 to 1.44 µg/kg/min). In order to account for the effect of changes in AA concentration on AA utilization, an AA clearance (utilization/concentration) was calculated for each AA, and was significantly increased for all the essential AA and all the non-essential AA except for TAU, GLN, CYS, CIT and ORN. Although LEU concentration increased by 18.0%, LEU clearance, as a measure of insulin effect on LEU utilization independent of LEU concentration, was enhanced by 45.4% in response to increased insulin concentration. Thus 66.3% of the increase in LEU utilization during the study period was insulin specific (1.15 µg/kg/min), and 33.7% was LEU concentration specific (2.27 µg/kg/min). In conclusion, at constant glucose and AA concentrations, the rate of fetal AA infusion needed to maintain baseline AA concentrations is an index of the effect of insulin on fetal AA utilization. This is the first study to delineate the independent effect of fetal insulin on fetal AA metabolism. Increased fetal plasma insulin concentration increases fetal AA utilization of all essential and most non-essential AA, producing a net protein anabolic effect of insulin in the ovine fetus. Using LEU as an index AA, physiological changes in insulin concentration produces a strong effect on fetal LEU utilization that is independent of the effect of LEU concentration.

*APS/SPR-NIH Student Research Trainee