Effects of Glucose Infusion on Leucine Transamination and Oxidation in the Ovine Fetus

Abstract

ABSTRACT. During fasting of the ewe, the rate of amino acid oxidation by the ovine fetus increases substantially. We hypothesized that the increase in amino acid oxidation derived mainly from reduced protein synthesis. We further hypothesized that fetal glucose supplementation would result in diminished amino acid oxidation. To test these hypotheses, nine ovine fetuses were infused with [15N,1-'3C]leucine to determine the rates of leucine appearance and disposal. Simultaneously, the fetal uptake of leucine was determined. Animals were studied in the fed and fasted state. After baseline measurements, glucose was infused into the fetal inferior vena cava at a rate estimated to match the fetal glucose uptake. Results of these studies indicate that leucine nitrogen flux, leucine carbon flux and fetal leucine uptake were constant. Leucine oxidation was increased by 50% in the fasted state (6.3 versus 13.4 pmol/ min); glucose infusion resulted in a 25% decline in oxidation (to 10.4 pmol/min) in the fasted state, but had no effect in the fed state. Mean leucine umbilical uptake during fasting was 9.3 pmollmin, 4.1 pmol/min less than leucine oxidation. These data suggest that leucine (and potentially other amino acids) may be in negative balance during maternal fasting, and can be spared by supplementation of the fetus with exogenous glucose. (Pediatr Res 30: [423][424][425][426][427][428][429]1991) Abbreviations KIC, a-ketoisocaproate GC/MS, gas chromatograph/mass spectrometry BCAA, branched chain amino acid ANOVA, analysis of variance in increased fetal oxidation of amino acids, a diminished rate of protein synthesis, and no significant change in the rate of protein degradation. To further test this hypothesis, a labeled amino acid was used as a tracer to allow the quantitative estimates of fetal protein breakdown, protein synthesis, and oxidation. Coupled with measurements of fetal uptake, all parameters of the movement of a given amino acid through fetal plasma could then be observed. Controlled perturbations of the physiologic state of the fetus were then initiated with the aim of determining the effect of substrate supply on protein synthesis, breakdown, and amino acid oxidation.We have chosen leucine as a representative amino acid to study fetal protein kinetics. The fetal uptake of this essential amino acid even under normal conditions is large relative to its carcass accretion rate (4), implying a significant contribution of this amino acid to oxidative or other pathways. In addition, leucine has been used extensively for modeling protein kinetics in postnatal animals.The aim of the present study was to investigate how the ovine fetus adapts its amino acid metabolism to augmentation of glucose intake. We hypothesized that augmentation of glucose supply to the fetus would result in diminished leucine oxidation. To study this question, the net rates of fetal uptake of leucine and rates of nonoxidative leucine disposal, oxidation, and leucine derived from protein breakdown were determined in the fed and fasted ...

Effects of insulin on ovine fetal leucine kinetics and protein metabolism.

“…Indeed, fetal amino acid nitrogen uptake significantly increases during hypoglycemic hyperinsulinemia (31 ). Estimates ofnormal fetal leucine uptake have ranged from 3.7 to 4.7 Atm/kg per min ( 12,14,27,29,40), values that agree with the control measurements of this study. The contribution of a-ketoisocaproate to the uptake of leucine carbon skeleton has been less well studied.…”

“…Second, any effects of somatostatin (either primary or secondary) on fetal protein metabolism should be equally present during both control and experimental conditions. Estimates of fetal leucine disposal using the reciprocal pool model (i.e., calculated from a-ketoisocaproate specific activity) have ranged from 10 to 14 Amol/min per kg ( 12,14,27,29), which are in excellent agreement with our control measurements. We found that fetal leucine disposal was unaffected by changing insulin concentrations from low to normal.…”

“…Other investigators (26)(27)(28) have, however, elected to consider this loss ofradioactivity part ofthe fetal disposal of leucine and calculate fetal leucine disposal before correction for transumbilical loss. In addition, the fetus receives a small amount of tracer (0-6% of the leucine lost) back across the umbilical circulation as a-ketoisocaproate, an amount that is in keeping with previous reports (27,29) and that, though minimal, we included in our calculation ofleucine disposal. Finally, the loss of labeled CO2 across the umbilical circulation is not corrected for retention in the bicarbonate pool of the fetus because Van Veen et al (30) have shown that 99.6% of '4CO2 infused into the sheep fetus is excreted across the umbilical circulation.…”

Amino Acid Metabolism in the Human Fetus at Term: Leucine, Valine, and Methionine Kinetics

“…Ovine premature fetuses showed reamination rates approximately twice the rate of leucine appearance from protein breakdown (23,24). This is in contrast with our results, where reamination rates are only one third of the proteolysis rates.…”

Uteroplacental Insufficiency Alters Liver and Skeletal Muscle Branched-Chain Amino Acid Metabolism in Intrauterine Growth-Restricted Fetal Rats

“…In a model of heat stress-induced IUGR, maternal-placental leucine flux is reduced and leucine is subsequently redirected toward fetal metabolism via decreased placental utilization and decreased leucine flux from the fetus to the placenta (36). Maternal starvation of pregnant ewes elevates fetal leucine oxidation, which is inversely correlated with fetal glucose concentration (7,9). Although both of these studies provide important physiologic insight, neither approach the organ-specific molecular biology behind their findings.…”