KINETICS OF FETAL LEUCINE AND KETOISOCAPROATE METABOLISM

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Normal fetal growth is critical to postnatal growth and development. Fetal metabolism and, in particular, energy requirements and fetal protein metabolism are directly associated with intrauterine growth. The overall objective of this proposal is to enhance our understanding of protein metabolism in the fetus during intrauterine life by assessing quantitatively the kinetics of amino acid metabolism and by characterizing the effect of metabolic changes in the mother on these indices of fetal metabolism. The endogenous flux rates of leucine as a representative essential amino acid as well as the flux rates of its ketoacid ketoisocaproic acid (KIC) and the rates of leucine carbon oxidation will be determined using a double isotope dilution technique in the chronically catheterized ovine fetus model. These dynamic quantitative aspects of amino acid metabolism will be used as kinetic indices of endogenous fetal protein metabolism in order to explore the effect of: A. Maternal fasting since fasting and undernutrition in the mother are associated with fetal growth retardation. B. Leucine infusion to the mother since leucine has been shown to play a regulatory role on protein metabolism in vitro and in vivo and therefore its effect on maternal protein metabolism may influence fetal amino acid metabolism and subsequently intrauterine growth. C. Fetal hyperinsulinemia during euglycemia as it occurs during poor control of maternal diabetes mellitus, which is associated with fetal overgrowth and metabolic changes in the fetus that are responsible for increased morbidity and mortality during intrauterine and immediate postnatal life. D. Maternal hypoglycemia as it occurs during strict control of diabetes mellitus in the mother. This study will enhance our understanding of fetal protein metabolism and the factors affecting this metabolism and possibly provide us with methods of therapeutic intervention during and following intrauterine life.