Essential amino acids in the diet provide replacement for obligatory amino acid losses in protein turnover and amino acid for protein accretion in growth. Unlike other essential amino acids, the branched-chain amino acids (BCAA's), leucine, isoleucine, and valine, are catabolized at extra-hepatic site and serve as a fuel source for skeletal muscle and other tissues. Because the first step in BCAA metabolism is reversible transamination to the branched-chain keto acids (BCKA's) the BCKA's may substitute for the BCAA's in the diet. For these reasons, BCAA and BCKA dietary supplementation has been proposed for treating diseases of hypermetabolism involving accelerated nitrogen loss (stress and trauma) or diseases requiring reduced nitrogen intake (chronic renal failure) even though our understanding of the role of human gut and liver in BCAA metabolism--especially in relation to processing of dietary BCAA's and BCKA's and the bioavailability of these dietary compounds for peripheral tissue utilization--is weak. Using simultaneous infusion of intravenous (i.v.) and intragastric (i.g.) leucine and ketoisocaproate (KIC) stable isotopically labeled tracers, the amount of dietary leucine and KIC removed by gut and liver on the 1st pass during absorption of the nutrients will be determined. This approach will also define the fates of the sequestered leucine and KIC in gut and liver and will investigate factors that improve or diminish bioavailability of the BCAA's an BCKA's to peripheral tissues. The non-essential amino acids glutamine and alanine are produced and released by skeletal muscle in quantities far greater than that of other amino acids. In a hypermetabolic state, glutamine production is further increased, but so is glutamine utilization. Nutritional supplementation of glutamine or glutamate to satisfy the increased demand should be investigated, but understanding the metabolic purpose of the glutamine and glutamate and the roles that gut and liver play in processing dietary glutamine and glutamate comes first. Using simultaneous i.g. and i.v. trace infusions of 15N-labeled glutamine and glutamate, the 1st pass removal and metabolic processing by gut and liver will be investigated. Finally, metabolic regulation of amino acid and protein is influenced by hormone secretion. In hypercatabolic disease states several hormone levels are elevated simultaneously. Specific metabolic effects can be assigned to individual hormones in terms of energy, fatty acid and carbohydrate metabolism. However, the role of hormones in altering human amino acid metabolism is more poorly characterized, especially for the catecholamines and cortisol. The dose response of amino acid kinetics assessed with stable isotope tracers to well-defined elevations of epinephrine and cortisol in the physiological range in normal subjects will be investigated. The results from these studies will be meshed with prior results for insulin and glucagon to produce a composite picture of amino acid regulation by circulating hormones.
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