AMINO ACID REGULATION OF GLUCOSE METABOLISM IN VIVO

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DESCRIPTION (Adapted from the applicant's abstract): Glucose and amino acids are widely utilized as sole nutrients, in the form of TPN, to patients with severe stress. This has generated considerable interest in the direct interactions between glucose and insulin as well as between insulin and amino acids in modulating nutrient requirements of these patients; few studies, however, examined the direct interaction between glucose and amino acids. My preliminary data indicate that amino acids decrease the rates of glucose disposal, both insulin-dependent and insulin-independent, in man and dogs. They also imply that amino acids blunt the effectiveness of insulin on lowering hepatic gluconeogenesis and glucose production. This "detrimental" effect of amino acids on glucose metabolism contrast with the investigators previous studies (Appendix) showing a "beneficial" effect of amino acids on insulin's inhibition of proteolysis and stimulation of protein synthesis. The present application proposes to address the influence of the interaction of glucose and amino acids on glycogen deposition and nitrogen accretion to determine how amino acid infusions, in amounts similar to those used in TPN solutions, affect whole body rates of glucose production and glucose utilization. The investigator will focus on the alterations in glycogen deposition and breakdown, as well as on protein synthesis and breakdown in both muscle and liver. It is also proposed to examine whether the infusion of amino acids alters hepatic gluconeogenesis or glucose oxidation in liver and muscle. The investigator will examine the special role of branched chain and glycogenic amino acids in the composition of these solutions on these metabolic alterations. The investigator will utilize the 4 day fasted dog model which has been found to represent a state of glycogen-depletion and insulin resistance, hallmarks of the stressed patient requiring TPN for nutritional supplementation. Glucose with or without amino acids will be infused for 4 days following the initial fast at the end of which further nutritional and metabolic assessment will be documented. Glucose and amino acid kinetics will be examined utilizing isotopic techniques that are well established in the investigators laboratory. Organ balances will be used to examine amino acid, glucose, urea and oxidation by the body. These studies will thereby define interactions of amino acids and glucose on the disposition of protein and glycogen stores. Hence, by defining the mechanism responsible for the interaction of these major metabolites, optimal nutritional regimes can be defined culminating in better disease outcomes.