During severe acute or chronic illness, protein wasting occurs and is associated with increased morbidity and mortality from muscle wasting and impaired immune function. Preservation of body protein under such circumstances may have clinical importance. The overall purpose of these studies is to test the hypothesis that glutamine has a protein anabolic effect in humans. Although glutamine is the most abundant amino acid in the body and can be synthesized de novo, muscle free glutamine pool can be depleted with stress and protein wasting diseases, and replenishment of the glutamine stores is associated with improved nitrogen balance in such conditions. Using isotopic techniques developed in our lab, we have obtained preliminary data suggesting that in healthy humans: 1) 30-5O% of glutamine turnover is either partially or totally oxidized; 2) the splanchnic bed is a prominent site of glutamine uptake; and 3) enteral glutamine acutely decreases the rate of whole body leucine oxidation and increases nonoxidative leucine disposal (NOLD), an index of whole body protein synthesis. The direction and magnitude of glutamine's anabolic effect were similar to those described with growth hormone (GH) administration; yet it remains to be established whether the anabolic effect of glutamine is mediated by GH. Conversely, although glutamine has the highest concentration of all amino acids in plasma, it is not known whether acute decreases in plasma glutamine concentration cause protein catabolism. Finally, it remains to be determined whether glutamine can stimulate protein synthesis under conditions of hypercatabolism such as that induced by glucocorticoids. The proposed studies will use infusions of stable and radioactive tracers of leucine and glutamine to determine in vivo in healthy humans: 1) whether glutamine stimulates GH secretion; 2) whether an acute decrease in plasma glutamine concentration--induced by the drug phenylbutyrate--has a protein catabolic effect; 3) whether enteral glutamine can alter the catabolic response to glucocorticoids; and 4) whether an acute decrease in plasma glutamine concentration enhances the protein catabolic response to glucocorticoids. These studies will expand our understanding of the physiologic role of glutamine in protein metabolism. In addition, should these studies provide evidence for an anabolic role of glutamine in humans, they would support the use of enteral or parenteral glutamine supplementation as an effective, inexpensive means of preserving body protein stores, and, potentially, decrease the morbidity and mortality of severe illness.
