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Supplement

Session II: Physiological Aspects of Glutamine Metabolism I— Discussion Summary¹

UTMB Shriners’ Burns Hospital, Galveston TX 77550

	INTRODUCTION

TOP INTRODUCTION LITERATURE CITED

 
Dr. Wolfe.

The major focus of this session has been the control of glutamine metabolism at the physiologic level, including its production, transport and interorgan movement.

Dr. Bier implied in his discussion of interorgan movement of glutamine that rapid utilization of glutamine, (e.g., by the immune system) causes increased release from the large reserve of free glutamine from the intramuscular pool. This implies that the release of glutamine from muscle must be sensitive to the plasma glutamine concentration because this would presumably be the mechanism responsible for the "pulling out" of intramuscular glutamine. Empirical observations are consistent with this general notion because the plasma glutamine concentration is usually close to normal even in patients with 90% depletion of the intramuscular pool. I would therefore like to ask Dr. Rennie and Dr. Bode if this physiologic observation is consistent with what is known about the regulation of the glutamine transporter?

A second general area of discussion is the control of glutamine production in vivo. The earlier presentation by Dr. Abcouwer gave us greater insight into the control of glutamine synthetase activity, yet it is uncertain whether enzyme activity in fact limits glutamine production under physiologic and pathologic conditions. In that regard, it is pertinent to consider glutamine production in relation to alanine production. A viable hypothesis is that in vivo glutamine production is determined largely by the availability of glutamate, which in turn is determined by the availability of pyruvate. Thus, when pyruvate is abundantly available, glutamate preferentially transaminates pyruvate to form alanine and -ketoglutarate, thereby limiting the availability of glutamate as a precursor for glutamine synthesis.

Finally, it is pertinent to consider the issue of whether intramuscular glutamine concentration affects the rate of muscle protein synthesis. This provocative notion was put forward almost 20 years ago, but has still not been tested directly. Part of the problem is that it is very difficult to replete muscle glutamine by nutritional intake. Splanchnic clearance of ingested glutamine is extensive, and muscle glutamine uptake from plasma is very low.

Dr. Bode.

Animal studies show that it is very difficult to increase blood levels of glutamine. Consequently, in patients, it is difficult to determine whether the depletion of muscle glutamine causes a suppression of protein synthesis. Perhaps, in this circumstance, the muscle will take up only glutamine if there is a concurrent anabolic signal, such as insulin. Additionally, there may be a specific signal to the transporter to pump glutamine in, rather than out. The altered transport in patients may result from changes in the physiologic properties of the cell membrane, such as the transmembrane electrical potential. This type of regulation is more likely than glutamine concentration, per se, regulating transport.

Dr. Rennie.

I think it is possible that control of muscle glutamine release is more complex than a simple "pull" from extra glutamine utilization elsewhere in the body. For example, under some circumstances, such as in acute acidosis, there could be excessive glutamine release from muscle that causes blood glutamine to increase. In other cases, excessive glutamine utilization in the liver could pull glutamine out of muscle.

Dr. Matthews.

Because the uptake of plasma glutamine by muscle is so limited, perhaps we should be trying to increase muscle glutamine by stimulating its synthesis in muscle.

Dr. Wolfe.

We have in fact shown that we could increase muscle glutamine levels in depleted burn patients by decreasing pyruvate availability by giving dichloroacetate. The decease in pyruvate availability limited the production of alanine from transamination, thereby increasing glutamate availability for glutamine synthesis. I am not sure of the role of glutamine synthetase activity in this response.

Dr. Abcouwer.

Changes in the amount of muscle glutamine synthetase are slow, requiring in the 6- to 10-h range. Up-regulation of the mRNA for the enzyme may require even more time.

Dr. Watford.

I agree that acute regulation of glutamine synthesis probably occurs independently of changes in glutamine synthetase activity because we have estimated previously that there is a vast excess of enzyme for any flux rate in vivo. A central question concerns the biochemical pathway for glutamine synthesis. What are the precursors for glutamate and ammonia?

Dr. Reeds.

I think identifying the source of ammonia is central to understanding the control of glutamine synthesis. It may be that in traumatic states, the flow of precursors into the system limits the synthesis of glutamine.

Dr. Souba.

The notion of a link between muscle protein catabolism and glutamine synthesis would explain why pharmacologic stimulation of net muscle protein synthesis (e.g., with growth hormone) might decrease muscle glutamine. Thus, decreased precursor availability limits glutamine synthesis.

Dr. Wolfe.

This interpretation fits with a recent paper by Biolo et al. (2000) , in which treatment of critically ill patients with growth hormone caused a fall in glutamine concentration. It may be that glutamine supplementation is appropriate when muscle protein synthesis is stimulated by a pharmacologic/hormonal treatment.

	FOOTNOTES

 
¹ Presented at the International Symposium on Glutamine, October 2–3, 2000, Sonesta Beach, Bermuda. The symposium was sponsored by Ajinomoto USA, Incorporated. The proceedings are published as a supplement to The Journal of Nutrition. Editors for the symposium publication were Douglas W. Wilmore, the Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School and John L. Rombeau, the Department of Surgery, the University of Pennsylvania School of Medicine.

	LITERATURE CITED

TOP INTRODUCTION LITERATURE CITED

 

1. Biolo G., Iscra F., Bosutti A., Toigo G., Ciocchi B., Geatti O., Gull A. & Guarnieri G. (2000) Growth hormone decreases muscle glutamine production and stimulates protein synthesis in hypercatabolic patients. Am. J. Physiol. 279:E323-E332.[Abstract/Free Full Text]

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