Clinical Use of Glutamine

Glutamine is a neutral amino acid that is electrophysiologically inert (1). Glutamine is by far the most abundant free amino acid in plasma and tissues in humans and plays a number of important physiological roles (2,3,4). In skeletal muscle glutamine alone accounts for more than 60% of the free amino acid pool (5).

Glutamine is an important conditionally essential amino acid with roles related with the immune response to muscle damage, and is also utilized as an energy source by lymphocytes and macrophages (6). Glutamine is also a component of cerebrospinal fluid, intestinal mucose and imunne cells as an energy substrate, and also serves as a nitrogen shuttle.

Plasma concentrations are between 400 and 600 ยตmol/l. Tissue concentrations vary between 2 and 20 mmol/l intracellular water (7). In intracellular water of enterocytes glutamine concentrations range between 2 and 4 mmol/l (8). For muscle and liver the concentrations range between 5 and 20 mmol/l (7,9).

Most of the glutamine synthesis occurs in skeletal muscle, which then gets released into plasma at high rates. In skeletal muscle, glutamine helps buffer acids and build glycogen (10,11) and protein (12). However, glutamine alone is no better than glucose alone at restoring muscle glycogen after glycogen-depleting exercise (11) and adding glutamine to essential amino acids and carbohydrate does not enhance muscle glycogen or protein synthesis after glycogen depleting endurance exercise (13).

Glutamine can also increase cell volume (14). Given the roles in immunity and anabolism, glutamine was advanced, or shall we say promoted as a vital supplement for endurance athletes (15,16) because plasma glutamine levels tend to be decreased for a few hours after prolonged exercise.

L-glutamine supplementation can restore plasma glutamine concentrations and improve systemic immune system function (17,18). Although the data is overall weak, some research supports positive effects of glutamine on immune function and the prevention of upper respiratory tract infections (19,20,21). These possible advantages explain in part the increase in popularity of glutamine supplementation for strength and endurance athletes.

On the other hand, few studies support the effectiveness on improving muscle function and reducing muscle soreness (22,23). There is no compelling evidence to support glutamine supplementation in terms of increasing lean body mass (24).

Clinical use of glutamine (Illness or trauma)

In diseased populations, or after trauma or surgery there’s an increased amount of free amino acids mobilized from skeletal muscle (25,26). A decrease in free glutamine concentration in skeletal muscle is very indicative of whole body protein catabolism (27,28,29). The same reduction in muscle glutamine is also observed after 3 days of total starvation (30).

Severe illness results in wasting of muscle mass and when prolonged, muscle loss can be extensive (31,32): a loss of lean body mass can occur after a few days of a major burn (33,34); a loss of lean body mass exceeding 15% of total weight results in a decrease in wound healing; a loss of 30% results in increased infections, severe weakness, skin breakdown and no wound healing (35); and in extreme cases 40% loss of lean body mass resulting in death usually from pneumonia (36).

An inevitable loss of lean body mass between 10-15% or more can occur over several weeks, but even though the cells are primed for anabolism after the injury or disease is resolved (37), the rate of lean mass gain or protein restoration is much slower than the loss (34,37).


Solid black line: control group, received no extra parenteral nutrition support; Broken line: received a full course of Total Parenteral Nutrition that began upon admission to the hospital 3 weeks after onset of the acute attack and continued perioperatively until 14 days postoperation (37).

Nevertheless, the release of amino acids from muscle during illness is considered essential for recovery, wound healing, immune response and energy requirements (38), with the two main amino acids released from muscle being alanine and glutamine (39). Alanine is mainly used by the liver to form glucose and glutamine and is required for cellular proliferation (40), fuel for the gut and is important for maintaining gut integrity from endotoxin translocation (41).

In severe burn patients there’s alterations in muscle glutamine transport with a significant increase in the unidirectional transport of glutamine from muscle leading to a fall in muscle glutamine concentrations (36). There is also accelerated production and release of alanine. Pyruvate is transminated with glutamate to form alanine, and glutamine is formed from glutamate and ammonia, thus the glutamate depletion to form alanine can limit the rate of glutamine synthesis (42). Other measurements also show an increased net release of glutamine from muscle, with reduced rates of glutamine transport and turnover within muscle tissue (43).

These changes in muscle glutamine metabolism could suggest a possible metabolic adaptation of muscle to prolong depletion of glutamine; the decrease in the rate of glutamine synthesis may limit further loss of muscle (44,45). On the other hand, healthy individuals with glutamine availability show a reciprocal decrease in glutamine production in muscle indicative of an appropriate feedback response to increased glutamine availability (46).

Nevertheless, in critical illness visceral consumption of glutamine remains high as glutamine availability decreases even though there’s an improved efficiency in glutamine transport out of muscle (36,47).

Increases in intramuscular sodium concentration, blood cortisol, adrenaline, glucagon, and decreases in plasma insulin, or exposure to endotoxin could all result in a decrease of intramuscular glutamine concentration (48).

Parenteral vs. Enteral

The choice of feeding route results in different metabolic handling of glutamine.


Positive effects from glutamine on catabolism (anti-catabolism) are only seen when it is administered via parenteral (intravenous) nutrition and in diseased populations, after surgery (49) or in response to trauma, acute stress, infection, and burns (36,50).

The plasma response of glutamine is more pronounced when parenterally administered than when enterally administered (51). Anabolic effects of parenteral glutamine feeding were seen in experimental animals (52,53) and in humans (54,55).


In one study when administered via the enteral (oral) route glutamine was entirely metabolized in the splanchnic (gut) compartment and didn’t have a discernable effect on whole-body protein and nitrogen kinetics (56). After a Ala-Gln dipeptide was enterally supplied a large part of glutamine was probably metabolised in the splanchnic area (51).

The glutamine in circulation is taken up by the small intestine (57,58), specially by the mucosa which uses glutamine as a substrate for energy production even in the presence of glucose (59). The total splanchnic use of enterally supplied glutamine is likely to represent 50–70% of glutamine ingestion (60,61), and is also used by the liver for gluconeogenesis in the fasted state.

Would you like to know more? Subscribe!

1. Bradford HF, McIlwain H. Ionic basis for the depolarization of cerebral tissues by excitatory acidic amino acids. J Neurochem 1966;13:1163-1177.
2. Kreider RB: Dietary supplements and the promotion of muscle growth with resistance exercise. Sports Med 1999, 27(2):97-110.
3. Garlick PJ: The role of leucine in the regulation of protein metabolism. J Nutr 2005, 135(6 Suppl):1553S-6S.
4. Smith RJ. Glutamine Metabolism and Its Physiologic Importance. JPEN J Parenter Enteral Nutr July 1990 vol. 14 no. 4 suppl 40S-44S
5. Bergstrom J, Furst P, Noree L-O, et al: Intracellular free amino acid concentration in human muscle tissue. J Appl Physiol 36:693- 697, 1974
6. Gleeson, M., Walsh, N. P., Blannin, A. K., Robson, P. J., Cook, L., Donnelly, A. E. et al. (1998). The effect of severe eccentric exercise-induced muscle damage on plasma elastase, glutamine and zinc concentrations. Eur.J Appl.Physiol Occup.Physiol, 77(6), 543-546. doi:10.1007/s004210050373
7. Vinnars E, Bergstom J, Furst P: Influence of the postoperative state on the intracellular free amino acids in human muscle tissue. Ann Surg 1975; 182: 665–671.
8. Hulsewe KW, van der Hulst RW, van Acker BA, von Meyenfeldt MF, Soeters PB: Inflammation rather than nutritional depletion determines glutamine concentrations and intestinal permeability. Clin Nutr 2004; 23: 1209–1216.
9. Haussinger D, Soboll S, Meijer AJ, Gerok W, Tager JM, Sies H: Role of plasma membrane transport in hepatic glutamine metabolism. Eur J Biochem 1985; 152: 597–603
10. Varnier M, Leese GP, Thompson J, Rennie MJ: Stimulatory effect of glutamine on glycogen accumulation in human skeletal muscle. Am J Physiol 1995, 269:E309-15.
11. J. L. Bowtell, K. Gelly, M. L. Jackman, A. Patel, M. Simeoni, M. J. Rennie. Effect of oral glutamine on whole body carbohydrate storage during recovery from exhaustive exercise. Journal of Applied Physiology Published 1 June 1999 Vol. 86 no. 6, 1770-1777
12. R. G. Hankard, M. W. Haymond, D. Darmaun. Effect of glutamine on leucine metabolism in humans. American Journal of Physiology - Endocrinology and Metabolism Published 1 October 1996 Vol. 271 no. 4, E748-E754 DOI:
13. Wilkinson SB, Kim PL, Armstrong D, Phillips SM. Addition of glutamine to essential amino acids and carbohydrate does not enhance anabolism in young human males following exercise. Appl. Physiol. Nutr. Metab. 2006; 31:518Y29
14. Roth E. Nonnutritive Effects of Glutamine. J Nutr. 2008 Oct;138(10):2025S-2031S.
15. Gleeson M. Dosing and efficacy of glutamine supplementation in human exercise and sport training. J. Nutr. 2008; 138:2045SY9.
16. Hiscock N, Pedersen BK. Exercise-induced immunodepression V plasma glutamine is not the link. J. Appl. Physiol. 2002; 93:813Y22.
17. Castell, L. M. (2003). Glutamine supplementation in vitro and in vivo, in exercise and in immunodepresion. Sports Medicine 33(5), 323-345.
18. Kuhn, K. S., Muscaritoli, M., Wischmeyer, P., & Stehle, P. (2010). Glutamine as indispensable nutrient in oncology: experimental and clinical evidence. Eur.J Nutr., 49(4), 197-210. doi:10.1007/s00394-009-0082-2
19. Castell LM. Can glutamine modify the apparent immunodepression observed after prolonged, exhaustive exercise? Nutrition 2002;18(5):371-375.
20. Krzywkowski K, Petersen EW, Ostrowski K, Kristensen JH, Boza 1, Pedersen BK. Effect of glutamine supplementation on exercise-induced changes in lymphocyte function. Am J Physiol Cell Physiol 2001;281(4):CI259- 1265.
21. Miller A1. Therapeutic considerations of L-glutamine: a review of the literature. Altern Med Rev 1999;414):239-248.
22. Rahmani, N. F., Farzaneh, E., Damirchi, A., & Shamsi, M. A. (2013). Effect of L-glutamine supplementation on electromyographic activity of the quadriceps muscle injured by eccentric exercise. Iran J Basic Med Sci, 16(6), 808-812.
23. Street, B., Byrne, C., & Eston, R. (2011). Glutamine supplementation in recovery from eccentric exercise attenuates strength loss and muscle soreness. Journal of Exercise Science and Fitness 9(2), 116-122.
24. Candow DG, Chilibeck PD, Burke DG, Davison KS, Smith-Palmer T: Effect of glutamine supplementation combined with resistance training in young adults. Eur J Appl Physiol 2001, 86(2):142-9.
25. Clowes G, Randall HT, Cha C-J. Amino acid and energy metabolism in septic and traumatized patients. JPEN 1980; 4:195-205.
26. Aulick LH, Wilmore DM. Increased peripheral amino acid release following burn injury. Surgery 1979; 85:560-565.
27. Bergstr6m J, Furst P, Nor6e L-O, Vinnars E. Intracellular free amino acid concentration in human muscle tissue. J Appl Physiol 1974; 36:693-696
28. Vinnars E, Furst P, Liljedahl S-O, et al. The effect of parenteral nutrition on intracellular free amino acid concentration. JPEN 1980; 4:184-187
29. Roth E, Funovics J, Muhlbacher F, et al. Metabolic disorders in severe abdominal sepsis: glutamine deficiency in skeletal muscle. Clin Nutr 1982; 1:25-41   
30. Vinnars E, Bergstr6m J, Furst P. Effects of starvation on plasma and muscle amino acid concentrations in normal subjects. Clin Nutr 1987; 7 (suppl):62   
31. Biolo G, Toigo G, Ciocchi B, et al: Metabolic response to injury and sepsis: Changes in protein metabolism. Nutrition 13:52S–57S, 1997
32. Demling RH, Seigne P: Metabolic management of patients with severe burns. World J Surg 24:673–680, 2000
33. Newsome, T., Mason, A., and Pruitt, B.: Weight loss following thermal injury. Ann. Surg. 178:215, 1973
34. Wolf, R.: Relation of metabolic studies to clinical nutrition: the example of bum injury. Am. J. Clin. Nutr. 64:800, 1996
35. Pollack, S.V.: Wound healing; a review of nutritional factors affecting wound healing. J. Dermatol. Surg. Oncol. 5:615, 1979
36. Mittendorfer B, Gore DC, Herndon DN, Wolfe RR. Accelerated glutamine synthesis in critically ill patients cannot maintain normal intramuscular free glutamine concentration. J Parent Ent Nutr 1999;23: 243-52.
37. Hill, G.L.: Body composition research: implications for the practice of clinical nutrition. J.P.E.N. 16:197-218, 1992
38. Wernerman J: Session on protein metabolism in stress and severe illness. Protein wasting in severe illness: Pathogenesis and therapy. Diabete Nutr Metab 13:21–24, 2000
39. Garber AJ, Karl IE, Kipnis DM: Alanine and glutamine synthesis and release from skeletal muscle. I: Glycolysis and amino acid release. J Biol Chem 251:826–829, 1976
40. Levintow L, Eagle H, Piez KA: The role of glutamine in protein biosynthesis in tissue culture. J Biol Chem 227:929–941, 1957
41. O’Dwyer ST, Smith RJ, Hwang TL, et al: Maintenance of small bowel mucosa with glutamine-enriched parenteral nutrition. JPEN 13:579–585, 1989
42. Wolfe RR, Jahoor F, Herndon DN, et al: Isotopic evaluation of the metabolism of pyruvate and related substances in normal adult volunteers and severely burned children: Effect of dichloroacetate and glucose infusion. Surgery 110:54–67, 1991
43. Gore DC, Wolfe RR. Glutamine supplementation fails to affect muscle protein kinetics in critically ill patients. JPEN J Parenter Enteral Nutr. 2002 Nov-Dec;26(6):342-50.
44. Essen P, McNurlan MA, Wernerman J, et al: Short-term starvation decreases skeletal muscle protein synthesis rate in man. Clin Physiol 12:287–299, 1992
45. Goodman MN, McElaney MA, Ruderman NB: Adaptation to prolonged starvation in the rat: Curtailment of skeletal muscle proteolysis. Am J Physiol 241:E321–E327, 1981
46. Hankard RG, Darmaun D, Sager BK, et al: Response of glutamine metabolism to exogenous glutamine in humans. Am J Physiol 269:E663–E670, 1995
47. Gore DC, Jahoor F: Glutamine kinetics in burn patients: Comparison with hormonally induced stress in volunteers. Arch Surg 129:1318–1323, 1994
48. Rennie MJ, Hundal HS, Babij P, MacLennan P, Taylor PM, Watt PW. Characteristics of a glutamine carrier in skeletal muscle have important consequences for nitrogen loss in injury, infection, and chronic disease. Lancet 1986;2:1008-12.
49. Hammarqvist F, Wernerman J, Ali R, von der Decken A, Vinnars E. Addition of glutamine to total parenteral nutrition after elective abdominal surgery spares free glutamine in muscle, counteracts the fall in muscle protein synthesis, and improves nitrogen balance. Annals of Surgery. 1989;209(4):455-461.
50. Biolo G, Fleming RYD, Maggi SP, Nguyen TT, Herndon DN, Wolfe RR. Inhibition of muscle glutamine formation in hypercatabolic patients. Clin Sci 2000;99:189-94.
51. Gerdien C. Melis, Petra G. Boelens1, Joost R. M. van der Sijp1, Theodora Popovici2, Jean-Pascal De Bandt,
Luc Cynober and Paul A. M. van Leeuwen. The feeding route (enteral or parenteral) affects the plasma response of the dipetide Ala-Gln and the amino acids glutamine, citrulline and arginine, with the administration of Ala-Gln in preoperative patients. British Journal of Nutrition (2005), 94, 19–26
52. Johnson DJ, Jiang ZM. Colpoys M. et al: Branched chain amino acid uptake and muscle free amino acid concentrations predict postoperative muscle nitrogen balance. Ann Surg 204:513-523, 1986
53. O’Dwyer ST, Smith RJ. Hwang TL, et al: Maintenance of small bowel mucosa with glutamine-enriched parenteral nutrition. JPEN 13:579-585, 1989
54. Stehle P, Mertes N, Puchstein CH, et al: Effect of parenteral glutamine peptide supplements on muscle glutamine loss and nitrogen balance after major surgery. Lancet 1:231-233, 1989
55. Hammarqvist F, Wernerman J, Ali R, et al: Addition of glutamine to total parenteral nutrition after elective abdominal surgery spares free glutamine in muscle, counteracts the fall in muscle protein synthesis, and improves nitrogen balance. Ann Surg 209:455-461, 1989
56. Parimi PS, Devapatla S, Gruca LL, Amini SB, Hanson RW, Kalhan SC. Effect of enteral glutamine or glycine on whole-body nitrogen kinetics in very-low-birth-weight infants. Am J Clin Nutr. 2004 Mar;79(3):402-9.
57. Souba WW, Smith RJ, Wilmore DW. Glutamine metabolism by the intestinal tract. JPEN 1985; 9:608-617.
58. Souba WW, Scott TE, Wilmore DW. Intestinal consumption of intravenously administered fuels. JPEN 1985; 9:18-22.
59. Windmueller HO, Spaeth AE. Uptake and metabolism of plasma glutamine by the small intestine. J Biol Chem 1974; 249:5070- 5079.  
60. Darmaun D, Matthews DE & Bier DM (1986) Glutamine and glutamate kinetics in humans. Am J Physiol 251, E117–E126.
61. Matthews DE, Marano MA & Campbell RG (1993) Splanchnic bed utilization of glutamine and glutamic acid in humans. Am J Physiol 264, E848–E854