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The Journal of Nutrition

7th Amino Acid Assessment Workshop


Nonnutritive Effects of Glutamine
13
Erich Roth*
Surgical Research Laboratories, Medical University of Vienna, A-1090 Vienna, Austria
Abstract
Glutamine is the most abundant free amino acid of the human body. Besides its role as a constituent of proteins and its
importance in amino acid transamination, glutamine has regulatory capacity in immune and cell modulation. Glutamine
deprivation reduces proliferation of lymphocytes, inuences expression of surface activation markers on lymphocytes and
monocytes, affects the production of cytokines, and stimulates apoptosis. Moreover, glutamine administration seems to
have a positive effect on glucose metabolism in the state of insulin resistance. Glutamine inuences a variety of different
molecular pathways. Glutamine stimulates the formation of heat shock protein 70 in monocytes by enhancing the stability
of mRNA, inuences the redox potential of the cell by enhancing the formation of glutathione, induces cellular anabolic
effects by increasing the cell volume, activates mitogen-activated protein kinases, and interacts with particular aminoacyl-
transfer RNA synthetases in specic glutamine-sensing metabolism. Glutamine is applied under clinical conditions as an
oral, parenteral, or enteral supplement either as the single amino acid or in the form of glutamine-containing dipeptides for
preventing mucositis/stomatitis and for preventing glutamine-deciency in critically ill patients. Because of the high
turnover rate of glutamine, even high amounts of glutamine up to a daily administration of 30 g can be given without any
important side effects. J. Nutr. 138: 2025S2031S, 2008.
Introduction
Glutamine is a nonessential amino acid that is important as a
constituent of proteins and as a central metabolite for amino
acid transamination via a-ketoglutarate and glutamic acid. The
organ-specic role of glutamine was documented by the work
of Krebs (1) showing a different tissue distribution of the key
enzymes of glutamine metabolism, namely glutaminase (mainly
present in the liver) and glutamine synthetase (mainly present in
skeletal muscle). Glutamine is 1 of the 20 proteinogenic amino
acids and accounts for 56% of bound amino acids. In addition,
glutamine is the most abundant amino acid in blood and the free
amino acid pool of the body. It is synthesized from other amino
acids (mainly the branched-chain amino acids and glutamate) in
the cell cytoplasm.
The clinical interest in glutamine research started from 2
major ndings. Firstly, glutamine is an important metabolite in
ammonia metabolism and is crucial for ammonia detoxication.
Secondly, the metabolic research group of Bergstrom et al. (2)
showed that intracellular free glutamine of skeletal muscle is
markedly reduced in the postaggression syndrome after opera-
tion, trauma, and inammatory states. Our group reported that
in nonsurviving septic patients, the amount of free glutamine in
skeletal muscle is reduced by 90% and is a reliable prognostic
marker (3). Moreover, in the septic state, the release of glutamine
from skeletal muscle is highly stimulated and glutamine is taken
up from the intestine and from blood cells. In this respect, glu-
tamine seems to be an extremely important substrate, especially
for proliferating cells. In 1959, Eagle (4) showed that glutamine
is the most required substrate for the cultivation of cells under in
vitro conditions and surpasses the demand of glutamate consid-
erably. In other words, although glutamine is not considered an
essential amino acid in humans, it is absolutely necessary for
cultivating human cells. In the postprandial state, glutamine is
the only amino acid released from skeletal muscle, which is a
continuous producer of glutamine, even using essential amino
acids for glutamine synthesis. Therefore, it is of interest to
elucidate why glutamine seems to be so important for human
metabolism.
Special emphasis should be given to the nonnutritive function
of glutamine, as outlined in the title of this review. Principally,
nutrition is seen as a means for maintaining nitrogen and energy
balance. However, apart from their role in nitrogen and energy
homeostasis, nutrients can also serve as immune and cell regu-
lators. Glutamine is a potent immune stimulator, as demon-
strated by different in vitro and in vivo experiments (57). With
respect to the in vitro experiments, biochemical and immuno-
logical analyses under glutamine starvation have to be distin-
guished from those performed under glutamine overfeeding.
1
Published in a supplement to The Journal of Nutrition. Presented at the
conference The Seventh Workshop on the Assessment of Adequate and Safe
Intake of Dietary Amino Acids held November 23, 2007 in Tokyo. The
conference was sponsored by the International Council on Amino Acid Science
(ICAAS). The organizing committee for the workshop was David H. Baker,
Dennis M. Bier, Luc A. Cynober, Yuzo Hayashi, Motoni Kadowaki, Sidney M.
Morris Jr, and Andrew G. Renwick. The supplement coordinators were David H.
Baker, Dennis M. Bier, Luc A. Cynober, Motoni Kadowaki, Sidney M. Morris Jr,
and Andrew G. Renwick. Supplement coordinator disclosures: all of the
coordinators received travel support from ICAAS to attend the workshop.
2
Supported by Fresenius-Kabi Nutrition, Bad Homburg, Germany.
3
Author disclosure: E. Roth, attendance of the 7AAAW meeting was nanced
by the ICAAS.
* To whomcorrespondence should be addressed. E-mail: erich.roth@meduniwien.
ac.at.
0022-3166/08 $8.00 2008 American Society for Nutrition. 2025S

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Glutamine: inuence on immune cells
Lymphocytes. The importance of glutamine for the prolifera-
tion of lymphocytes was rst demonstrated by the group of
Newsholme studying the metabolism of glucose, glutamine, and
long-chain fatty acids, which were thought to function as fuel for
lymphocytes (8). Astonishingly, none of these 3 substrates was
oxidized in great quantities via acetyl groups and the common
Krebs cycle. Whereas glucose is converted almost totally into
lactate, the fatty acids are metabolized into ketone bodies. Both
lymphocytes and macrophages have high rates of glutamine
utilization. Newsholme et al. (8) explained the high rates of
glutaminolysis by the need of the cells to be provided with
metabolites for the response to an immune challenge at any time.
For lymphocytes, this need involves cell proliferation and for
macrophages, it is the synthesis of mRNA for secretory proteins,
peptide messengers, and protein receptors. Glutamine is a
known precursor in purine and pyrimidine synthesis, which
are needed rapidly when lymphocytes or macrophages are
activated. Indeed, the proliferation of lymphocytes after activa-
tion with RNA or mitogenic antibodies directed against the
cluster of differentiation (CD)3
4
(marker for mature lympho-
cytes) component of the T-cell receptor is highly dependent on
the glutamine concentration of the culture medium (9). A
glutamine dependence of lymphocytes was also shown for the
expression of the cell surface activation markers CD25
[interleukin (IL)-2 receptor a chain], CD45RO (leukocyte
common antigen), and CD71 (transferring receptor), and also
for the production of interferon g and tumor necrosis factor-a
(9). Glutamine depletion arrests the cells in 0 and 1 phase (10),
reduces lymphokine-activated killer cell activity (11), and
impairs cellular stress response (12). (Table 1).
Monocytes. Monocytes and macrophages belong to the mono-
nuclear phagocyte system, are widely distributed in normal
tissue and accumulated in inamed tissue, and play a central role
in both specic and nonspecic immunity against bacterial,
viral, and fungal infection (13,14). Secretory products of mono-
cytes and macrophages include several proteins and metabolites
such as IL, granulocyte-macrophage colony-stimulating factor,
platelet-activating factor, prostaglandins, substance P, leukotri-
enes, proteases, and complement components. A substantial
decrease in the number of functional phagocytes has been
reported in septic patients. Monocytes express major histocom-
patibility complex class II molecules which play a crucial role in
antigen presentation to T-helper lymphocytes. Recent investiga-
tions have shown that changes in major histocompatibility
complex class II expression on monocytes are indicative of
developing infections after major surgery and that fatality and
recovery rates among patients suffering frominfection, sepsis, or
active ulcerative colitis are linked to levels of human leucocyte
antigen on DR locus (HLA-DR) expression.
In an in vitro study, we investigated whether blood monocyte
marker expression and function from healthy donors are
inuenced by glutamine when lowering the glutamine concen-
tration in culture medium from 2 mmol/L to 200 mmol/L (15).
We showed that both the expression of various cell surface
molecules and the function of monocytes are regulated by
glutamine. The expression of HLA-DR, high afnity IgG Fc
receptor (FcgRI/CD64), CD11b/CD18, and complement recep-
tor 4 (CR4; CD11c/CD18) was downregulated by glutamine in a
concentration-dependent manner. However, the expression of
low afnity IgG Fc receptor (FcgRIII/CD64), as well as CD14,
the lipopolysaccharide-binding protein receptor on the mono-
cytes, and CD71, the transferrin receptor, was not affected by
lowering the glutamine concentrations.
Decreasing the concentration of glutamine from 2 mmol/L
(commonly used for in vitro cell culture) to 50 mmol/L reduced
HLA-DR expression by 58% (15). HLA-DR expression signif-
icantly decreased after lowering the glutamine concentration
from 600 mmol/L (physiological range of glutamine in the
plasma) to 200 mmol/L (plasma concentration found in critically
ill patients). Interestingly, reduced HLA-DR expression was
paralleled by the diminished capacity of monocytes to present
tetanus toxoid antigen to T cells. Intracellular adhesion molecule-
1/CD54 is involved in the costimulation of resting T-cells. The
constitutive expression of this accessory molecule on monocytes
was also signicantly downregulated by low concentrations of
glutamine.
Reduced glutamine concentrations led to a downregulation
of the molecules responsible for the phagocytic capacity of the
monocytes, such as the high afnity receptor for IgG (FcgRI/
CD64) and CR3 (CD11b/CD18). Previous in vitro studies
revealed that the ability of murine peritoneal MF to phagocy-
tose
125
I-labeled yeast cell walls (Zymosan) or
51
Cr-labeled
sheep red blood cells is dependent on the concentration of gluta-
mine (16,17). These results are in accordance with our ndings.
The phagocytosis of sensitized ox erythrocytes and opsonized
Escherichia coli was found to be glutamine dependent. However,
the phagocytosis of latex particles by human monocytes was not
inuenced by glutamine.
Cell regulative capacity of glutamine
Regulation of cell volume. There is a close relationship
between the regulation of cell volume, glutamine levels, and
TABLE 1 Cell and immune regulation by glutamine (7)
Regulation of cell functions
Precursor of purine and pyrimidine
Precursor of glutathione
Interferes with L-arginine and nitric oxide metabolism
Regulates cell size by osmosignaling
Stimulates Hsp formation
Stimulates AMP-activated protein kinase pathway
Activates extracellular signal-regulated kinases
Regulation of lymphocyte function
Stimulates Con-A- and PHA-induced proliferation
Activates the expression of CD25, CD71, and CD45RO
Stimulates interferon g secretion
Stimulates lymphokine-activated killer-cells
Inhibits apoptosis
Stimulates intestinal immunity (GALT)
Increases proportion of natural killer cells in spleen
Regulation of monocyte function
Stimulates RNA synthesis
Increases IL-1 secretion
Stimulates phagocytosis of opsonized E. coli and oxidized erythrocytes
Stimulates antigen presentation
Increases expression of surface antigens
Influences differentiation
Improves antioxidant defenses
4
Abbreviations used: AMP, adenosine-monophosphate; ASK, apoptosis signal-
regulating kinase; BW, body weight; CD, cluster of differentiation; Con-A,
concanavalin A; CR, complement receptor; FcgRI/CD54, Fc receptor for IgG;
GALT, gut associated lymphoid tissue; GSH, reduced glutathione; GSSG,
oxidized glutathione; HLA-DR, human leucocyte antigen on DR locus; Hsp,
heat shock protein; PHA, phytohaemagglutinin; PP, Peyers patches; RS,
transfer RNA synthetase; tRNA, transfer RNA.
2026S Supplement

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protein catabolism. The administration of glutamine to hepato-
cytes stimulates anabolic processes within the cell involving an
increased synthesis of DNA, RNA, and proteins (18). Further-
more, the mitogenic stimulation or immunological activation of
lymphocytes or macrophages may result from the concomitant
increase in cell volume which is related to an increase in
glutamine metabolism (19). The addition of glutamine to the
culture medium causes cell swelling. Previously, we demon-
strated that both glutamine and heat shock protein (Hsp) are
protective against hypertonic challenge in a human monocyte
cell line (U937) (20). The observed cytoprotective effect of both
Hsp and glutamine seems to result from inuencing ion
transport across the cell membrane and maintaining (protecting)
the intracellular ion milieu. Glutamine-induced cell swelling also
activates extracellular signal-regulated kinases and p38 (mitogen-
activated protein kinase). A similar relation of glutamine to
osmosignaling pathways is described also in other cell types,
including myelocytic human promyelocytic leukemia cells and
adipocytes. Therefore, it seems that the osmo-regulatory effect
of glutamine is not restricted to glutamine-consuming cells.
Stimulation of Hsp. Cells express a group of proteins that are
essential to cellular survival under stressful conditions, the Hsp
(21). Hsp70 induction protects cells against cytotoxic mediators
and reduces organ dysfunction and mortality in animal models
of sepsis (22). Under conditions with low plasma glutamine,
such as polytrauma, severe sepsis, and acute respiratory distress
syndrome, Hsp70 expression was impaired in granulocytes (23),
monocytes (24), and lymphocytes (25). Hsp70 shows a reduced
inducibility (247%) at pathological glutamine levels (0.2 mmol/L).
This indicates that glutamine-starving cells are unable to express
normal amounts of Hsp70. Proteomic analysis revealed that
especially in short-duration glutamine starvation, the protein
expression of Hsp70 is reduced. Therefore, we investigated at
which molecular level the glutamine starvation interferes with
Hsp70 expression. We tested the glutamine dependence of
transfer RNA (tRNA) association and the inuence of glutamine
on the stimulation of heat-shock factor 1 and on transcription
and translation of Hsp70 (26,27). Our results revealed that the
overall level of tRNA-bound glutamine remained unaffected as
did the formation of heat-shock factor 1 (27). Also the tran-
scriptional and the translational control of Hsp70 expression
remained unchanged. However, glutamine starvation enhanced
mRNA decay. U937 cells cultured with low amounts of
glutamine had a drastically shortened half-life of Hsp70
mRNA (45 min vs. 4 h). Therefore, in U937 cells the lower
expression of Hsp70 seems to be related to a reduced half-life of
mRNA (27). It has to be mentioned that the molecular mech-
anism responsible for the decrease in Hsp70 expression in U937
due to glutamine starvation must not be pertinent to other cell
populations such as lymphocytes or neutrophils.
The group of Wischmeyer et al. (28) investigated the role of
Hsp with respect to glutamine in sepsis and lung injury. In a
recent publication, they were able to show that glutamine
administration improved survival after cecal ligation and puncture-
induced sepsis only in wild-type mice but not in mice with a
deletion of the Hsp70 gene. These results conrm the hypothesis
that Hsp70 expression is required for the benecial glutamine
effect on survival, tissue injury, and the inammatory response
after systemic inammatory injury.
Glutathione metabolism
Glutamine (via glutamate), cysteine, and glycine are the precur-
sor amino acids for glutathione, which is present within the cell
in a reduced (GSH) and an oxidized form (GSSG). The ratio of
GSH:GSSG is the most important regulator of the cellular redox
potential. GSHsynthesis can be altered via the administration of
glutathione precursors or via the activity of GSHperoxidase and
GSH reductase. The synthesis of inammatory cytokines and
adhesion molecules is dependent on the activation of the
transcription factor nuclear factor kB, which relies on the
cellular redox potential and therefore on the intracellular ratio
of GSH:GSSG (2931). Furthermore, the SH-containing tripep-
tide glutathione is effective in the protection of SH-carrying
proteins against oxygen radicals and may thereby be especially
important for dividing cells, because they are particularly
susceptible to reactive oxygen intermediates. It should be
mentioned that the GSH concentration in cancer cells is 1050
times higher than in nonmalignant cells, which gives the cancer
cell an additional protection against oxygen radicals.
There is a signicant correlation between glutamine supply,
the rate of lymphocyte proliferation, and intracellular glutathi-
one content. The importance of glutathione for lymphocyte
function especially in HIV-infected patients was reviewed by
Dro ge et al. (32). A depletion of the intracellular glutathione
pool reduces blast transformation and the proliferation and
generation of cytotoxic T cells. Cultivation of peripheral blood
mononuclear cells with glutamine and IL-2 revealed a maximum
of growth stimulation that was accompanied by increasing
intracellular GSH content (31). A dysfunction of lymphocytes in
the septic state may be related to a 60% decreased glutathione
synthesis as shown in septic pediatric patients (33). Moreover,
glutamine is able to preserve hepatic glutathione levels after
hepatic injury (34). In recent studies, we fed mice with either
glutamine or a mixture of glutamine, glycine, arginine, and (n-3)
fatty acids (eicosapentaenoic acid, docosahexaenoic acid) and
measured the lymphocyte numbers and also the GSH content
in the spleen and in Peyers patches (PP) (35,36). We showed that
glutamine-fed mice had increased GSH content in both tissues
and that the number of lymphocytes in the PP positively cor-
related with the GSH content. The administration of buthionine
sulfoximine, an inhibitor of GSH synthesis, led to a reduced
number of lymphocytes in the PP. These studies indicated that
glutamine is an effective precursor for GSH synthesis in lym-
phocytes of PP and the spleen, which seems to be associated with
an enlarged number of lymphocytes in the respective organs.
These results are supported by in vitro experiments and in rats
after depletion of glutathione stores by diethyl maleate (37,38).
Glucose metabolism
In vitro studies as well as experiments in animals have shown
glutamine to be one of the most effective substrates for gluco-
neogenesis (39,40). Glutamine is the major gluconeogenic pre-
cursor in the kidney. In contrast to alanine, the carbon skeleton
of glutamine originates mainly from protein and other amino
acids and may therefore provide more to the new glucose pool
than alanine (41). Tracer studies revealed that nearly twice as
much of the carbon in glucose is transferred from protein-
derived glutamine than from alanine. Infusion of large amounts
of glutamine (28 g/4 h) resulting in 3-fold increased plasma
glutamine concentrations caused a 7-fold increase in glucose
formation without changes in plasma insulin and glucagon levels
(42). These results provide evidence that, in humans, glutamine
may act both as a substrate as well as a modulator of its
metabolism to glucose. In contrast, in mice genetically predis-
posed to become overweight and develop hyperglycemia, the
administration of glutamine as part of a high-fat diet reduced
body weight (BW) and attenuated hyperglycemia and hyperin-
Nonnutritive effects of glutamine 2027S

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sulinemia (43). This glucose-lowering effect of glutamine may be
in relation to the known effect of glutamine on fat metabolism
such as inhibition of fatty acid oxidation and lipolysis and is
possibly involved in the attenuation of insulin resistance induced
by fat. Therefore, it was hypothesized that glutamine may be
useful as an antiobesity and antidiabetic agent in prediabetic and
diabetic subjects. This assumption was recently conrmed in
intensive care unit patients, because parenterally administered
glutamine (in the form of alanyl-glutamine) prevented worsen-
ing of insulin sensitivity in multiple-trauma patients (44). A
possible explanation of these results would be that glutamine
improved the sensitivity of adipose tissue to insulin, decreased
lipolysis, and subsequently improved glucose metabolism.
Effect on signaling and amino acid sensing
Glutamine-utilizing cells react in a specic manner in the case of
glutamine deprivation. The data described above show that
glutamine deprivation inuences glutathione metabolism, de-
creases the mRNA half-life of Hsp70, leads to cell shrinkage,
and lowers intracellular ATP content. It remains remarkable that
the reduced concentration of 1 amino acid causes such a variety
of different effects. A possible explanation is that the signaling
pathways via AMP-activated protein kinase or mammalian
target of rapamycin seem to be inuenced by amino acid
deprivation. Furthermore, translational initiation is inuenced
by amino acid metabolism in the form of an amino acid sensing.
The existing data are mainly derived from basic research, e.g.
from yeast physiology, and must be conrmed for other cell
types. A specic way of glutamine sensing can be achieved via
aminoacyl-tRNA synthetases, which catalyze the attachment of
specic amino acids to their cognate tRNAs, thereby ensuring
the faithful translation of the genetic code. In addition to their
enzymatic function, these enzymes have been discovered to regu-
late various cellular functions such as tRNA export, ribosomal
RNA synthesis, apoptosis, inammation, and angiogenesis (45).
Various aminoacyl-tRNAsynthetase species can interact directly
with a number of different regulatory proteins: Ile-tRNA
synthetase (RS) binds to Hsp90, Lys-RS to superoxide dismu-
tase, Val-RS and His-RS to various translation factors, and
glutaminyl-RS to apoptotic signal-regulating kinase 1 (ASK1). In
the latter case, glutaminyl-RS binds directly to the catalytic
domain of ASK1, which thereby loses its ability to phosphor-
ylate c-Jun N-terminal kinase (46). The suppressive association
of glutaminyl-RS with ASK1 is controlled by the presence of
glutamine. Because glutaminyl-RS can recognize glutamine spe-
cically, it is considered a glutamine-sensor protein that renders
the ASK1 activity glutamine sensitive.
Supply of glutamine under clinical conditions
Glutamine administration can be performed orally, enterally, or
parenterally. Because glutamine is not stable in aqueous
solution, for parenteral or enteral products, stable glutamine-
containing dipeptides such as alanyl-glutamine or glycyl-glutamine
are used. Information on the maximum upper limits of gluta-
mine supply is available from clinical data and from volunteers
receiving glutamine (or the corresponding glycyl- or alanyl-
glutamine dipeptides) in dose-nding studies (Table 2).
Healthy volunteers. Wilmore et al. (47,48) infused increasing
doses of glutamine up to 0.570 gkg
21
d
21
. Plasma glutamine
concentrations increased signicantly with glutamine adminis-
tration but reached a plateau at concentrations ;25% above
control values. They reported that the diets were well tolerated
and neither ammonia nor glutamate, potentially toxic metabo-
lites of glutamine, increased signicantly.
Cancer patients. An oral glutamine dosage of 7.5 g for 3 wk
administered for preventing mucositis/stomatitis of breast can-
cer patients receiving anthracycline-based chemotherapy did not
cause any side effects but reduced the incidence of clinically
TABLE 2 Supply of glutamine under clinical conditions
Subjects
Glutamine
supply,
unit/70 kg BW
Probants,
n Administered as Mode of supply
Duration of
study
Change in
plasma
GLN, % Side effects References
Healthy 28 g/4 h 16 Glutamine Parenteral 4 h 1200 None Periello et al. (42)
Healthy volunteers 40 g/d 12 Glutamine Parenteral 5 d 125 None Lowe et al. (47)
Ziegler et al. (48)
Breast cancer 7.5 g/d 163 Glutamine Oral 3 wk n.d.
1
None Peterson et al. (49)
Metastatic cancer 30 g/d 51 Glutamine Oral 15 d n.d. None Choi et al. (50)
Colorectal cancer 30 g/d 86 Glutamine Oral 7 d n.d. None Wang et al. (51)
Cancer/intestinal
failure
20 g/d 7 Glutamine Home parenteral 4 wk n.d. Elevated liver
enzymes
in 3/7
Hornsby-Lewis et al. (52)
Liver diseases 11.2 g/4 h 16 Glycyl-glutamine Enteral vs. parenteral 4 h n.d. Increased NH
3
levels
Plauth et al. (53)
Polytrauma 28 g/d 9 Glycyl-glutamine Parenteral 3 d 170 None Weingartmann et al. (54)
Critically ill 24 g/4 h 20 Alanyl-glutamine Parenteral peripher 3 d 1200 None Berg et al. (55)
Head trauma 24 g/20 h 8 Alanyl-glutamine Parenteral 20 h n.d. None Berg et al. (56)
Postoperative 30 g/d 14 Alanyl-glutamine 1 glycyl-
glutamine
Enteral 5 d n.d. Nausea hiccups
flatulence
in 3/14
Schroeder et al. (57)
Postoperative 30 g/d 20 Alanyl-glutamine 1 glycyl-
glutamine
Enteral 3 d n.d. None Senkal et al. (58)
Postoperative,
posttraumatic
42 g/d 61 Glutamine Enteral 3 d n.d. None Schulman et al. (59)
1
n.d., Not determined.
2028S Supplement

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signicant oral mucositis (49). In another study, patients with
advanced or metastatic cancer receiving uorouracil/leucovorin
in chemotherapy were supplemented with glutamine at 30 g/d
for 15 d for preventing mucositis/stomatitis (50). In this study, a
reduction of mucositis/stomatis was also observed without any
side effects attributable to glutamine supplementation. Similarly,
30 g oral glutamine given daily to colorectal cancer patients
receiving oxaliplatin reduced the incidence and severity of
peripheral neuropathy and also did not cause any side effects
(51). In a mixed patient group (cancer or intestinal failure) on
home total parenteral nutrition due to colon resection or
inammatory enteropathy, the parenteral infusion of glutamine
at a dose of 0.285 g/kg BW (equivalent to 20 g/70 kg BW) for
4 wk resulted in the elevation of liver enzymes in 3 patients
(52). Those abnormities subsided after discontinuation of the
glutamine-total parenteral nutrition administration. Interest-
ingly, during the course of the study, plasma levels of glutamine
did not increase. Therefore, it seems questionable whether the
increase in liver enzymes was due to glutamine or to the
concomitant overload of fat application [(n-6) fatty acids] or
glucose supply. Both factors increase liver enzymes under certain
conditions. Interestingly, the 3 patients received a rather high
level of total energy (2888, 2574, and 2314 kcal
5
, respectively),
which, rather than the glutamine supplementation, may have
triggered the deterioration of hepatic metabolism.
Patients with liver failure. Patients with liver diseases seem to
be more sensitive to glutamine administration. In cirrhotic
patients (pre- and postliver transplantation), the administration
of 10 g glutamine signicantly increased venous blood ammonia
and impaired reaction time following oral glutamine challenge
(60). We compared enteral and parenteral glutamine supply in
patients with transjugular intrahepatic portosystemic shunt and
liver cirrhosis and measured mesenteric venous-arterial concen-
tration differences of ammonia and glutamine (53). Our data
demonstrated that enteral glutamine supply resulted in a higher
portal ammonia load and a higher degree of systemic hyperam-
monemia. Therefore, oral/enteral glutamine administration can
signicantly affect ammonia metabolism in patients with an
impaired liver function and therefore inuence hepatic coma.
Recent publications propose that elevation in plasma and brain
glutamine levels associated with hepatic failure may, by
increasing g-aminobutyric acid release, produce some of the
manifestations of hepatic encephalopathy (61,62).
Critically ill patients. Both enteral and parenteral supply of
glutamine (dipeptides) was investigated in critically ill patients.
Our group infused increasing daily dosages of glycyl-glutamine up
to 570 mg glycyl-glutamine (equivalent to 28 g glutamine for a
70-kg BW patient) in polytraumatized patients (54). This dosage
caused a sustained rise in arterial glutamine concentrations, which
remained stable during the 4-d study period. No pathological
accumulation of free glycine or the dipeptide was detected and no
side effects occurred. The group of Wernerman et al. (55,63)
performed extensive studies on the safety of alanyl-dipeptide
infused to severely ill patients. In this respect, it was shown that the
infusion of 0.5 g/kg alanyl-glutamine (equivalent to 27 g gluta-
mine/70 kg BW) over 4 h in a peripheral vein on 3 consecutive
days was safe and did not cause thrombophlebitis. Patients on
continuous renal replacement therapy were also not affected by i.v.
glutamine supplementation (64). Glutamine infusions to neuro-
surgical patients were questioned, because glutamine is a precur-
sor of glutamate that may evoke adverse effects by accumulation
in the brain. However, the group of Jan Wernerman could
demonstrate that even high amounts of alanyl-glutamine infusions
(0.34g/kg BWof glutamine in 20 h) to head trauma patients leaves
the cerebral glutamate concentration unaffected (56).
Three different groups examined the safety of a high dose of
enteral glutamine-dipeptide supply in postoperative and criti-
cally ill patients. Administration of 30 g glutamine in the formof
glutamine dipeptides (together with a special mixture of
antioxidants) for 5 d to patients after upper gastrointestinal
surgery was well tolerated and metabolically safe (57). Only
minor signs of nausea, hiccups, and atulence (3/14 patients)
were observed. Similarly, administration of the same mixture (a
supplement of Fresenius) to postoperative cancer patients had no
adverse effects on organ functions and hematology (58). In
critically ill patients, a mean daily dose of 0.6 g/(kg BW
21
d)
(42 g glutamine/70 kg BW) did not inuence the acquisition or
characteristics of infections. Again, no adverse effects of high
dose enteral glutamine supply were identied (59). In conclu-
sion, enteral administration of glutamine up to a daily dose of
42 g/70 kg or of 35 g/(70 kg
21
d) in dipeptide form seems to be
safe in critically ill patients.
In summary, the results of recently performed studies conrm
former investigations summarized in 2 earlier reviews (65,66),
that acute administration of glutamine in a dose up to 3040
g/70 kg BW is safe when given for a number of weeks. However,
no data are yet available about chronic consumption of
glutamine by healthy subjects of all age groups. Scientic data
about nonnutritive effects of glutamine as presented in this
review demonstrate the great variety of cell- and immune-
modulating capacity of glutamine. Because of the described
negative effects of glutamine starvation, a shortage of gluta-
mine in clinical conditions should be avoided. Oudemans-van
Straaten et al. (67) have demonstrated that plasma glutamine
depletion is an independent outcome factor in critically ill
patients. Therefore, to support the cellular defense mechanism,
an exogenous glutamine supply seems to be necessary in the case
of reduced plasma glutamine levels (68). However, up to now, no
data support an advantage of glutamine supplementation to
people with normal plasma glutamine concentrations.
Other articles in this supplement include references (6979).
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