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The Route of Administration (Enteral or Parenteral) Affects the Conversion of Isotopically Labeled L-[2-15N]Glutamine Into Citrulline and Arginine in Humans
Gerdien C. Ligthart-Melis, RD, MSc*, ,
Marcel C. G. van de Poll, MD ,,
Cornelis H. C. Dejong, MD, PhD,
Petra G. Boelens, MD, PhD*,
Nicolaas E. P. Deutz, MD, PhD and
Paul A. M. van Leeuwen, MD, PhD*
From the * Department of Surgery, VU University
Medical Center, Amsterdam, The Netherlands; and the
Department of Surgery, University Hospital
Maastricht, Nutrition and Toxicology Research Institute Maastricht (NUTRIM),
Maastricht, The Netherlands
Correspondence: Paul A. M. van Leeuwen, MD, PhD, Department of Surgery, VU
University Medical Center, Amsterdam, The Netherlands. Electronic mail may be
sent to
pam.vleeuwen{at}vumc.nl.
Background: Glutamine exhibits numerous beneficial effects in
experimental and clinical studies. It has been suggested that these effects
may be partly mediated by the conversion of glutamine into citrulline and
arginine. The intestinal metabolism of glutamine appears to be crucial in this
pathway. The present study was designed to establish the effect of the feeding
route, enteral or parenteral, on the conversion of exogenously administered
glutamine into citrulline and arginine at an organ level in humans, with a
focus on gut metabolism. Methods: Sixteen patients undergoing upper
gastrointestinal surgery received an IV or enteral (EN) infusion of
L-[2-15N]glutamine. Blood was sampled from a radial
artery and from the portal and right renal vein. Amino acid concentrations and
enrichments were measured, and net fluxes of [15N]-labeled
substrates across the portal drained viscera (PDV) and kidneys were calculated
from arteriovenous differences and plasma flow. Results: Arterial
[15N]glutamine enrichments were significantly lower during enteral
tracer infusion (tracer-to-tracee ratio [labeled vs unlabeled
substrate, TTR%] IV: 6.66 ± 0.35 vs EN: 3.04 ± 0.45;
p < .01), reflecting first-pass intestinal metabolism of glutamine
during absorption. Compared with IV administration, enteral administration of
the glutamine tracer resulted in a significantly higher intestinal fractional
extraction of [15N]glutamine (IV: 0.15 ± 0.03 vs
EN: 0.44 ± 0.08 µmol/kg/h; p < .01). Furthermore,
enteral administration of the glutamine tracer resulted in higher arterial
enrichments of [15N]citrulline (TTR% IV: 5.52 ± 0.44
vs EN: 8.81 ± 1.1; p = .02), and both routes of
administration generated a significant enrichment of [15N]arginine
(TTR% IV: 1.43 ± 0.12 vs EN: 1.68 ± 0.18). This was
accompanied by intestinal release of [15N]citrulline across the
PDV, which was higher with enteral glutamine (IV: 0.38 ± 0.07
vs EN: 0.72 ± 0.11 µmol/kg/h; p = .02), and
subsequent [15N]arginine release in both groups.
Conclusions: In humans, the gut preferably takes up enterally
administered glutamine compared with intravenously provided glutamine. The
route of administration, enteral or IV, affects the quantitative conversion of
glutamine into citrulline and subsequent renal arginine synthesis in
humans.
Numerous studies indicate that parenteral or enteral (EN) administration of
the amino acid glutamine to critically ill patients improves clinical
outcome.1,2
However, it is not clear whether the route of administration of glutamine, EN
or parenteral, affects the metabolic fate of glutamine, with possible
implications for clinical outcome.
It has been suggested that intestinal metabolism of glutamine is important
for 2 reasons. First, glutamine is a crucial metabolite for intestinal mucosal
cells and may play a role in the preservation of the gut
barrier.3–10
Second, metabolites of intestinal glutamine conversion may play a role
downstream through their interorgan
conversion.11 For
instance, citrulline derived from intestinal glutamine metabolism may become a
precursor for renal arginine
synthesis.12–16
The latter may contribute to the positive effects of glutamine on clinical
outcome.17
The route of administration determines whether the gut is the first organ
or one of the initial organs to receive glutamine. A landmark study in rats
showed that arterial administered 6-diazo-5-oxo-L-norleucine (DON),
a glutaminase inhibitor, inhibited the hydrolysis of both luminal and
arterially provided
glutamine,18
suggesting that a difference is not expected from the route of administration
of glutamine. The question is whether this theory is applicable to humans as
well. Our group showed, in patients, that EN administration of
alanyl-glutamine resulted in higher plasma concentrations of glutamate and
citrulline than parenterally infused alanyl-glutamine, suggesting that the
route of administration might affect the metabolic fate of glutamine in
humans.19
Furthermore, recent animal data indicate that EN administration of glutamine
compared with parenteral administration generated more citrulline and resulted
in more de novo arginine derived from
glutamine.20,21
Until now, no data have been available on the metabolic fate of enterally
or parenterally administered glutamine in humans and whether there is a
difference between the route of administration. The present study was designed
to investigate the effect of the feeding route, EN or parenteral, on the
intestinal conversion of glutamine into citrulline and the renal conversion of
citrulline into arginine, and to investigate whether there is a difference in
intestinal fractional extraction of glutamine with enterally or parenterally
administered glutamine. For this purpose, the stable isotope tracer
L-[2-15N]glutamine was provided intravenously or
enterally to patients undergoing major abdominal surgery.
 |
MATERIALS AND METHODS
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Patients
Sixteen patients undergoing gastrointestinal surgery at the University
Hospital Maastricht were studied. Patients with known parenchymal liver
disease, inborn errors of metabolism, or diabetes mellitus type 1 were
excluded from the study. Patient characteristics are presented in
Table I. Oral intake except for
water was stopped at 8 PM on the day of admission and all patients
were operated at 8 AM the next day. The study was approved by the
Medical Ethical Committee of the University Hospital Maastricht, and all
patients gave written informed consent. Patients received
L-[2-15N]glutamine by the EN (n = 8) or parenteral route
(n = 8) in a randomized fashion. A self-propelling nasojejunal tube (Bengmark;
Nutricia, Zoetermeer, The Netherlands) was used for EN
L-[2-15N]glutamine administration. This tube was placed
after induction of anesthesia and manually positioned in the jejunum during
surgery.
L-[2-15N]Glutamine
The tracer L-[2-15N]glutamine (>98% mole percent
enrichment) was obtained from Cambridge Isotope Laboratories (Woburn, MA). The
tracer was dissolved in sterile water, and sodium chloride was added to create
an isotonic solution. Sterility and nonpyrogenicity were tested and confirmed
by the hospital pharmacy. Before the experiment, aliquots of the stock
solution were diluted in normal saline to obtain the final solution.
Study Protocol
Anesthetic management included placement of 2 peripheral venous catheters,
an epidural catheter for pre- and postoperative analgesia, an arterial line,
and a central venous line. Anesthesia was performed using isoflurane and
propofol. After induction of anesthesia, an additional peripheral venous
catheter was placed in an antecubital vein for tracer infusion. This catheter
was kept patent with normal saline until the start of the tracer infusion.
After laparotomy and (when appropriate) verification of the intrajejunal
position of the enteric tube, a baseline blood sample was drawn from the
arterial line, followed by the start of a primed continuous tracer infusion of
L-[2-15N]glutamine (dosages in
Table II). Blood samples were
drawn from the arterial line every 30 minutes for the subsequent 2 hours.
After 1 hour, when based on prior experience an isotopic steady state was
known to be
present,22 blood
was drawn from the portal vein and the renal vein by direct puncture,
simultaneously with arterial blood sampling.
Blood was collected in prechilled heparinized vacuum tubes (BD Vacutainer,
Franklin Lakes, NJ) and placed on ice. Within 1 hour, blood was centrifuged
(10 minutes, 4000 rpm, 4°C) and 500 µL of plasma was added to 80 mg dry
sulfosalicylic acid (Across Inc, Geel, Belgium) to precipitate plasma
proteins. After vortex mixing, deproteinized plasma samples were snap frozen
in liquid nitrogen and stored at –80°C until analysis. Before
centrifugation, hematocrit of each blood sample was determined using a
microcapillary and a manual hematocrit reader.
Duplex Flow Measurement
Intestinal and renal blood flow (BF) were measured by means of color
Doppler ultrasound (Aloka Prosound SSD 5000; Aloka Co, Ltd, Tokyo, Japan) as
described before.23
Briefly, time-averaged mean velocity of the bloodstream and cross-sectional
area of the portal vein and right renal vein were measured before their
bifurcations into the organ. BF was calculated by multiplying the
cross-sectional area of the vessel with the velocity of the bloodstream.
Plasma flow (PF) was calculated by correcting BF for hematocrit (PF = BF
x [1 – Ht]). Total renal flow was estimated by multiplying flow
through the right renal vein by 2. Mean PFs were used to calculate organ
fluxes.
Laboratory Analysis
Amino acid concentrations in deproteinized samples and infusates were
measured using high-performance liquid chromatography, as described
elsewhere.24
Isotopic enrichment was expressed as tracer-to-tracee (= labeled vs
unlabeled substrate) ratio (TTR, %), which was corrected for background TTR
determined in the baseline sample. Glutamine, citrulline, and arginine TTRs
were measured by liquid chromatography–mass
spectrometry.25
Coefficients of variation were 2.7% for [15N]glutamine TTR, 5.9%
for [15N]citrulline TTR, 3.0% for [15N]arginine TTR, and
<2% for amino acid concentrations.
Calculations
Organ net balances (NB) of amino acids were calculated from the differences
between arterial (A) and venous (V) amino acid concentrations and from the
corresponding PF:
Hereby, a positive value indicates net amino acid uptake and a negative value
indicates net release by the organ.
Net tracer organ balances (nb) were calculated accordingly, from arterial
and venous amino acid concentrations, corresponding [15N]
enrichments (TTR), and from the appropriate PF:
Organ tracer nb are presented as absolute values. Whether the tracer nb
represent net release or net uptake by the organ will be specifically
mentioned in the text. To calculate the NB of glutamine and tracer nb of
[15N]glutamine across the portal drained viscera (PDV) in patients
receiving EN tracer infusion, the EN infusion rate was added to the calculated
PDV amino acid NB and tracer nb.
Statistics
Results are expressed as mean ± SEM. Differences between the IV and
EN groups were tested using Student's t-test. Arteriovenous gradients
were tested vs a theoretical mean of zero using a 1-sample
t-test. All statistical calculations were performed using Prism 4.03
for Windows (GraphPad Software Inc, San Diego, CA). A p value <
.05 was considered to indicate statistical significance.
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RESULTS
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Patient Characteristics (Table I)
Patients received comparable surgical treatment. No difference was observed
for the baseline characteristics gender, age, and body weight. No liver or
renal dysfunction was observed in either of the groups. Plasma concentrations
of glutamine, citrulline, and arginine were similar for both groups during
surgery.
Systemic Isotopic Enrichments
An isotopic steady state was achieved for [15N]glutamine within
1 hour in both groups (IV: 6.66 ± 0.35; EN: 3.04 ± 0.45 TTR%).
Arterial [15N]glutamine TTR was significantly higher in the
patients who received the glutamine tracer intravenously compared with the
patients who received the glutamine tracer by the EN route
(Figure 1A). This difference
reflects the splanchnic extraction of the glutamine tracer in the EN
group.
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FIGURE 1. Arterial tracer-to-tracer ratio (TTR) of [15N]-labeled amino
acids in patients receiving either l-[2-15N]glutamine by IV or
enteral (EN) administration (n = 8 per group). TTR was significantly different
from zero (p < .001). Arterial [15N]glutamine TTR was
significantly higher in the IV group, reflecting splanchnic extraction of the
enterally administered tracer (A). Arterial [15N]citrulline TTR was
higher in the enteral group, indicating that enterally delivered glutamine is
transformed to [15N]citrulline in considerable measure, either
immediately in the gut or via precursors that are formed within the gut and
released in the portal vein (B). Arterial [15N]arginine TTR tended
to be higher in the enteral group, also reflecting the conversion of enterally
delivered [15N]glutamine to [15N]arginine. EN, enteral;
TTR%, enrichment, expressed as tracer-to-tracee (labeled vs unlabeled
substrate) ratio x 100 (%), corrected for natural TTR determined in the
baseline sample. *p < .05.
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The [15N]citrulline TTR, on the other hand, was significantly
higher in the group receiving the glutamine tracer enterally (IV: 5.52
± 0.44; EN: 8.81 ± 1.1 TTR%;
Figure 1B). No difference was
observed between arterial [15N]arginine TTR with parenteral or EN
administration of L-[2-15N]glutamine (IV: 1.43 ±
0.12; EN: 1.68 ± 0.18 TTR%; Figure
1C).
The PDV: Metabolism of Exogenously Administered Glutamine
Due to the lower systemic [15N]glutamine TTR, supply of
[15N]glutamine to the PDV via the circulation was lower in
the EN group. However, this difference was not observed when the total
[15N]glutamine supply to the PDV was corrected by adding the amount
of EN-delivered [15N]glutamine to the amount of
[15N]glutamine supplied through the circulation
(Figure 2A).
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FIGURE 2. Metabolism of [15N]glutamine by the portal drained viscera (PDV)
in patients receiving l-[2-15N]glutamine by IV or enteral (EN)
administration (n = 8 per group). Tracer net balances of glutamine were
significantly different from zero in both groups (p = .001) Total
l-[2-15N]glutamine supply (via the gut lumen and the circulation)
was not different between groups (A). The gut metabolized
[15N]glutamine more avidly when it was supplied enterally because
uptake and fractional extraction were higher with EN than with IV
administration (p < .05; B and C). *p < .05.
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Both absolute uptake and the fractional extraction of
[15N]glutamine were higher with EN administration of
[15N]glutamine compared with IV administration
(Figure 2B and C). Furthermore,
in patients receiving the glutamine tracer enterally, there was a
significantly higher net release of [15N]citrulline by the PDV
(Figure 3A). No significant net
release of [15N]arginine by the PDV was observed with IV or EN
administration of the glutamine tracer
(Figure 3B).
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FIGURE 3. Formation of [15N]citrulline (A) and [15N]arginine
(B) by the portal drained viscera (PDV) in patients receiving
L[2-15N]glutamine by IV or enteral (EN) administration (n = 8 per
group). The tracer net balance of citrulline was significantly different from
zero in both groups (p = .001). [15N]citrulline release was higher
after enteral tracer administration compared with IV administration (p = .02).
The release of [15N]arginine by the PDV was not statistically
different from zero in both groups. *p < .05.
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Renal Metabolism of Citrulline and Arginine Derived From Exogenously Administered Glutamine
An uptake of [15N]citrulline by the kidneys was observed, as
well as a net release of [15N]arginine, which was comparable for
both routes of administration (results not shown).
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DISCUSSION
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The objective of this study was to investigate the effect of the route of
administration, parenteral or EN, of glutamine on its intestinal conversion
into citrulline, the renal conversion of glutamine-derived citrulline into
arginine, and the intestinal fractional extraction of glutamine.
We observed that the TTR of [15N]glutamine was lower with EN
administration of the glutamine tracer, reflecting the splanchnic extraction
of enterally provided glutamine. Enterally administered glutamine was observed
to result in a higher release of [15N]citrulline by the portally
drained viscera and a higher intestinal fractional extraction of
[15N]glutamine when compared with parenteral administration of the
glutamine tracer.
To our knowledge, this is the first time that the preference of the gut for
enterally provided glutamine has been shown in humans by metabolic
tracing.
It can be suggested that the human gut preferably takes up glutamine from
the EN side in order to secure important effects on the gut; for instance,
intestinal oxidation, gut integrity, gut protection with heat shock proteins,
and by serving as a substrate for the gut-associated lymphoid tissue (GALT)
and synthesis of
glutathione.3–10
Because the TTR of [15N]glutamine was observed to be higher with
parenteral administration of the glutamine tracer, it can be speculated that
the maximum effect of glutamine administration is obtained with a combination
of parenterally and enterally administered glutamine in order to secure the
maximum systemic effect and the optimal local effect on the gut.
Because EN provision of glutamine was observed to result into a higher
release of citrulline by the portally drained viscera, which was observed to
be a precursor for the de novo synthesis of arginine, it can be
suggested that enterally provided glutamine probably affects the immune system
also at a systemic level. However, de novo production of arginine is
not expected to be enhanced when enough arginine is available. It was shown by
our group that plasma levels of arginine are regulated by the kidney, meaning
that the kidney only generates arginine when plasma levels are
low.26 This
observation was supported by recent observations in preoperative patients and
mice by our
group.19–21
Patients and mice demonstrated normal plasma levels of arginine and received a
high dose of glutamine enterally or parenterally. EN administration of
unlabeled glutamine in the patients resulted in a higher plasma concentration
of citrulline, and EN administration of labeled glutamine to the mice was
observed to contribute more to the de novo synthesis of citrulline
and arginine. However, the plasma levels of arginine were not enhanced by EN
provision of glutamine in the patients, and the total de novo
synthesis of arginine was similar for both routes of administration in the
mice. The results of the current study support these observations because no
differences were observed in the TTR of [15N]arginine or renal
[15N]arginine release between both routes of administration.
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CONCLUSIONS
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In conclusion, this is the first study in humans which proves that the
metabolic fate of glutamine is different with EN or parenteral administration
of glutamine, showing a preference of the gut for enterally provided
glutamine.
This finding will force us to reevaluate prior research involving the
clinical benefit of glutamine because results of clinical studies with
parenterally or enterally administered glutamine are now expected to be
different due to differences in metabolism. This study furthermore raises the
question whether other amino acids are also metabolized in a different fashion
when offered enterally or parenterally. In new studies with the aim to
investigate the effect of glutamine on clinical outcome, the difference in
metabolism should be taken into account. It will also be interesting to
evaluate the effect of a combination of enterally and parenterally
administered glutamine on clinical outcome.
Considering the previously established importance of glutamine for human
nitrogen metabolism, the preference of the gut for luminally offered glutamine
might in part explain the beneficial effects of enterally provided
nutrition.
The work was supported by grants from The Netherlands Organization for
Health Research and Development to MCGvdP (920-03-317 AGIKO), PGB (920-03-185
AGIKO) and CHCD (907-00-033 Clinical Fellowship) and by a grant from
Fresenius-Kabi, Bad Homburg, Germany. The authors thank L. R. Belliot
(Radiology, VU University Medical Center, Amsterdam, NL) for his support with
the Duplex flow measurements.
 These authors contributed equally to this work and share first
authorship. 
Received for publication December 13, 2006.
Accepted for publication February 26, 2007.
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Discussant
Juan B. Ochoa, MD
University of Pittsburgh Medical Center
What this group has demonstrated is that the metabolism of glutamine (and
therefore the ultimate biologic effects) is drastically different, depending
on the route through which it is given: IV vs enteral. This article
therefore forces several important paradigmatic changes, including (a) a
reevaluation of all the previously published literature, especially articles
that have assumed that both routes were equivalent; (b) the possibility of
targeting different biologic effects, depending on the route of glutamine
administration; and (c) guiding the design of prospective trials. Thus, I
believe that this is really a landmark article with profound effects in the
nutrition world. It is quite appropriate to present this work at the
A.S.P.E.N. Clinical Nutrition Week. I do have several questions:
- If glutamine (when given enterally) generates arginine and significantly
increases arginine plasma levels and availability, should we limit its use in
the instances where arginine supplementation is controversial, such as
sepsis?
- Oral glutamine supplementation has shown some biologic effects on T-cell
function. Could it be that this is due to the production of arginine and not
through a direct effect on T cells?
- Would the "beneficial" effects on T-cell function observed with
enteral glutamine be prevented when glutamine is delivered parenterally?
- Should we give glutamine parenterally and enterally at the same time?
- Some investigators have attempted to signal the possible dangers of
arginine and called for a moratorium on its use while suggesting that
glutamine is indeed beneficial. Is it true that these 2 amino acids are that
different, especially when given enterally? After all, are we giving arginine
when we give enteral glutamine?
Author's Response
- No, several studies have shown that glutamine is safe, even at a high dose.
Moreover, it has been shown by our group that plasma levels of arginine are
regulated by the
kidney,1 meaning
that the kidney only generates arginine when the levels are low. This is
supported by recent observations in preoperative patients and mice by our
group.2–4
Both patients and mice received a high dose of glutamine enterally and
parenterally. Enteral administration of unlabeled glutamine in the patients
resulted in higher plasma levels of citrulline when compared with IV
administration, without enhancing the plasma levels of arginine. The mice
received a high dose of labeled glutamine, and although enterally supplied
glutamine was observed to contribute more to the de novo synthesis of
arginine than intravenously supplied glutamine, the total de novo
synthesis of arginine was similar for both groups. Thus, by administering
glutamine, you get the arginine free.
- Both glutamine and arginine exert biologic effects on T-cell function.
However, their function is quite specific. Our group showed that after trauma
there is a shift from a T1 to a T2 response, which is reversed by
glutamine.5 Also,
glutamine is capable of inhibiting the apoptosis of T
cells.6
Arginine enhances T-cell proliferation and enhances the induction of
T-helper 1 and T-helper 2 cytokine synthesis in the Peyer's
patches.7
However, in humans, one cannot rule out that glutamine given enterally can
exert arginine-like effects on the immune
system.8–10
- Glutamine provided parenterally will also affect the immune system but is
suspected to have a less pronounced effect on the GALT. Clinical studies
showing a beneficial effect of parenteral glutamine on infectious
complications exist, but to our knowledge no study has been performed that
compares the effects of both routes of administration on infectious
complications.
- Yes, we think that glutamine should be administered by both routes in order
to secure optimal effects on the gut but also to exert systemic effects in
patients with depressed levels of glutamine.
- Yes, we are giving arginine when we give glutamine enterally, but only when
the body needs the arginine. No toxic levels of arginine are reached, because
plasma levels of arginine are thought to be regulated in a physiologic
fashion. We have to exclude short bowel and kidney failure because both organs
are necessary to secure this pathway.
- Prins HA, Houdijk AP, Wiezer MJ, et al. Reduced arginine plasma
levels are the drive for arginine production by the kidney in the rat.Shock.
1999;11:199
–204.[Web of Science][Medline]
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- Boelens PG, van Leeuwen PA, Dejong CH, Deutz NE. Intestinal renal
metabolism of L-citrulline and D-arginine following enteral or parenteral
infusion of L-alanyl-L-[2,15N]glutamine or L-[2,15N]glutamine in mice.Am J Physiol Gastrointest Liver Physiol.2005; 289:G679
–G685.[Abstract/Free Full Text]
- Boelens PG, Melis GC, van Leeuwen PA, Ten Have GA, Deutz NE. The
route of administration (enteral or parenteral) affects the contribution of
D-glutamine to the de novo D-arginine synthesis in mice: a stable
isotope study. Am J Physiol Endocrinol Metab.2006; 291:E683
–E690.[Abstract/Free Full Text]
- Melis GC, Boelens PG, van der Sijp JR, et al. 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. Br J Nutr.2005; 94:19
–26.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Boelens PG, Houdijk AP, Fonk JC, et al. Glutamine-enriched enteral
nutrition increases in vitro interferon-gamma production but does not
influence the in vivo specific antibody response to KLH after severe
trauma: a prospective, double blind, randomized clinical study. Clin
Nutr. 2004;23:391
–400.[CrossRef][Web of Science][Medline]
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- Chang WK, Yang KD, Chuang H, Jan JT, Shaio MF. Glutamine protects
activated human T cells from apoptosis by up-regulating glutathione and Bcl-2
levels. Clin Immunol.2002; 104:151
–160.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Kobayashi T, Yamamoto M, Hiroi T, McGhee J, Takeshita Y, Kiyono H.
Arginine enhances induction of T helper 1 and T helper 2 cytokine synthesis by
Peyer's patch alpha beta T cells and antigen-specific mucosal immune response.Biosci Biotechnol Biochem.1998; 62:2334
–2340.[CrossRef][Medline]
[Order article via Infotrieve]
- Manhart N, Vierlinger K, Akomeah R, Bergmeister H, Spittler A, Roth
E. Influence of enteral diets supplemented with key nutrients on lymphocyte
subpopulations in Peyer's patches of endotoxin-boostered mice. Clin
Nutr. 2000;19:265
–269.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Moinard C, Caldefie-Chezet F, Walrand S, Vasson MP, Cynober L.
Evidence that glutamine modulates respiratory burst in stressed rat
polymorphonuclear cells through its metabolism into arginine. Br J
Nutr. 2002;88:689
–695.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Newsholme P. Why is D-glutamine metabolism important to cells of
the immune system in health, postinjury, surgery or infection? J
Nutr. 2001;131(9
suppl): 2515S–2522S.[Abstract/Free Full Text]
Journal of Parenteral and Enteral Nutrition, Vol. 31, No. 5,
343-350 (2007)
DOI: 10.1177/0148607107031005343
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MATERIALS AND METHODS
RESULTS
