1 Centre de Recherche en Nutrition Humaine, and 3 Laboratoire de Nutrition et Alimentation, Ecole Nationale Vétérinaire de Nantes, 44093 Nantes, France; 2 Division of Clinical Nutrition, School of Medicine of Ribeirão Preto, 14049-900 Ribeirão Preto, Brazil; and 4 Nemours Children's Clinic, Jacksonville, Florida 32207
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ABSTRACT |
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To determine whether glutamine acutely
stimulates protein synthesis in the duodenal mucosa, five healthy
growing dogs underwent endoscopic biopsies of duodenal mucosa at the
end of three 4-h primed, continuous intravenous infusions of
L-[1-13C]leucine
on three separate days, while receiving intravenous infusion of
1) saline,
2)
L-glutamine (800 µmol · kg1 · h
1),
and 3) isonitrogenous amounts of
glycine. The three infusions were performed after 24 h of fasting, a
week apart from each other and in a randomized order. Glutamine
infusion induced a doubling in plasma glutamine level, and glycine
caused a >10-fold rise in plasma glycine level. During intravenous
infusions of
[13C]leucine, the
plasma leucine labeling attained a plateau value between 3.22 and 3.68 mole % excess (MPE) and
[13C]ketoisocaproate
([13C]KIC) of
2.91-2.84 MPE; there were no significant differences between
glutamine, glycine, and saline infusion days. Plasma leucine appearance
rate was 354 ± 33 (SE), 414 ± 28, and 351 ± 35 µmol · kg
1 · h
1
(not significant) during glycine, saline, and glutamine infusion, respectively. The fractional synthetic rate (FSR) of duodenal mucosa
protein was calculated from the rise in protein-bound
[13C]leucine
enrichment in the biopsy sample, divided by time and with either plasma
[13C]KIC or tissue
free [13C]leucine as
precursor pool enrichment. Regardless of the precursor pool used in
calculations, duodenal protein FSR failed to rise significantly during
glutamine infusion (65 ± 11%/day) compared either with saline (84 ± 18%/day) or glycine infusion days (80 ± 15%/day). We conclude
that 1) plasma
[13C]KIC and tissue
free [13C]leucine can
be used interchangeably as precursor pools to calculate gut protein
FSR; and 2) short intravenous
infusion of glutamine does not acutely stimulate duodenal protein
synthesis in well-nourished, growing dogs.
stable isotopes; nutrition; small intestine; [13C]leucine
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INTRODUCTION |
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ALTHOUGH GLUTAMINE CAN BE SYNTHESIZED de novo and is therefore considered a nonessential amino acid, it is believed to play a significant role in the regulation of protein balance (21). A decade ago, animal studies revealed a unique correlation between free glutamine concentration and the rate of protein synthesis in skeletal muscle (20, 22). This correlation has not, however, been a universal finding: in other animal studies, the size of muscle glutamine pool failed to correlate with the protein synthesis rate (37). In humans, supplementation of intravenous nutrition with glutamine or glutamine-containing dipeptides enhanced nitrogen balance in patients undergoing major gastrointestinal surgery (32, 35) or bone marrow transplantation (39). Glutamine may affect protein balance by enhancing rates of protein synthesis rather than through inhibition of protein breakdown, because we observed in a previous study that a doubling in plasma glutamine concentration, achieved through enteral glutamine infusion, enhanced nonoxidative leucine disposal, an index of whole body protein synthesis, in healthy adult volunteers in the postabsorptive state compared with saline or glycine infusion (15). However, in another study no alterations were observed in leucine and phenylalanine kinetics when healthy adult volunteers were fed a complete amino acid mixture supplemented with oral glutamine (17). The potential role of glutamine as an anabolic agent, therefore, remains to this day controversial.
In addition, the specific organ site of glutamine's putative anabolic effect remains uncertain. Because glutamine is extensively extracted in the small intestine (24, 31), several groups have hypothesized that glutamine may stimulate gut protein synthesis (13, 16, 26, 31). Accordingly, glutamine has a trophic effect on the small intestine of rodents submitted to several models of stress (13, 26, 31). A few studies in humans point to a better preservation of small intestinal structure or absorptive function in critically ill patients receiving glutamine-supplemented parenteral nutrition compared with conventional glutamine-free intravenous nutrition (33, 34).
The aim of this study, therefore, was to determine whether a short-term intravenous infusion of glutamine was able to enhance gut mucosa protein synthesis in healthy fasting dogs.
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MATERIALS AND METHODS |
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Animals. All studies were conducted in accordance with current guidelines from the French Department of Agriculture for the care and use of animals in biological research. After approval by the National School of Veterinary Medicine at Nantes, five young (142.2 ± 0.1-day-old) beagle dogs participated in the study. Each animal participated in three experiments performed 7 days apart and in a randomized order. Only healthy animals that had a hematocrit >38%, a leukocyte count below 18,000/mm3, a good appetite, normal stools, and body temperature between 38.5 and 39.5°C and were on no medication were studied. The animals' weight (8.28 ± 0.12 kg) did not change between experimental days.
Materials. Natural L-glutamine and glycine were obtained from Sigma (St. Louis, MO). L-[1-13C]leucine (99% 13C) was obtained from MassTrace (Woburn, MA). Tracer solutions were determined to be pyrogen free (limulus lysate assay), sterile (plate culture), and 99% chemically and optically pure before use. Stable isotope tracers were weighed on a high-precision scale and dissolved in known volumes of sterile 0.9% NaCl. Solutions were prepared no earlier than 24 h before study, sterilized by passing through a 0.22-µm filter, stored in sterile sealed containers, and kept at 4°C until used. The concentration of tracer was verified by gas chromatography-mass spectrometry (GC-MS) in triplicate aliquots of each infusate.
Protocol design. Dogs were studied after 24 h of fasting, on three different days, in random order, and with an interval of 1 wk between infusions. On the basal experiment day, each dog received a parenteral infusion of 0.9% NaCl (saline). On another study day, dogs were studied under identical conditions except that they received parenteral glutamine infusion. Finally, each dog underwent an identical study while it received parenteral glycine infusion. To determine whether the rate of incorporation of tracer into mucosal protein was stimulated by glutamine, distal duodenal mucosal biopsies were taken under direct endoscopy at 4 h of tracer and substrate infusion.
Before each study the dogs received standard chow diet for 5-7 days. The diet supplied 9.0 ± 0.3 g · kgAnalytic methods. Plasma amino acid concentrations were determined on an amino acid analyzer (Beckman, Anaheim, CA).
Total plasma protein from the preinfusion samples, precipitated by use of 12% (wt/vol) trichloroacetic acid (TCA), was used to estimate background body protein [13C]leucine labeling for use in the calculation of mucosal protein synthetic rate. In our experience, the background 13C enrichment of plasma free leucine and protein-bound leucine was consistently aboutCalculations. Isotopic steady state in plasma leucine and KIC was established by demonstrating with linear regression that the slope of the isotope enrichment against time was not different from zero.
Total leucine flux (µmol · kg
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Statistical analysis. Data are presented as means ± SE. Data were compared between treatments by repeated-measures ANOVA, a paired Student's t-test, and Kruskall-Wallis nonparametric tests. Significance was established at P < 0.05.
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RESULTS |
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Plasma amino acid concentrations (Table 1)
were measured twice during the last 20 min of each glutamine, glycine,
or saline infusion, when a steady state was apparent on the basis of
[13C]leucine plateau
(see below). Glutamine infusion induced a doubling in plasma glutamine
level, and glycine caused a >10-fold rise in plasma glycine level. In
contrast, neither glutamine nor glycine infusion altered the plasma
concentrations of leucine, KIC, or of most other essential or
nonessential amino acids.
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During intravenous infusion of
[13C]leucine, the
plasma leucine labeling attained a plateau value between 3.22 and 3.68 mole % excess (MPE), and
[13C]KIC of
2.91-2.84 MPE, and there were no statistical differences during
infusion of glutamine, glycine, or saline. There were no differences
for leucine flux calculated from plasma KIC enrichment (Table
2).
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FSRs of duodenal mucosa protein were calculated from different
precursor pool enrichments (Table 3). The
results obtained from tissue fluid free leucine pool and plasma KIC
were not significantly different, and they were higher than those
calculated using the plasma
[13C]leucine pool.
Again there were no statistically significant differences after
glutamine or glycine infusion.
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DISCUSSION |
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The present study used continuous infusion of stable isotope-labeled leucine to examine the effect of a short, intravenous infusion of natural glutamine on the FSR of duodenal mucosa protein in healthy, growing dogs. We observed that 1) the use of either plasma KIC or tissue fluid free leucine as a precursor pool resulted in estimates of protein FSR that were not statistically different; and 2) regardless of the precursor pool used for calculations, glutamine failed to stimulate duodenal protein FSR compared with either saline or isonitrogenous glycine infusion.
The lack of stimulation of gut protein FSR by glutamine observed in the current study is at odds with several previous studies documenting stimulation of cell proliferation by glutamine in human or rat ileum in vitro (16, 26, 29) or enhanced protein content in rat jejunum (13) and prompts us to question either the isotopic approach used, the dose of glutamine, the animal model, or the study design used.
In vivo assessment of the rates of tissue protein synthesis has relied
either on continuous tracer, most commonly
[13C]leucine, infusion
or on the flooding dose method (14, 28, 30). Although each of these
approaches has its own limitations, the main limitation to the
continuous infusion method is the inability to directly assess the
isotopic enrichment of the direct precursor amino acid pool used for
tissue protein synthesis, i.e., tRNA [13C]leucine. Previous
studies have suggested that plasma KIC could be used as the precursor
pool in lieu of tissue free leucine in muscle and liver (2, 4). The
current study documents that isotopic enrichments did not differ
significantly between plasma KIC and gut free leucine. The intersubject
coefficient of variation (CV = 100 × SD/mean) in measured
enrichments was, however, 30% in the saline infusion experiments
(with an SD of 0.89 for a mean of 2.89 MPE; Table 3). It can thus be
estimated that, in a paired study design, nine dogs would be required
to detect a 30% difference in measured enrichments between KIC and
mucosal free leucine with an
<0.05 and 1
= 0.80. With
this reservation in mind, the data nevertheless suggest that KIC may be
used as a fair estimate of the precursor pool for protein synthesis in
the gut, even during intravenous administration of large amounts of
amino acids. Our data are consistent with earlier studies showing that
the 13C enrichment of leucyl-tRNA
in stomach mucosa was the same as that of plasma KIC during a
continuous infusion of
[13C]leucine in pigs
(8).
For this reason, it is unlikely that inaccurate assessment of precursor pool enrichment accounts for the apparent lack of effect of glutamine. Similarly, the intravenous route of tracer infusion is unlikely to affect the results, because other workers have reported that similar gut protein FSR could be obtained by use of either intravenous or enteral [13C]leucine (25).
We used the
[13C]leucine
enrichment in mixed plasma protein-bound leucine as an estimate of the
baseline enrichment in gut protein-bound leucine. The choice is
reasonable for the first isotope infusion day, since there is no reason
to believe that, in "naive" dogs that have never received any
tracer infusion,
[13C]leucine content
should differ between tissues, yet this may not apply for the second
and third infusion days. Because the bulk of mixed plasma protein is
albumin, which has a turnover rate of only 8-10% per day (11),
the residual
[13C]leucine
enrichment in plasma albumin may largely exceed that in gut protein,
which turns over at a rate of
60-90% per day. To address this
issue, additional experiments were carried out (data not shown) in
which gut protein-bound
[13C]leucine
enrichment was measured 1 wk after the performance of a
[13C]leucine infusion
in a single dog. Residual enrichment remained at 0.0440 MPE in plasma
protein vs. only 0.0234 MPE in gut protein in samples obtained
simultaneously. The use of same-day plasma protein enrichment as a
baseline thus overestimates the residual enrichment in gut protein and,
as a consequence, underestimates the rate of
[13C]leucine
incorporation and gut protein FSR during the second and third infusion
days. On the other hand, using the first-day initial value of plasma
protein enrichment before the first isotope infusion will result in
underestimating residual enrichment and overestimating gut protein
synthesis during the second and third isotope infusions. Table
4 displays results from two sets of calculations that use either same-day or first-day plasma protein [13C]leucine content
as an estimate of baseline 13C
abundance in gut protein. Although the absolute values of gut protein
FSR were altered depending on the baseline chosen, we failed to detect
any significant rise in gut protein FSR on the glutamine infusion day.
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On the other hand, the putative protein anabolic effect of glutamine may be species specific, and it may be nonexistent in the dog. The dog has been used extensively as a model for the investigation of whole body leucine metabolism (1, 2). Moreover, because glutamine is extensively taken up by the gut and inhibits lipolysis and ketogenesis in dogs (5, 6), as it does in humans (10), this animal model seemed reasonably similar to humans with regard to glutamine metabolism. Whereas earlier studies documenting intestinal glutamine extraction, as well as glutamine's inhibitory effect on lipolysis, used 96-h-fasted adult dogs (5, 6), we used young, growing dogs after a 24-h fast. In addition, among the many metabolic effects attributed to glutamine, inhibition of leucine oxidation and enhancement of nonoxidative leucine disposal, together an index of whole body protein synthesis, have only been documented in healthy humans (15), not in healthy dogs; accordingly, whereas glutamine infusion decreased plasma leucine concentration in studies performed in humans (10, 15), glutamine failed to affect plasma leucine level in the current report.
The lack of effect of glutamine may be due to the experimental design itself, e.g., a type II statistical error, the fasting condition of the animals, their preexisting nutritional status, or the dosage or timing of glutamine infusion.
In theory, the small size of the population studied could have
precluded the detection of glutamine's anabolic effect: indeed, given
the large intersubject CV (= 100 × SD/mean) in gut protein FSR
(e.g., 48% in the saline infusion experiments), the minimal change
that could be detected with 80% power and an
<0.05 would be an
67% change in gut FSR (when a 2-sided test is used) or an
55%
rise (when a 1-sided test is used) (7). Whereas the purpose of the
study was to determine whether glutamine was able to enhance gut
protein FSR, there was, however, a trend (not significant) toward a
lower (rather than an enhanced) rate of gut protein FSR on the
glutamine infusion day (Table 3) compared with saline or glycine infusion.
Glutamine was administered to animals in the fasting state, and the gut
may only be capable of mounting a protein anabolic response in the fed
state. However, in previous studies, glutamine enhanced whole body
estimates of protein synthesis in postabsoptive humans (15). The
amounts of glutamine infused into our dogs (970 µmol · kg1 · h
1,
i.e., 0.57 g/kg over 4 h), were equivalent to 100% (39) and 200% (19)
of the daily doses administered by others to critically ill humans:
insufficient dosage therefore hardly seems a plausible explanation for
the lack of effect of glutamine. However, in rat skeletal muscle,
protein synthesis may correlate with the concentration of free
glutamine (20). If the same is true for the small intestine, the
failure of glutamine to elicit an anabolic effect in the current study
may reflect an inability to increase intracellular glutamine concentration; although plasma glutamine doubled, glutamine
concentration was not measured in the duodenal mucosa in the current study.
The duration of the glutamine supplement may have been too short to elicit any anabolic effect. Accordingly, even though a 5-day glutamine supplementation enhanced both nitrogen balance and polyribosome concentration in skeletal muscle from surgical patients (35), a short, 5.5-h course of intravenous glutamine failed to affect muscle protein synthesis after surgery (19). Also, preexisting depletion of the body glutamine pools may be a prerequisite for glutamine supplementation to elicit its protein anabolic effect. Although the size of muscle or gut glutamine pools was not assessed in the current studies, we speculate that glutamine pools were intact at baseline in the animals studied, because they had received ample amounts of protein, and therefore large amounts of glutamine as a protein-bound residue, in their diet before the study. Earlier studies indeed suggest that rates of protein synthesis in the gut may depend on dietary protein intake in growing animals (37).
It should be pointed out that the lack of stimulation of mixed duodenal protein synthesis by acute glutamine infusion does not rule out a beneficial effect of glutamine on small intestinal mucosa. Indeed, glutamine may enhance the synthetic rate of a few specific proteins in the tissue without altering the overall FSR of mixed gut protein. In addition, a trophic effect of glutamine could be mediated through a number of other mechanisms, including 1) a simple "nutritional" effect, as glutamine provides energy to gut mucosa (21, 24, 31); 2) increased synthesis of DNA, because glutamine is a known donor of nitrogen for the synthesis of purines and pyrimidines (12), the building blocks of nucleic acids that are in high demand during cell replication; 3) enhancement of intestinal immune function, as glutamine is the main fuel for lymphocytes and macrophages (3); 4) increased intestinal blood flow (18); or 5) enhanced glutathione synthesis, because intestinal glutathione plays a critical role in the defense of mucosal cells against oxidative stress (23), and glutamine may be a source for glutathione synthesis in the gut (27).
Finally, the organ site of glutamine's putative protein anabolic effect may be skeletal muscle, rather than the small intestine. Further studies performed in dogs undergoing stress and/or protein wasting may be warranted to determine the "target" organ of glutamine's effect on tissue protein homeostasis.
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ACKNOWLEDGEMENTS |
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We are indebted to Drs. Lucille Martin, Etienne Pouteau, and Henri Dumon for assistance with the handling and surgical preparation of the animals, and to Lynda Everlyne (Biochemical Genetics Lab, Nemours Children's Clinic) for the amino acid concentration assay.
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FOOTNOTES |
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This study was supported, in part, by National Institute of Diabetes and Digestive and Kidney Diseases Grant RO1-DK-51477 (to D. Darmaun) and grants from the Fondation pour la Recherche Médicale (Paris, France) and Fundação de Amparo à Pesquisa do Estado de São Paulo, Brasil (95/09776-1 to J. S. Marchini).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests: D. Darmaun, Centre de Recherche en Nutrition Humaine, CHU Hotel-Dieu, 44093 Nantes cedex 1, France (E-mail: ddarmaun{at}nantes.inserm.fr).
Received 15 January 1998; accepted in final form 10 December 1998.
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