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Rowett Research Institute, Bucksburn, Aberdeen, AB21 9SB, United Kingdom
2To whom correspondence should be addressed. E-mail: g.lobley{at}rri.sari.ac.uk
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONProduction anabolismN carrier and hepatic...Health and proliferative tissuesLITERATURE CITED |
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65%) is derived in vivo from plasma glutamine. In sheep, endotoxin
challenge elevates the plasma flux of glutamine, with a corresponding
decrease in plasma concentration. At the same time, both the glutamate
accumulation and fractional rate of protein synthesis within
lymphocytes are enhanced. These lymphocyte responses, however, are not
altered by an AA supplement that contains glutamine. Overall, although
glutamine obviously plays important metabolic roles within the body,
supplementation does not appear to provide consistent beneficial or
therapeutic effects, except during certain catabolic situations.
Glutamine availability, therefore, does not seem to be a limitation in
many challenge situations. Rather, glutamine may signal alterations in
nutrient demands among organs and a better understanding of this role
may increase understanding of where modulation of glutamine status
would be beneficial.
KEY WORDS: • glutamine • digestive tract • liver • immune system • endotoxin
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONProduction anabolismN carrier and hepatic...Health and proliferative tissuesLITERATURE CITED |
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Within the body glutamine plays many roles, including as a provider of
carbon for energy (Nurjhna et al. 1995
), a precursor for
glutamate (Young and Ajami 2000
), a carrier of N plus
acting as either a signal or regulator of metabolic demands
(Häussinger et al. 1994
). These roles have often
been investigated under conditions of adverse challenges (e.g., injury,
Soeters 1995
and surgery, Watt et al. 1992
), where changes in priorities within the body lead to a
net catabolic state. Such repartitioning of nutrient supply and use
also may occur in response to normal physiological demands, e.g.,
within the digestive tract at the onset of weaning, muscle
deposition during rapid growth or for milk output in the
high-yielding dairy cow. What is the evidence that glutamine plays
important roles during either normal metabolic functioning or in
the response to adverse challenges within commercial species?
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Production anabolism |
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TOPABSTRACTINTRODUCTIONProduction anabolismN carrier and hepatic...Health and proliferative tissuesLITERATURE CITED |
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The concept that glutamine, along with a number of other amino acids
(AA)4
transported into cells by Na+-dependent
mechanisms (Häussinger et al. 1994
), leads to
changes in cell volume that regulate the metabolism of macromolecules,
stimulated attention on whether glutamine might act as a direct
regulator. This action is a function of the transport into, and
accumulation of glutamine within, the tissues. Within this mechanism,
glutamine might even be considered an anabolic agent. Indeed,
deprivation of glutamine in vitro has marked effects on protein
turnover (Taylor et al. 1999
), while metabolism within
primary myoblasts is acutely sensitive to glutamine-mediated
osmotic effects (Low et al. 1997
). Nonetheless, direct
(or even indirect) effects of glutamine on anabolism in vivo are
controversial and may be restricted to recovery from catabolic
situations. For example, early reports suggested that supplementation
with glutamine stimulated muscle protein synthesis in humans recovering
from surgery (Barua et al. 1992
) and rodents treated
with glucocorticoids (Watt et al. 1992
). A more recent
claim is that muscle protein synthesis also can be augmented in
clinically normal humans (Rennie et al. 1996
). In
contrast, glutamine had no effect on restoring muscle protein synthesis
rates to normal in rats treated with turpentine, although the
trauma-induced decrease in muscle glutamine concentration (-40%)
was restored by the supplementation (Wusteman et al. 1995
).
Observations on glutamine-mediated responses in growth with normal
animals also present a confused picture. In 3-d-old piglets
supplemented with 10 g of glutamine per 100 g of parenteral
AA, there was a trend (P = 0.07) for increased body
weight but total protein, fat and ash were unaltered (House et al. 1994
). Chloride space was altered, indicating increased
extracellular water retention. In contrast, in growing steers given a
protein-restricted diet, infusion into the abomasum (true stomach)
of either casein or glutamine increased N retention (P
< 0.05) compared with controls (Reecy et al. 1996
). Interestingly, although casein led to an increase in
urinary N
-methylhistidine
elimination (an index of muscle protein degradation), this was
decreased significantly with glutamine supplementation. This is
consistent with observations on the effects of glutamine in vitro, in
which protein degradation is often more sensitive than protein
synthesis to changes in cell hydration (Vom Dahl and Häussinger 1996
). These data might suggest that under
conditions of elevated protein degradation, as occurs when muscle is
net mobilized, glutamine might act as a metabolic regulator and improve
anabolism (or reduce catabolism). Such circumstances might include
infection, inflammation, early lactation or undernutrition. The latter
situation has been examined recently across the hind-quarters of
sheep (Roy et al. 1999
and unpublished data) maintained
at 0.6 x maintenance (and, thus, in negative N balance) and
supplemented with a 4-d intravenous supplement of glutamine (6 mmol/h;
equivalent to 50% of the plasma flux). The glutamine
supplementation increased glutamine concentration in plasma (512 vs.
394 µmol, P < 0.001), muscle (4.8 vs. 3.4 mmol,
P < 0.01) and skin (1.4 vs. 0.9 mmol, P
< 0.001). Despite these increases, there was no improvement in
whole-body N retention and the net loss of phenylalanine (-75 vs.
-94 µmol/h, not significant) across the hind-quarters was not
altered. Also unaffected by glutamine supplementation were the
hind-quarter rates of protein synthesis and degradation (based on
arterio-venous
[2H5]phenylalanine
kinetics), and phenylalanine influx and efflux, as assessed by the
models of Biolo et al. (1995
) also were unaffected.
Taken together, these data do not provide strong support for direct effects in vivo of glutamine on muscle protein kinetics.
Lactation.
In terms of normal physiological events, lactation provides the
greatest metabolic challenge in terms of both protein and energy
demand. In high yielding dairy cows, for example, > 1 kg of milk
proteins is secreted daily, equivalent to > 30% of plasma
protein flux (Bequette et al. 1996
). This output can be
sustained for 300 d/y and, during the later stages, may have the
additional demands of pregnancy superimposed. To achieve this
productive output intake is increased (by up to threefold), with a
concomitant increase in the mass of the digestive tract. The adaptation
in voluntary food intake takes time, however, and during the first 6 to
10 wk of lactation, parts of the demand of the mammary gland are met by
mobilization of body reserves, particularly muscle. Thus, interorgan
priorities are changed.
Three roles for glutamine during lactation have been proposed. First,
glutamine and glutamate comprise 6.5–12.5% and 7.2–10.0%,
respectively, of AA residues in bovine caseins (Eigel et al. 1984
), compared with 4.4% for muscle protein (Kuhn et al. 1999
). Thus, both the uptake and synthesis of glutamine by
the mammary gland must be considerable to accommodate this demand
(Meijer et al. 1993
). Second, because the uptake of most
nonessential AA by the mammary gland is below that required for milk
protein synthesis (Meijer et al. 1995a
), glutamine may
provide both C and N sources for their intracellular biosynthesis.
Third, glutamine may act as a regulator of intracellular activity
through transport-mediated changes in cell volume
(Häussinger et al. 1994
) and protein metabolism
within the rodent mammary gland in vivo is responsive to the cellular
hydration state (Millar et al. 1997
).
Based on these concepts, it was hypothesized that glutamine supply and
uptake might limit milk protein production (Meijer et al. 1993
), particularly during early lactation when the plasma
concentrations of both glutamate and glutamine decrease by 25% (while
most other nonessential AA increase). Similarly, over the same period,
the most depleted free AA in muscle is glutamine (-25%; Meijer et al. 1995b
). In practice, however, although improvements in
both total milk yield and protein output have been reported in response
to intravenous glutamine infusion (leading to increased plasma
glutamine concentration), these improvements have not been consistent
within the same series of studies (Meijer et al. 1995a
).
Furthermore, inclusion of glutamine in an intravenous infused mixture
of essential plus nonessential AA failed to elicit a further milk
protein response over that achieved with the essential AA alone for
cows in midlactation (11–28 wk; Metcalf et al. 1996
).
Finally, cows, 29–99 d in milk, failed to exhibit any production
response (total milk yield or composition) to glutamine supplementation
(Plazier et al. 2001
). Thus, at best, the current
evidence is equivocal in support of a major role for glutamine in the
nutrient partitioning that occurs during lactation.
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N carrier and hepatic metabolism |
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TOPABSTRACTINTRODUCTIONProduction anabolismN carrier and hepatic...Health and proliferative tissuesLITERATURE CITED |
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For most species, glutamine is the most abundant free AA in tissues
(2–15 mmol; e.g., Meijer et al. 1995b
, Le Boucher et al. 1997
). What advantages are conferred by maintaining such high
intracellular concentrations? One option is as potential energy stores
(Darmaun 1995
), while other functions may include
precursor provision for glutamate synthesis (Young and Ajami 2000
), regulation of intermediary metabolism
(Häussinger et al. 1994
) and specific functions
associated with the amido and amino groups. The amido group has
received particular attention due to involvement in ammonia
detoxification (Lobley and Milano 1997
) and regulation
of acid-base balance (see below). Studies in both humans and sheep,
however, have shown that similar plasma fluxes are obtained with both
2-15 N and 5-15 N glutamine
(food-deprived humans, Darmaun et al. 1986
and fed
sheep,15.2 and 12.4 mmol/h,respectively,n = 3,G. E. Lobley,unpublished results). These data indicate that
interorgan amino group transfers are at least as important as those of
the amido-N, although such flows appear to only involve 5%
of the total body free glutamine (Hankard et al. 1995
).
Within the tissues, a putative role has been proposed for glutamine in
the protection of essential AA from oxidation, through reamination of
their oxo-acids. Across species (Cooper and Meister 1972
, Costa et al. 1986
), tissues involved in AA
catabolism, such as liver and kidney, contain glutamine
aminotransferase in either of two isoforms (L and K) that catalyze the
reversible transamination between a variety of amino-group donors
and oxo-acid acceptors. In practice, however, the prevalence of
glutamine in the tissues ensures that this is the probable amino donor.
Of the oxo-acid acceptors, data in vitro suggest that those of
methionine and phenylalanine are preferred acceptors
(Häussinger et al. 1985
, Blarzino et al. 1994
). Methionine plays important roles in the body and, for
ruminants fed fresh or conserved forage, may be the first limiting AA
(Storm and Orskov 1984
). Similarly, much of the absorbed
phenylalanine is often removed across the liver (Lobley and Milano 1997
, Le Floc’h et al. 1999
) and has
been suggested as a limiting AA for acute phase protein synthesis
(Reeds et al. 1994
). Thus, any mechanism that protects
these AA against hepatic oxidation is likely to be beneficial. In both
fed and food-deprived sheep infused with
2-15N-glutamine, label was
incorporated into most AA (except lysine and threonine, which do not
undergo transamination) within plasma and liver constitutive proteins,
as well as hepatic free AA (Fig. 1
; Hoskin et al. 2001
). Interestingly, enrichments were
greater for methionine than for phenylalanine and this is consistent
with the substrate specificity in vitro of the bovine
L-isoform (Blarzino et al. 1994
).
Enrichments in the essential AA were lower, in general, than for most
of the nonessentials, particularly glutamate and, therefore, it is not
possible to distinguish between direct transfer from glutamine to the
oxo-acid and indirect transfers through glutamate. From these
studies it was calculated that 5% of hepatic methionine
amino-N could be derived from glutamine. This might provide
an important salvage mechanism when dietary methionine is limited but
needs to be tested in practice. Interestingly, if this amino group
transfer was not direct from glutamine but was mediated via glutamate,
then 50% of hepatic methionine flux would involve the
transamination pathway (Benevenga et al. 1983
), a
pathway generally considered minor compared with
trans-sulfuration (Storch et al. 1988
).
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One aspect of metabolic stress in which there is an accepted role for
glutamine is in regulation of acid-base balance. During acidosis in
rodents, there is a switch from urea production to glutamine synthesis
in the liver (Welbourne et al. 1986
, May et al. 1992
). The bicarbonate spared from the lowered ureagenesis is
then available to neutralize protons. The glutamine is then both
deamidated and deaminated in the kidney (Wright and Knepper 1992
) and ammonium ions are eliminated in the urine. Support
for this mechanism is derived from studies with rodent hepatocytes in
which ureagenesis and glutamine synthesis show an inverse relationship
with each other in response to pH (Boon and Meijer 1988
;
Table 1
). In contrast, both processes are insensitive to pH in the perfused
ovine liver (Roussow et al. 1999
, Table 1
). These latter
data support observations in sheep, where during HCl-induced
acidosis, both hepatic urea and glutamine synthesis are unaltered
(Lobley et al. 2000
). Although the increased urinary
elimination of ammonium ions does arise primarily from glutamine, this
is of nonhepatic origin (Lobley et al. 2000
).
Arterio-venous data indicate that some of the additional glutamine
may arise from reduced removal by the digestive tract (Lobley et al. 1995
, Milano 1997
), with a significant
decrease in ornithine release across the ovine portal-drained
viscera (Milano 1997
). Other differences between rats
and sheep during acidosis include increased whole-body protein
degradation in rodents, compared with lowered protein synthesis in
ruminants. Both routes lead to reduced net protein retention via
different regulatory mechanisms. Part of these interspecies differences
may relate to the experimental models used, e.g., use of ammonium
chloride to induce acidosis will also stimulate hepatic metabolism to
remove the added ammonia. Nonetheless, such data indicate the potential
errors that may arise when extrapolating to other species, particularly
to humans.
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Health and proliferative tissues |
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TOPABSTRACTINTRODUCTIONProduction anabolismN carrier and hepatic...Health and proliferative tissuesLITERATURE CITED |
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Probably most attention on glutamine metabolism has focused on the
digestive tract. This relates to the pioneering work of Windmueller and
colleagues who demonstrated the extensive use of glutamine by the gut
tissues. In part, this was related to possible contribution to energy
needs, although this was less than for glutamate (Windmueller and Spaeth 1980
), a point confirmed in more detail recently
(Reeds et al. 2000
). Mucosal cells of the digestive
tract have, along with other rapidly proliferating cells, an obligate
requirement for glutamine. This may involve a role as the provider,
through the action of cytosolic carbamoyl phosphate synthetase II, of
one-half the N requires for both purine and pyrimidine synthesis.
Indeed, Szondy and Newsholme (1989
) suggested that the
high intracellular flux of glutamine maintains instant supplies of
nucleic acid-N precursor and allows for immediate responses
to proliferative needs without disrupting other metabolic flows. Thus,
a doubling of the amount of glutamine to nucleic acid biosynthesis
would only represent a small proportion of the total glutamine flow. In
sheep subjected to a 24-h fast, only 6% of
[5-15N]glutamine flux across the
small intestine was transferred into either RNA or DNA synthesis
(Gate et al. 1999
, Fig. 2
). Although these studies did not separate activity between enterocytes
and other proliferative cells of the tract (e.g., intraepithelial
lymphocytes; Dugan et al. 1994
), the pattern of
incorporation into nucleic acids agreed well with known rates of cell
replacement. Thus, mucosal enrichments exceeded those in the serosa,
while isotope incorporation was greater in the upper compared with the
lower small intestine. A predictable pattern also was observed beyond
the digestive tract with incorporation into DNA being greatest for
spleen followed, in descending order, by lymph nodes, liver, kidney and
muscle. The fate of the rest of the glutamine flux across the digestive
tract appeared to differ between ruminants and nonruminants in that the
sheep showed less conversion to ammonia and secondary products, such as
alanine, citrulline, proline and arginine, than was reported for
rodents or pigs (Windmueller and Spaeth 1980
, Wu et al. 1996
, Gate et al. 1999
). Thus, based on 15 N
enrichments and transfers in the fasted sheep, although 25% of the
glutamine extracted across the digestive tract was converted to
ammonia, the amido-group only represented 5% of total ammonia
production across the tissue bed (Gate et al. 1999
).
Stoll et al. (1999
) also reported that in pigs ammonia
production was considerably in excess of endogenous glutamine
extraction by the digestive tract. These data contrast with the fate of
supplemental glutamine, 24–60% of which may be converted to ammonia
in calves (see Nappert et al. 1999
). Metabolism of
endogenous and supplemental glutamine may differ, therefore, at least
in the relative distribution to metabolic pathways.
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). Enterocytes from the
new-born piglet can synthesize arginine from glutamine and this may
play an important early anabolic role (Blachier et al. 1993
). Later in development, glutamine is a precursor for both
arginine and proline synthesis within the digestive tract
(Blachier et al. 1993
, Wu et al. 1994
)
and these synthetic processes may supplement dietary supplies of these
AA and help prevent limitations in growth. In 4-d-old suckled pigs,
glutamine (at 4.5% inclusion in a TPN mixture) increased villi height
and area in the jejunum but did not alter protein or DNA mass
(Burrin et al. 1994
). This null effect on
macro-constituents was also observed with 1-wk-old mini-pigs
(Burrin et al. 1991
). When pigs are early weaned, the
concomitant atrophy of the villi in the jejunum, but not the duodenum,
can be prevented by inclusion if 1% glutamine in the diet (Wu et al. 1996
). Challenges associated with diarrhea also are
mitigated by glutamine. The effect may involve both electroneutral and
electrogenic Na+ absorption (Rhoads et al. 1990
). The latter (a villus tip phenomenon) may also be
overcome by other therapies (e.g., use of 2% glucose and glycine in
oral rehydration strategies). Glutamine-linked
Na+ transport can occur at both the villus tip
and in the crypt cells, and glutamine administration has been shown, in
K99+ infected calves, to be more effective than glucose therapy
(Brooks et al. 1997
). This effect may be enhanced by
ensuring that other therapies are balanced to prevent inhibition by
prostaglandins of the glutamine-stimulated neutral
Na+ transport (see Hunt et al. 1999
). The deleterious changes in digestive tract permeability
associated with endotoxin challenges also can be decreased by glutamine
supplementation (Dugan and McBurney 1995
).
Despite these observations, when pigs are challenged with rotavirus,
neither glutamine nor alanylglutamine supplementation produced
beneficial effects in reducing the magnitude or duration of scour,
although inclusion of plasma protein in the diet eliminated diarrhea
(Odle and Harrell 2001
). Similarly, the rate of recovery
from the rotavirus infection was not enhanced by glutamine
supplementation. The therapeutic effects of glutamine also have been
examined in sheep subjected to subclinical infestation with the upper
small intestine parasite, Trichlostongylus columbriformis.
This parasite leads to marked net catabolism of leucine by the
portal-drained viscera, increased protein synthesis and secretory
losses (MacRae 1993
, Yu et al. 2000
),
with, in consequence, lowered net AA availability to the liver and
beyond (Yu et al. 2000
). Parasitized sheep given a daily
supplement of 5 g of glutamine (plus 1 g cysteine) into the
abomasum failed to show improvements in either live-weight gain or
N retention, and urea kinetics were also unaltered compared with
nonsupplemented parasitized animals (S. O. Hoskin and G. E.
Lobley, unpublished data). However, responses to the
glutamine-cysteine supplementation were observed for eosinophil
counts (a marker of parasite response), which increased (P
< 0.05), while the fractional rate of albumin synthesis decreased
(P < 0.05).
In summary, there are circumstances in which glutamine supplementation aids digestive tract function and metabolism, particularly under challenge situations. However, it does not provide a universal panacea and some beneficial actions may be substituted by alternative therapies.
Immune system.
The rate of proliferation of lymphocytes in culture increases with
external glutamine concentration in a near Michaelis-Menten manner
(Calder 1995
). Much of the glutamine is metabolized,
with ammonia, glutamate, carbon dioxide and aspartate (in descending
order) as the main products in bovine lymphocytes (Wu and Greene 1992
). The relative importance of glutamine to the energetic
needs of lymphocytes differs among species. For cattle lymphocytes in
vitro, glutamine provides only 30% of the ATP available from glucose
(Wu and Greene 1992
), whereas in rodents ATP yield from
glutamine is approximately equal to that of glucose (Wu et al. 1991
). In pigs, however, the situation with intraepithelial
lymphocytes is similar to cattle, with glucose providing threefold
greater amounts of ATP than glutamine (Dugan et al. 1994
). Despite this use of exogenous glutamine, intracellular
concentrations are low in both human (Fukuda et al. 1982
) and sheep (<2 nmol/107
cells) lymphocytes. In contrast, glutamate concentrations are high (29 and 12
nmol/107 cells, for humans (Fukuda et al. 1982
) and sheep (see Fig. 3
), respectively.
Lymphocyte [15N]glutamate
enrichments in vivo were 65% (SE 9%) of plasma
[2-15N]glutamine in sheep (Fig. 3)
,
indicating that the primary source of the accumulated intracellular
glutamate was extracellular glutamine.
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) or surgery (e.g., Van Acker et al. 1999
), plasma glutamine concentrations decrease,
despite increased mobilization from muscle (Mjaarland et al. 1993
). This is probably due to increased metabolic usage at
various sites, including the immune system and across the liver and
spleen (Deutz et al. 1992
). The quantitative aspects of
such demands, however, are still unresolved, and recent observations
that, after surgery, the rate of appearance of glutamine in the plasma
remains unaltered (Jackson et al. 1999
, Van Acker et al. 1999
) have fueled the debate as to the role of glutamine
under conditions of trauma. Recently, the responses to a continuous,
20-h intravenous challenge of lipopolysaccharide (LPS) from
Escherichia coli (2 ng/min per kg live weight) have been
monitored in sheep. The mild inflammatory reaction provoked transient
pyrexia but intake was maintained. There were rapid changes in plasma
AA concentrations that then stabilized between 6 and 20 h
(unpublished results). Under these conditions, glutamine decreased by
24% (Fig. 4
), with a similar decline for leucine (-23%) and a larger decline for
threonine (-73%). In contrast, phenylalanine concentration increased
(+18%). Interestingly, although the decrease in concentration for
threonine and the increase in concentration for phenylalanine were both
associated with corresponding changes in plasma flux (-36%,
P = 0.002; +17%, P = 0.004,
respectively; see Fig. 4
), the decline in glutamine concentration was
accompanied by an increase in
[2-15N] glutamine plasma flux
(+20%, P < 0.05; Fig. 4
). Because net absorption from
the digestive tract is probably unaffected (S. O. Hoskin and
G. E. Lobley, unpublished results), this suggests that there is
increased transport from tissues, in contrast to the recent findings in
humans. Under such circumstances, glutamine supplementation may well
prove beneficial and this is under investigation.
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Although the obligate requirement of the immune system for glutamine is well-established, the net demands that this requirement places on the organism are not defined. Furthermore, the fact that glutamate rather than glutamine is concentrated within lymphocytes might suggest that the latter merely provides a transportable substrate for the latter. Whether glutamine supplementation would either aid stimulation of the immune system or reduce the rate of peripheral tissue metabolism and hasten restoration of lean body mass is still unknown.
Glutamine clearly plays an important role in metabolism of both animals and humans, with an obligate requirement in many situations that pertain to cell proliferation. The quantitative needs of such processes, however, are not defined. Similarly, although studies in vitro have shown that glutamine can act as a metabolic regulator, particularly through osmotic actions and alterations in the status of cell hydration, these effects are less certain under conditions in vivo. The clearest action of glutamine as a therapeutic agent relates to digestive tract disorders, but for a number of these, alternative nutritional strategies may have a similar beneficial role. There may be specific periods, e.g., during early weaning, when glutamine supplementation is beneficial but these are usually of relatively short duration and the timing may well be critical to achieve effective treatment. Although the involvement of glutamine in maintenance and activation of the immune system would seem to be important, effective strategies will probably involve supplementation with other critical AA, rather use of glutamine alone. It is clear that there are important differences among species in various aspects of glutamine metabolism and caution must be used when extrapolating data across species, particularly in application to human therapies.
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FOOTNOTES |
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3 Present address: Institute for Food, Nutrition and Human Health, Massey University, Private Bag 11 222, Palmerston North, New Zealand.
4 Abbreviations used: AA, amino acid; LPS,
lipopolysaccharide.
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LITERATURE CITED |
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