summary, these data suggest that after consump-
tion of protein-containing meals, BCAA and glu-
tamate are taken up by muscle and their carbon
skeletons are used for de novosynthesis of
glutamine.
Function of muscle glutamine synthesis
and release
In the previous sections it has become clear that
glutamine is the main end product of muscle
amino acid metabolism both in the overnight
fasted state and during feeding. Alanine only
serves to export part of the amino groups. Gluta-
mine is the most abundant amino acid in human
plasma (600–700mm) and in the muscle free
amino acid pool (20 mm; 60% of the intramuscu-
lar pool excluding the nonprotein amino acid
taurine). The synthesis rate of glutamine in
muscle is higher than that of any other amino
acid. Extrapolations of limb production rates in
the fed and fasted state suggest that between 10
and 25 g of glutamine is synthesized in the com-
bined human skeletal muscles per day. Tracer
dilution studies even indicate that 80 g of gluta-
mine is produced per day (Darmaun et al. 1986),
but this may be a methodological overestimation
due to slow mixing of the glutamine tracer with
the large endogenous glutamine pool in muscle
(Van Acker et al. 1998). Furthermore, although
muscle is the main glutamine-producing tissue,
other tissues (e.g. adipose tissue, liver and brain)
may also contribute to the rate of appearance of
glutamine in the plasma pool that is measured by
tracer dilution techniques.
The reason for this high rate of glutamine pro-
duction in muscle probably is that glutamine
plays an important role in human metabolism in
other organs. Sir Hans Krebs (1975) has already
written:
Maybe the significance of glutamine synthesis
is to be sought in the role of glutamine in other
organs, as a precursor of urinary ammonia and
as a participant in the biosynthesis of purines,
NAD+, amino sugars and proteins. Glutamine
is an important blood constituent, present in
higher concentrations than any other amino
124 nutrition and exercise
acid, presumably to serve these various func-
tions. Muscle may play a role in maintaining
the high plasma concentration of glutamine.
Glutamine has been shown to be an important
fuel for cells of the immune system (Ardawi &
Newsholme 1983) and for mucosal cells of the
intestine (Windmueller & Spaeth 1974; Souba
1991). Low muscle and plasma glutamine con-
centrations are observed in patients with sepsis
and trauma (Vinnars et al.1975; Rennie et al. 1986;
Lacey & Wilmore 1990), conditions that also are
attended by mucosal atrophy, loss of the gut
barrier function (bacterial translocation) and a
weakened immune response. Although the link
between the reduced glutamine concentrations
and these functional losses has not been fully
underpinned by experimental evidence, the pos-
sibility should seriously be considered that it is a
causal relationship. Due to its numerous meta-
bolic key functions and a potential shortage in
patients with sepsis and trauma, glutamine has
recently been proposed to be a conditionally
essential amino acid (Lacey & Wilmore 1990),
which should especially be added to the nutri-
tion of long-term hospitalized critically ill and
depleted patients. These patients have a reduced
muscle mass due to continuous muscle wasting
and therefore probably also a reduced capacity
for glutamine production.Glutamine–glutamate cycle
The existence of the glutamine–glutamate cycle
was first demonstrated by Marliss et al. (1971). In
muscle there is a continuous glutamate uptake
and glutamine release with the glutamate uptake
accounting for about half of the glutamine
release. Most of the glutamine produced by
muscle is extracted by the splanchnic bed, most
probably partly by the gut (Souba 1991) and
partly by the liver (Ross et al. 1967). This gluta-
mine is converted to glutamate and ammonia by
glutaminase. When generated in the gut, the
ammonia is transported via the portal vein to the
liver and disposed of as urea; the same holds for
ammonia generated in the liver. About half of the
glutamate is retained in the splanchnic area and