liferation of lymphocytes and for mRNA synthe-
sis and DNA repair in macrophages. This will
also be important for the production of these
and other cells in the bone marrow, especially
when stimulated to increase their production
during trauma, infection, burns and if white cells
are damaged, for example, during exercise.
However, when it has been quantitatively
studied—so far, only in lymphocytes—the rate of
glutaminolysis is very markedly in excess of the
rates of synthesis of these compounds. For
example, the rate of utilization of glutamine by
lymphocytes is very much greater than the
measured rate of synthesis of uridine nucleotides
and much higher than the maximum activity of
the rate limiting enzyme, carbamoyl phosphate
synthase II (Newsholme & Leech 1999).
A theory has been proposed which accounts
both for these high rates of glutamine utilization
and the fact that its oxidation is partial. The syn-
thetic pathways for de novonucleotide synthesis
require specific and precise increases in the rate
of synthesis of these nucleotides during the
proliferative process. This theory is known as
branched point sensitivityand has been discussed
in detail elsewhere (Newsholme et al.1985). The
important point to emerge from this is that gluta-
mine (and glucose) must be used at a high rate by
some of the cells of the immune system even
when they are quiescent, since an immune chal-
lenge can occur at any time so that cells must be
‘primed’ to respond whenever there is an inva-
sion by a foreign organism. This requires gluta-
mine to be available in the bloodstream at a fairly
constant level. Furthermore, if pyruvate pro-
duced from glutamine were fully oxidized via
the Krebs cycle, the cells might produce too
much ATP, and this could lead to inhibition of the
rates of glutaminolysis and branched-point
sensitivity would be lost. Consistent with the
branched-point sensitivity theory, it has been
shown that a decrease in the glutamine concen-
tration in culture medium below that normally
present in plasma decreases the maximum rate of
proliferation and slows the response to a mito-
genic signal in both human and rat lymphocytes,
even though they are provided with all other
160 nutrition and exercise
nutrients and growth factors in excess (Parry-
Billingset al.1990b). In addition, a decrease in
glutamine concentration also decreased phago-
cytosis and the rate of cytokine production by
macrophages.
Several tissues, including liver, muscle,
adipose and lung, can synthesize and release glu-
tamine into the bloodstream. This is important,
since 50–60% of the glutamine that enters the
body via protein in the diet is utilized by the
intestine. Thus, the glutamine required by other
tissues, including the immune system, must be
synthesized within the body. Quantitatively, the
most important tissue for synthesis, storage and
release of glutamine is thought to be skeletal
muscle. As much glutamine is stored in muscle
as glycogen is stored in liver, and the rate of
release across the plasma membrane, which
occurs via a specific transporter, appears to be
controlled by various hormones (Newsholme &
Parry-Billings 1990). Because of the importance
of glutamine for cells of the immune system, it is
suggested that immune cells may communicate
with skeletal muscle to regulate the rate of gluta-
mine release. This may also involve some
cytokines and glucocorticoids.
The plasma concentration of glutamine is
decreased in conditions such as major surgery
(Powellet al.1994); burns (Stinnett et al.1982;
Parry-Billingset al.1990b); starvation (Marliss
et al.1971); sepsis (Clowes et al.1980; Roth et al.
1982). There is also evidence that the immune
system is suppressed in clinical trauma (Baker et
al.1980; Green & Faist 1988). The requirement for
glutamine, synthesized within muscle and other
cells, will therefore be increased in these condi-
tions, since there will be increased activity of the
immune system, and an increased number of
cells involved in proliferation and repair. Simi-
larly, damage caused to muscle by prolonged,
exhaustive exercise will also lead to a greater
demand for glutamine. Although the plasma
glutamine concentration is increased in athletes
undertaking short-term exercise (Decombaz et al.
1979), it is decreased in prolonged, exhaustive
exercise (Poortmans et al.1974; Castell et al.1996)
and in overtraining (Parry-Billings 1989; Parry-