According to the original formulation of the
glucose–alanine cycle, the pyruvate used for
alanine production in muscle either was derived
from glycolysis of blood glucose or from pyru-
vate derived from metabolism of other muscle
protein-derived amino acids. The alanine is then
released to the blood and converted to glucose
via gluconeogenesis in the liver. Carbon derived
from muscle protein in this way was suggested to
help maintain blood glucose concentrations after
overnight fasting and during prolonged starva-
tion. The implication, however, of the above con-
clusions is that all pyruvate is either derived
from glycolysis of blood glucose or from break-
down of muscle glycogen followed by glycolysis.
In a recent tracer study in man (Perriello et al.
1995), 42% of the alanine released by muscle was
reported to originate from blood glucose. This
implies that more than half of the alanine
released by muscle is formed from pyruvate
derived from muscle glycogen. This route pro-
vides a mechanism to slowly mobilize the sitting
muscle glycogen stores during starvation, such
that these stores can be used to help and maintain
the blood glucose concentrations (Fig. 9.2) and
function as fuel in tissues that critically depend
on glucose such as brain, red blood cells and
kidney cortex. The amino acids liberated during
starvation by increased net rates of protein
degradation (Rennie et al. 1982; Cheng et al. 1987;
Pacyet al. 1994) are instead converted to gluta-
mine, which also is a precursor for gluconeogen-
esis in the liver in the postabsorptive state (Ross
et al. 1967). Glutamine also is a precursor for glu-
coneogenesis in the kidney (Wirthensohn &
Guder 1986), but renal gluconeogenesis only
starts to be significant (>10% of total glucose
output) in man after 60 h starvation (Björkman et
al.1980) and is at its highest rate after prolonged
(4–6 weeks) starvation (Owen et al. 1969).
Protein-derived amino acids metabolized in
muscle thus still can help maintain blood glucose
concentration during starvation but by a differ-
ent route from that suggested in the original for-
mulation of the glucose alanine cycle. Recent
tracer studies in man also suggest that glutamine
is more important than alanine as a gluco-
neogenic precursor after overnight starvation
(Nurjhanet al. 1995), and that glutamine is more
important than alanine as a vehicle for transport
of muscle protein-derived carbon and nitrogen
through plasma to the sites of gluconeogenesis or
further metabolism (Perriello et al. 1995).Effect of ingestion of protein or a mixed meal
Following ingestion of a mixed protein-
containing meal, small amounts of most amino
acids are taken up by muscle and most other
tissues as there is net protein deposition in the
fed state (protein synthesis > protein degrada-
tion), which compensates for the net losses in the
overnight fasting period (Rennie et al. 1982;
Chenget al. 1987; Pacy et al. 1994). An excessively
large uptake of BCAA and glutamate is seen in
the 4-h period after ingestion of a mixed meal
(Eliaet al. 1989) and after ingestion of a large
steak (Elia & Livesey 1983). BCAA and glutamate
then together cover more than 90% of the muscle
amino acid uptake. The BCAA originate from
dietary protein. After digestion of dietary protein
most of the resulting BCAA escape from uptake
and metabolism in gut and liver due to the low
BCAA aminotransferase activity in these tissues
(Wagenmakers & Soeters 1995; Hoerr et al. 1991).
The source of the glutamate is not clear today.
The diet only seems to deliver a minor propor-
tion as both a [^15 N] and [^13 C] glutamate tracer
were almost quantitatively removed in the first
pass through the splanchnic area (gut and liver;
Matthews et al. 1993; Batezzati et al. 1995).
Marlisset al. (1971) showed that the splanchnic
area (gut and liver) in man constantly produces
glutamate both after overnight and after pro-
longed starvation. After ingestion of a large steak
the muscle release of glutamine more than
doubles, while the alanine release is reduced to
10% of the overnight fasted value. In the 4-h
period after ingestion of a mixed meal (Elia et al.
1989), the dominance of glutamine in carrying
nitrogen out of skeletal muscle was even more
clear than after overnight fasting. Glutamine
then accounted for 71% of the amino acid release
and 82% of the N-release from muscle. In