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chapter 15
Carbohydrate Metabolism II: Gluconeogenesis, Glycogen Synthesis and Breakdown, and Alternative Pathways
These actions of all four transport proteins are re-
versible. Phosphate transport protein
Toft
can transport
pyrophosphate and carbamoyl phosphate as well as PH
pro-
viding substrates and removing products for several other
reactions (of unknown metabolic significance), which
are also catalyzed by glucose-
6
-phosphatase. The impor-
tance of each member of the glucose-
6
-phosphate hy-
drolysis system is reflected in the occurrence of glyco-
gen storage diseases. Deficiency of any of these five
proteins leads to glycogen storage diseases (discussed
later).
Thus, gluconeogenesis requires the participation of en-
zymes of the cytosol, mitochondrion, and smooth endo-
plasmic reticulum, as well as of several transport systems,
and it may involve more than one tissue. The complete
gluconeogenic pathway, culminating in the release of glu-
cose into the circulation, is present only in liver and kidney.
Most tissues contain only some of the necessary enzymes.
These “partial pathways” are probably used in glycero-
genesis and in replenishing tricarboxylic acid (TCA) in-
termediates. Muscle can also convert lactate to glycogen,
but this probably takes place only in one type of muscle
fiber and only when glycogen stores are severely depleted
and lactate concentrations are high, such as after heavy
exercise.
Under normal conditions, the liver provides 80% or
more of the glucose produced in the body. During pro-
longed starvation, however, this proportion decreases,
while that synthesized in the kidney increases to nearly
half of the total, possibly in response to a need for NH
3
to neutralize the metabolic acids eliminated in the urine in
increased amounts (Chapter 22).
Gluconeogenesis is a costly metabolic process. Conver-
sion of two molecules of pyruvate to one of glucose con-
sumes six high-energy phosphate bonds (4ATP + 2GTP
-> 4ADP + 2GDP +
6
Pj) and results in the oxidation of
two NADH molecules (Figure 15-1). In contrast, gly-
colytic metabolism of one molecule of glucose to two
of pyruvate produces two high-energy phosphate bonds
(2ADP + 2Pj —►
2ATP) and reduces two molecules of
NAD+. For gluconeogenesis to operate, the precursor sup-
ply and the energy state of the tissue must be greatly
increased. Using some gluconeogenic precursors to pro-
vide energy (via glycolysis and the TCA cycle) to con-
vert the remainder of the precursors to glucose would be
inefficient, even under aerobic conditions. Usually, the
catabolic signals (catecholamines, cortisol, and increase
in glucagon/insulin ratio) that increase the supply of glu-
coneogenic precursors also favor lipolysis, which provides
fatty acids to supply the necessary ATP.
When amino acid carbons are the principal gluco-
neogenic precursors, the metabolic and physiological
debts are particularly large compared to those incurred
when lactate or glycerol is used. Amino acids are derived
by breakdown of muscle protein, which is accompanied
by a loss of electrolytes and tissue water. One kilo-
gram of muscle contains about 150 g of protein, which
can be used to form about 75 g of glucose. However,
1 kg of muscle also contains 1,200 mM of K+, 27 mM
of phosphate, and
8
mM of Mg2+, all of which must
be excreted by the kidney. The ammonia released from
catabolism of the amino acids is converted to urea in an
energy-requiring process, and the urea further increases
the osmotic load on the kidney. Renal excretion of these
solutes necessitates mobilization of at least 2 L of water
from other tissues in addition to the 750 mL released
from the muscle, and osmotic diuresis may result from
catabolism of even a relatively small amount of mus-
cle. Finally, if fat metabolism is stimulated, as in star-
vation and diabetes mellitus, increased plasma levels of
fatty acids and ketone bodies causes acidemia. To pre-
vent severe acidosis, renal proton excretion is increased
by increasing secretion of ammonia into the renal tubules.
Excretion of nitrogen as ammonia avoids energy con-
sumption due to urea synthesis, but it doubles the os-
motic load per nitrogen excreted, causing even greater
diuresis. Without a compensatory increase in water in-
take, profound depletion of blood volume can occur
(Chapter 22).
Gluconeogenic Precursors
Gluconeogenic precursors include lactate, alanine, and
several other amino acids, glycerol,
and propionate
(Chapter 22).
Lactate,
the
end
product
of
anaerobic
glucose
metabolism, is produced by most tissues of the body,
particularly skin, muscle, erythrocytes, brain, and in-
testinal mucosa. In a normal adult, under basal condi-
tions, these tissues produce 1,300 mM of lactate per
day, and the normal serum lactate concentration is less
than 1.2 mM/L. During vigorous exercise, the produc-
tion of lactate can be increased several fold. Lactate is
normally removed from the circulation by liver and kid-
ney. Because of its great capacity to use lactate, liver
plays an important role in the pathogenesis of lactic aci-
dosis, which may be thought of as an imbalance between
the relative rates of production and utilization of lactate
(Chapter 39).
Alanine,
derived from muscle protein and also syn-
thesized in the small intestine, is quantitatively the most
important amino acid substrate for gluconeogenesis. It
is converted to pyruvate by alanine aminotransferase
(Chapter 17):
Alanine + a-ketoglutarate2- <
— pyruvate- + glutamate-
