section 15.3
Alternative Pathways of Glucose Metabolism and Hexose Interconversions
291
with its concentration in the blood. The postprandial rise
in blood glucose contributes to the inhibition of hepatic
glycogenolysis and to the activation of glycogen synthesis.
Following a meal, the blood level of insulin also rises,
while that of glucagon falls. As glucagon concentration
decreases, activity of the hepatocyte adenylate cyclase
decreases and cytosolic cAMP concentration falls owing
to degradation by phosphodiesterase. The result is a de-
creased phosphorylation of glycogen synthase and phos-
phorylase, activation of the synthase, and inhibition of the
phosphorylase. Insulin, which may accelerate this shift,
can also directly antagonize the cAMP-mediated effects of
glucagon. The mechanisms of insulin action may include
activation of a low-A"m
cAMP-phosphodiesterase, reduc-
tion in basal activity of cAMP-dependent protein kinase,
or increase in basal activity of glycogen synthase phos-
phatase. Since the effects on the kinase and phosphatase
are on basal activities, insulin may affect the metabolism
of glycogen that has not been previously stimulated by
glucagon. The net effect of blood glucose, insulin, and
glucagon, then, is to coordinate the relative rates of hep-
atic glycogen synthesis and breakdown (see Chapter 22).
In shock, inadequate perfusion of the heart, brain, and
other organs is due to a variety of causes. The body’s re-
sponses include release of epinephrine from the adrenal
medulla, release of vasopressin from the neurohypoph-
ysis, and activation of the renin-angiotensin system with
elevation of angiotensin II. In the liver, epinephrine (act-
ing as an a-adrenergic agonist), vasopressin, and an-
giotensin II increase the intrahepatocytic [Ca2+], stimulat-
ing glycogenolysis. The consequent rise in blood glucose
provides a rapid energy source in times of stress. Since
shock is often caused by an absolute (hemorrhage) or rel-
ative (vasodilation) decrease in intravascular volume, re-
lease of the large amount of water of hydration stored with
glycogen may contribute to restoration of blood volume.
Glycogen Storage Diseases
This group of diseases is characterized by accumulation
of normal or abnormal glycogen due to deficiency of
one of the enzymes of glycogen metabolism. Although
all are rare (overall incidence of ~ 1:25,000 births), they
have contributed greatly to the understanding of glyco-
gen metabolism. They are summarized in Table 15-1 and
Figure 15-13.
Infants with type I disease (subtypes la, lb, Ic, and Id)
develop hypoglycemia even after feeding because of in-
ability to convert glucose-
6
-phosphate to glucose. Lac-
tate is produced at a high rate in extrahepatic tissues and
is transported to the liver for gluconeogenesis. The low
insulin and high glucagon levels caused by hypoglycemia
promote glycogenolysis, leading to an unusual metabolic
substrate cycle in these infants (Figure 15-14). The small
amount of glucose released by the action of debranching
enzyme is the only endogenous source of glucose available
to these patients.
Many characteristics of type I disease are attributed to
the attendant hypoglycemia, and patients have been treated
with frequent daytime feedings and continuous nocturnal
intragastric feeding with a high-glucose formula. This
regimen produces substantial improvement in growth,
reduction in hepatomegaly, and normalization of other
biochemical parameters. Feeding uncooked cornstarch
every
6
hours resulted in normoglycemia, resumption of
normal growth, and reduction in substrate cycling and
liver size. The success of this simple nutritional therapy
is thought to depend on slow hydrolysis of uncooked
starch in the small intestine by pancreatic amylase, with
continuous release and absorption of glucose. (Cornstarch
that is cooked or altered in other ways is ineffective,
presumably because of too rapid hydrolysis.) The therapy
is ineffective in patients with low pancreatic amylase
activity due, for example, to prematurity.
15.3 Alternative Pathways of Glucose
Metabolism and Hexose Interconversions
Glucuronic A cid Pathway
The
glucuronic acid pathway
(Figure 15-15) is a quanti-
tatively minor route of glucose metabolism. Like the pen-
tose phosphate pathway, it provides biosynthetic precur-
sors and interconverts some less common sugars to ones
that can be metabolized.
The first steps are identical to those of glycogen
synthesis, i.e., formation of glucose-
6
-phosphate, its iso-
merization to glucose-
1
-phosphate, and activation of
glucose-1-phosphate to form UDP-glucose. UDP-glucose
is then oxidized to UDP-glucuronic acid by NAD+ and
UDP-glucose dehydrogenase. An aldehyde intermediate
is formed that remains bound to an amino group on the
enzyme as a Schiff base. Since this is a four-electron oxi-
dation, two molecules of NAD+ are used for each molecule
of UDP-glucuronic acid formed. UDP-glucuronic acid is
bound to the enzyme as a thioester and is released by
hydrolysis.
UDP-glucuronic acid is utilized in biosynthetic reac-
tions that involve condensation of glucuronic acid with a
variety of molecules to form an ether (glycoside), an es-
ter, or an amide, depending on the nature of the acceptor
molecule. As in condensation reactions that use nucleotide
sugars as substrates, the high-energy bond between UDP
and glucuronic acid provides the energy to form the new
