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chapter 15
Carbohydrate Metabolism II: Gluconeogenesis, Glycogen Synthesis and Breakdown, and Alternative Pathways
increased by glucocorticoids, thyroxine, and glucagon.
The concentration of glucose-
6
-phosphate, which is also
elevated in diabetes mellitus and following ethanol admin-
istration, is increased 300-fold after a 48-hour fast. Con-
sumption of a low-protein diet reduces the concentration of
glucose-
6
-phosphate. A futile cycle involving glucoki-
nase and glucose-
6
-phosphatase does not occur because
glucose-
6
-phosphatase is active only when the concen-
tration of glucose-
6
-phosphate is high, and glucokinase
is active only when glucose-
6
-phosphate concentration
is low.
ATP
AOP
G lu c o s e ,
— ! G lu c o s e
6
- p h o s p h a te <—
G lu c o n e o g e n e s is
F o r e x tra h e p a tic
G ly c o g e n
G lycolysis
P e n to s e
tis s u e u tilizatio n
s y n th e s is
p h o s p h a te
p a th w a y
Abnormalities of Gluconeogenesis
Glucose is the predominant fuel for cells that depend
largely on anaerobic metabolism, cells that lack mitochon-
dria, and tissues such as brain that normally cannot use
other metabolic fuels. An adult brain represents only 2%
of total body weight, but it oxidizes about
1 0 0
g of glucose
per day, accounting for 25% of the basal metabolism. Brain
cannot utilize fatty acids because they are bound to serum
albumin and so do not cross the blood-brain barrier. Ke-
tone bodies are alternative fuels, but their concentration
in blood is negligible, except in prolonged fasting or di-
abetic ketoacidosis (Chapters 18 and 22). Brain and liver
glycogen stores are small relative to the needs of the brain,
and gluconeogenesis is essential for survival. Decreased
gluconeogenesis leads to hypoglycemia and may cause
irreversible damage to the brain. Blood glucose levels be-
low 40 mg/dL (2.2 mM/L) in adults or below 30 mg/dL
(1.7 mM/L) in neonates represent severe hypoglycemia.
The low levels may result from increased glucose utiliza-
tion, decreased glucose production, or both. Increased glu-
cose utilization can occur in hyperinsulinemia secondary
to an insulinoma. In a diabetic pregnancy, the mother’s
hyperglycemia leads to fetal hyperglycemia and causes fe-
tal and neonatal hyperinsulinemia. Insufficiency of gluco-
corticoids, glucagon, or growth hormone and severe liver
disease can produce hypoglycemia by depressing gluco-
neogenesis (Chapters 22 and 32). Ethanol consumption
can cause hypoglycemia, since a major fraction of ethanol
is oxidized in the liver by
cytosolic alcohol dehydroge-
nase,
and the NADH and acetaldehyde generated inhibit
gluconeogenesis:
CH
3
CH2OH + NAD+ -> CH
3
CHO + NADH + H+
Excessive
NADH
decreases
the
cytosolic
[NAD+]/
[NADH] ratio, increasing lactate dehydrogenase activity
and thereby increasing conversion of pyruvate to lactate.
The decrease in pyruvate concentration inhibits pyruvate
carboxylase. Acetaldehyde inhibits oxidative phosphory-
lation, increasing the [ADP]/[ATP] ratio, promoting gly-
colysis, and inhibiting gluconeogenesis. Hypoglycemia
and lactic acidosis are common findings in chronic
alcoholics.
Pyruvate carboxylase deficiency can cause intermittent
hypoglycemia, ketosis, severe psychomotor retardation,
and lactic acidosis. The deficiency of either cytosolic
or mitochondrial isoenzyme form of phosphoenolpyru-
vatecarboxykinase (PEPCK), is characterized by a fail-
ure of gluconeogenesis. Both these disorders are rare
and the mitochondrial PEPCK deficiency is inherited as
an autosomal recessive trait. The major clinical mani-
festations include hypoglycemia, lactic acidosis, hypo-
tonia, hepatomegaly and failure to thrive. The treatment
is supportive and is based upon symptoms. Fructose-
1
,
6
-bisphosphatase deficiency, inherited as an autosomal
recessive trait, severely impairs gluconeogenesis, caus-
ing hypoglycemia, ketosis, and lactic acidosis. Glucose-
6
-phosphatase deficiency, also an autosomal recessive
trait, causes a similar condition but with excessive de-
position of glycogen in liver and kidney (discussed
later).
Hypoglycin A
(2-methylenecyclopropylalanine), the
principal toxin of the unripe akee fruit, produces severe
hypoglycemia when ingested. A less toxic compound, hy-
poglycin B, is a y -glutamyl conjugate of hypoglycin A.
The akee tree is indigenous to western Africa and grows
in Central America and the Caribbean. Hypoglycin causes
vomiting (“vomiting sickness”) and central nervous sys-
tem depression. In Jamaica, symptoms apparently occur
in epidemic proportions during colder months when the
akee fruit is unripe and other food sources are limited.
The edible portion of the ripe akee fruit, which contains
only small amounts of hypoglycin, is a main dietary staple
in Jamaica.
Hypoglycin A causes hypoglycemia by inhibiting glu-
coneogenesis. In the liver, hypoglycin A forms nonme-
tabolizable esters with CoA (shown below) and carnitine,
depleting the CoA and carnitine pools, thereby inhibit-
ing fatty acid oxidation (Chapter 18). Since the principal
source of ATP for gluconeogenesis is mitochondrial oxida-
tion of long-chain fatty acids, gluconeogenesis is stopped.
Intravenous administration of glucose relieves the hypo-
glycemia.
