section 15.3
Alternative Pathways of Glucose Metabolism and Hexose Interconversions
297
3-phosphate
and
glyceraldehyde.
Glyceraldehyde
is
phosphorylated by triokinase, and glyceraldehyde 3-
phosphate and dihydroxyacetone 3-phosphate can either
enter the glycolytic pathway or be combined to form
fructose- 1,6-bisphosphate by the action of fructose-1,6-
bisphosphate aldolase. Thus, fructose metabolism by-
passes phosphofructokinase, the major regulatory site of
glycolysis.
Most dietary fructose is converted to glucose by way
of gluconeogenesis, through condensation of the triose
phosphates to fructose-1,6-bisphosphate. However, ad-
ministration of large doses of fructose (i.e., by intra-
venous feeding) may lead to hypoglycemia and lactic
acidosis because of saturation of aldolase B, causing
accumulation of fructose-1-phosphate, and depletion of
intracellular ATP and inorganic phosphate. This situa-
tion may be likened to
hereditary fructose intolerance,
which is caused by inadequate amounts of aldolase B
activity. Although normally asymptomatic, individuals
with this condition exhibit hypoglycemia, metabolic aci-
dosis, vomiting, convulsions, coma, and signs of liver
failure following ingestion of fructose or sucrose. The
fructose-induced hypoglycemia arises from accumulation
of fructose-1-phosphate, reduction in the [ATP]/[ADP]
ratio, and depletion of inorganic phosphate. Fructose-1-
phosphate depresses gluconeogenesis and promotes gly-
colysis, while inorganic phosphate depletion inhibits ATP
synthesis (Chapter 14). Glycogenolysis is inhibited by
fructose-1-phosphate at the level of phosphorylase. If su-
crose, fructose, and sorbitol are eliminated from the diet,
complete recovery occurs. High levels of fructose also in-
crease purine turnover owing to enhanced ATP utilization,
which leads to increased production of purine degradation
products—inosine, hypoxanthine, xanthine, and uric acid
(Chapter 27).
Fructose and sorbitol have been recommended as sub-
stitutes for sucrose in diabetic diets because they are much
sweeter than sucrose. Foods can be made more palatable
even when the total carbohydrate content is reduced by
replacing sucrose with fructose or sorbitol. Their insulin-
independent metabolism has also been cited as a reason for
substituting them for glucose or sucrose in diabetic diets.
In severe physical injury, hyperglycemia and insulin resis-
tance are common, and inclusion of fructose and sorbitol in
the parenteral nutrition formulations for these patients has
been suggested. In small amounts, fructose and sorbitol
could benefit both groups of patients. In large amounts,
however, they can severely damage the liver by depleting
ATP stores, and they can cause hypoglycemia and lactic
acidosis.
When sorbitol and fructose are taken by mouth, the
increase in blood fructose is modulated by their rates
of absorption from the intestine, preventing the serious
metabolic problems caused by high concentrations of
these sugars. Most normal diets do not result in adverse
effects, except in patients with hereditary fructose intol-
erance. However, when sorbitol and fructose are given
parenterally, this important modulating action is lost, and
serious side effects can occur. Sorbitol and fructose as in-
travenous nutrients are not widely employed in the United
States.
Sorbitol has been implicated in cataract formation in
diabetics. In general, cataracts are formed when the lens
of the eye becomes cloudy, probably because of a change
in solubility of lens proteins. Because entry of glucose
into the lens does not require insulin, intravenous and in-
tralenticular glucose concentrations increase in parallel.
In diabetics, quite high concentrations can be achieved.
In the lens, glucose is converted to sorbitol by aldose re-
ductase, an NADPH-dependent enzyme present in many
tissues. Unlike glucose, sorbitol does not diffuse readily
across the lenticular membrane but accumulates within the
lens, increasing osmolarity and causing water retention. A
reduction in lens glutathione concentration parallels the
increase in water content and may reflect the depletion
of NADPH by the aldose reductase reaction and lead to
oxidation and denaturation of lens proteins. The lens is
particularly susceptible to oxidative damage because it is
exposed to a high oxygen concentration.
Galactose Metabolism
Most galactose ingested by humans is in the form of lactose
(Chapter 9), the principal sugar in human and bovine milk.
Milk sugar other than lactose is found in the sea lion and
marsupials, whose first pouch milk contains a trisaccha-
ride of galactose. Lactose is hydrolyzed to galactose and
glucose by lactase, located on the microvillar membrane
of the small intestine (Chapter 12). Following absorption,
galactose is transported to the liver, where it is converted to
glucose (Figure 15-17). The enzymes required are found
in many tissues, but the liver is the quantitatively most
important site for this epimerization.
Galactose is a poor substrate for hexokinase; it is
phosphorylated by galactokinase. Galactose-1-phosphate
is converted to UDP-galactose by galactose-1-phosphate
uridylyltransferase. This enzyme may be regulated by sub-
strate availability, since the normal hepatic concentration
of galactose-1-phosphate is close to the
Km
for this en-
zyme. The transferase is inhibited by UDP, UTP, glucose-
1-phosphate, and high concentrations of UDP-glucose.
Deficiency of galactokinase or transferase can cause
galactosemia.
Galactose is isomerized to glucose by UDP-galactose-
4-epimerase in what may be the rate-limiting step in
galactose metabolism. The reaction, which is freely
