Metabolic Homeostasis
humans can exist with little or no dietary carbohydrate in-
take. In Western cultures, the diet generally consists of
approximately 45% carbohydrate, 43% lipid, and 10%
protein. Of the carbohydrate, about 60% is starch, 30%
sucrose, and most of the remainder lactose. In less affluent
cultures, the typical diet contains more grains and vegeta-
bles, with correspondingly higher levels of carbohydrate.
Dietary carbohydrate is digested to glucose (80%), fruc-
tose (15%), and galactose (5%). Glucose and galactose are
actively transported directly into the blood by the intestinal
cells. Fructose is absorbed by a specific system that is dis-
tinct from glucose and galactose absorption (Chapter 12).
Part of the fructose is metabolized by the intestinal cells,
and the rest enters the portal blood. Liver and kidney are
the other sites of fructose utilization (Chapter 13).
Disposition of High Glucose Intake
A temporary rise in plasma glucose concentration immedi-
ately follows a meal, but within 2-3 hours the level returns
to the preprandial level. Several factors influence the blood
glucose profile.
1. Digestion and absorption of carbohydrate are very
rapid. The rate of appearance of glucose in plasma is
determined by gastric motility and emptying and by
intestinal absorption. The glucose peak is
characteristically only 30-50% above the fasting
level. If the total amount of glucose in a typical meal
(50-100 g) were to enter the blood and not be used
immediately, total blood glucose would go up almost
fourfold. This rise does not occur because the glucose
entering the plasma is rapidly taken up by the tissues.
The influx of glucose following a meal is
accompanied by a rapid decrease in hepatic secretion
of glucose, while utilization by tissues dependent
on glucose remains unchanged. Thus the rise in blood
glucose level after a meal reflects only a portion of
the glucose entering the system from digestion and
absorption. During fasting blood glucose remains at a
constant level because utilization is matched by
2. The rise in blood glucose level is quickly followed by
a rise in the blood insulin level which increases three-
to tenfold. An elevated blood glucose level directly
stimulates pancreatic insulin release, as do leucine
and arginine derived from digestion of protein.
Release of gastrin, cholecystokinin, gastric inhibitory
peptide, and glicentin appears to stimulate insulin
release in an anticipatory manner in addition to
regulating other digestive responses.
3. Concomitant with insulin release are changes in
glucagon release, whose magnitude and direction
depend on dietary composition. If the diet contains
only carbohydrate, glucagon secretion falls
precipitously because of direct inhibition of the
cells by glucose and of the insulin released from
cells. On a diet high in protein, glucagon secretion
is stimulated as a consequence of amino acid influx.
After a meal that contains both carbohydrate and
protein, plasma glucagon levels may not change
4. The liver is freely permeable to glucose and typically
extracts about half of the carbohydrate load. This
glucose is phosphorylated to glucose-
-phosphate by
glucokinase and hexokinase. After a glucose load,
glucokinase is more important because it has a high
is inducible, and is sensitive in a wide range of
glucose concentrations. After overnight fasting, most
carbohydrate taken up by the liver is converted to
glycogen. This regulation is illustrated in
Figure 22-10.
Insulin promotes dephosphorylation of the inactive
glycogen synthase D to the active glycogen synthase I
form. Depressed levels of glucagon and elevated
levels of insulin decrease hepatic cAMP levels and
the cAMP-dependent protein kinase inactivation of
glycogen synthase. High levels of glucose promote
high levels of glucose-
-phosphate, a feed-forward,
allosteric, positive modifier of glycogen synthase, and
result in hepatic glucose storage. Glycogen synthesis
is affected by the level of glycogen itself, which
inhibits glycogen synthase phosphatase. All of these
events occur rapidly. Insulin also has a long-term
effect on the liver by inducing the synthesis of
glucokinase (see also Chapter 15).
-phosphate .
Glycogen synthase D
ΓΏ \ Protein kin ase-
cA M P
Glycogen synthase I
FIGURE 22-10
Hepatic glycogen synthesis after a meal. The permeability of the liver to
glucose provides the substrate for hepatic glycogen synthesis. This
synthesis is controlled by (1) activation of glycogen synthase by insulin,
(2) allosteric activation of glycogen synthase by glucose-6-phosphate, and
(3) absence of cAMP, blocking the cAMP-dependent protein kinase
inactivation of glycogen synthase. Synthesis ends when glycogen stores are
high as a result of inhibition of glycogen synthase phosphatase by
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