Human Physiology, 14th edition (2016)

Regulation of Metabolism 679

molecules are thus increased while the plasma concentrations of

glucose and amino acids are decreased. It should be noted that

skeletal muscles are the primary targets of insulin action, and are

responsible for most of the insulin-stimulated uptake of plasma

glucose.

A nonobese 70-kg (155-lb) man has approximately 10 kg

(about 82,500 kcal) of stored fat. Because 250 g of fat can sup-

ply the energy requirements for 1 day, this reserve fuel is suffi-

cient for about 40 days. Glycogen is less efficient as an energy

reserve, and less is stored in the body; there are about 100 g

(400 kcal) of glycogen stored in the liver and 375 to 400 g

(1,500 kcal) in skeletal muscles. Insulin promotes the cellular

uptake of glucose into the liver and muscles and the conversion

of glucose into glucose 6-phosphate. In the liver and muscles,

this can be changed into glucose 1-phosphate, which is used as

the precursor of glycogen. Once the stores of glycogen have

been filled, the continued ingestion of excess calories results in

the production of fat rather than of glycogen.

The high insulin secretion during the absorptive state, when

blood glucose levels are rising, also inhibits the liver from secret-

ing more glucose into the blood. Insulin may directly inhibit

glucose production by the liver, but evidence also supports an

indirect action by way of the CNS. In this, insulin acts on the

hypothalamus (particularly the arcuate nucleus) to inhibit vagus

nerve stimulation of the liver’s glucose secretion. By contrast,

during the postabsorptive state, when blood glucose and insulin

secretion are falling (discussed next), the liver is freed from this

inhibition and does secrete glucose into the blood.

Insulin and Glucagon:

Postabsorptive State

The plasma glucose concentration is maintained surprisingly

constant during the fasting, or postabsorptive, state because of

the secretion of glucose from the liver. This glucose is derived

from the processes of glycogenolysis and gluconeogenesis,

which are promoted by a high secretion of glucagon coupled

with a low secretion of insulin.

Glucagon stimulates and insulin suppresses the hydrolysis of

liver glycogen, or glycogenolysis. Thus during times of fasting,

when glucagon secretion is high and insulin secretion is low, liver

glycogen is used as a source of additional blood glucose. This

results in the liberation of free glucose from glucose 6-phosphate

by the action of an enzyme called glucose 6-phosphatase (chap-

ter 5; see fig. 5.5). Only the liver has this enzyme, and therefore

only the liver can use its stored glycogen as a source of additional

blood glucose. The liver has about 100 g of stored glycogen,

whereas skeletal muscles have about 400 g of glycogen. However,

the muscles can use their stored glycogen only for themselves,

because muscles lack the glucose 6-phosphatase enzyme needed

to form free glucose for secretion into the blood.

The 100 g of stored glycogen in the liver would not last

long during prolonged fasting or exercise if this were the

only source of glucose for the blood. However, the low lev-

els of insulin secretion during fasting, together with elevated

solution is reversed to normal levels within two hours follow-
ing glucose ingestion. In contrast, the plasma glucose concen-
tration remains at 200 mg/dl or higher two hours after the oral
glucose challenge in a person with diabetes mellitus.
Insulin secretion is also stimulated by particular amino
acids derived from dietary proteins. Meals that are high in pro-
tein, therefore, stimulate the secretion of insulin; if the meal is
high in protein and low in carbohydrates, glucagon secretion
will be stimulated as well. The increased glucagon secretion
acts to raise the blood glucose, while the increased insulin pro-
motes the entry of amino acids into tissue cells.

Effects of Autonomic Nerves

The islets of Langerhans receive both parasympathetic and sym-
pathetic innervation. The parasympathetic division of the auto-
nomic system is activated during meals and stimulates both
gastrointestinal function and the secretion of insulin from the beta
cells of the islets. This occurs because ACh stimulates muscarinic
ACh receptors to cause a depolarization. By contrast, norepineph-
rine released by sympathetic axons, and somatostatin released by
the delta cells of the pancreatic islets, inhibit insulin secretion by
promoting membrane repolarization. At the same time, sympa-
thetic nerve stimulation promotes the secretion of glucagon from
the alpha cells of the islets. Glucagon and epinephrine then work
together to produce a stress hyperglycemia (due to hydrolysis of
glycogen to glucose and the secretion of glucose from the liver)
when the sympathoadrenal system is activated.

Effects of Intestinal Hormones

Surprisingly, insulin secretion increases more rapidly when
glucose is taken by mouth than when glucose is injected intra-
venously. This is because, when glucose is taken orally, the intes-
tine secretes hormones that stimulate insulin secretion before the
glucose has even been absorbed. Insulin secretion thus begins to
rise “in anticipation” of a rise in blood glucose. Two intestinal
hormones that are powerful stimulators of insulin secretion are
glucagon-like polypeptide 1 (GLP-1), secreted by the ileum, and
glucose-dependent insulinotropic polypeptide (GIP), secreted
by the duodenum. These two intestinal hormones that stimulate
insulin secretion in anticipation of glucose absorption have been
termed incretins, as described in chapter 18, section 18.6.

Insulin and Glucagon:

Absorptive State

The lowering of plasma glucose by insulin is, in a sense, a side
effect of the primary action of this hormone. Insulin is the major
hormone that promotes anabolism in the body. During absorp-
tion of the products of digestion into the blood, insulin promotes
the cellular uptake of plasma glucose and its incorporation into
energy-reserve molecules of glycogen in the liver and muscles,
and of triglycerides in adipose cells (chapter 11; see fig. 11.31).
Insulin also promotes the cellular uptake of amino acids and their
incorporation into proteins. The stores of large energy-reserve