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U N I T 9
Endocrine System
class of drugs has been shown to reduce hyperglycemia
in patients with diabetes.
5
Glucagon
Glucagon, a polypeptide molecule produced by the alpha
cells of the islets of Langerhans, helps to maintain blood
glucose between meals and during periods of fasting.
2,3
Like insulin, glucagon travels through the portal vein
to the liver, where it exerts its main action, which is to
increase blood glucose (Table 33-1). The most dramatic
effect of glucagon is its ability to initiate glycogenolysis
(the breakdown of glycogen) as a means of raising blood
glucose, usually within a matter of minutes. Glucagon
also increases the transport of amino acids into the liver
and stimulates their conversion into glucose through the
process of gluconeogenesis. Because liver glycogen stores
are limited, gluconeogenesis is important in maintaining
blood glucose levels over time. Other actions of glucagon
occur only when the hormone is present in high concen-
trations, usually well above those normally present in the
blood. At high concentrations, glucagon activates adipose
cell lipase, making fatty acids available for use as energy.
2
Glucagon secretion is regulated by blood glucose.
A decrease in blood glucose concentration produces
an immediate increase in glucagon secretion, and an
increase produces a decrease in glucagon secretion. High
concentrations of amino acids, as occur after a protein
meal, also can stimulate glucagon secretion. In this way,
glucagon increases the conversion of amino acids to glu-
cose as a means of maintaining the body’s glucose levels.
Glucagon levels also increase during strenuous exercise
as a means of preventing a decrease in blood glucose.
Amylin, Somatostatin, and Gut-Derived
Hormones
Islet amyloid polypeptide, or
amylin,
was originally
identified as a major constituent of pancreatic amyloid
deposits in persons with type 2 diabetes and subsequently
shown to be a polypeptide that is cosecreted with insu-
lin from the beta cells in the pancreas.
3,5
Plasma levels
of amylin increase in response to nutritional stimuli to
produce inhibition of gastric emptying and glucagon
secretion. As with insulin, the active form of amylin is
derived from a larger proamylin precursor. Although the
active form of amylin is soluble and acts as a hormone,
there has been renewed interest in the less soluble and
insoluble forms, which may cause degeneration of the
beta cells and contribute to the pathogenesis of overt
diabetes.
5
Somatostatin
is a polypeptide hormone contain-
ing only 14 amino acids that has an extremely short
half-life.
2,3
Somatostatin secreted by the delta cells acts
locally in the islets of Langerhans to inhibit the release
of insulin and glucagon. It also decreases gastrointes-
tinal activity after ingestion of food. Almost all fac-
tors related to ingestion of food stimulate somatostatin
secretion. By decreasing gastrointestinal activity, soma-
tostatin is thought to extend the time during which food
is absorbed into the blood, and by inhibiting insulin and
glucagon, it is thought to extend the use of absorbed
nutrients by the tissues.
2
Several
gut-derived hormones
have been identified
as having what is termed an
incretin effect,
meaning
that they increase insulin release after an oral nutri-
ent load
2,3,6
(see Chapter 28). This suggests that gut-
derived factors can stimulate insulin secretion after a
predominantly carbohydrate meal. The two hormones
that account for about 90% of the incretin effect are
glucagon-like peptide-1, which is released from L cells
in the distal small intestine, and glucose-dependent insu-
linotropic polypeptide, which is released by K cells more
proximally (mainly in the jejunum).
Counterregulatory Hormones
Other hormones that can affect blood glucose include
the catecholamines, growth hormone, and the gluco-
corticoids. These hormones, along with glucagon, are
sometimes called
counterregulatory hormones
because
they counteract the storage functions of insulin in reg-
ulating blood glucose levels during periods of fasting,
exercise, and other situations that either limit glucose
intake or deplete glucose stores.
Epinephrine.
Epinephrine, a catecholamine, helps to
maintain blood glucose levels during periods of stress.
Epinephrine has the potent effect of stimulating glyco-
genolysis in the liver, thus causing large quantities of
glucose to be released into the blood. It also inhibits
insulin release from the beta cells and thereby decreases
the movement of glucose into muscle cells, while at the
same time increasing the breakdown of muscle glycogen
stores. Although the glucose that is released from muscle
glycogen cannot be released into the blood, the mobi-
lization of these stores for muscle use conserves blood
glucose for use by other tissues such as the brain and
nervous system. Epinephrine also has a direct lipolytic
effect on adipose cells, thereby increasing the mobiliza-
tion of fatty acids for use as an energy source. The blood
glucose–elevating effect of epinephrine is an important
homeostatic mechanism during periods of hypoglycemia.
Growth Hormone.
Growth hormone has many met-
abolic effects. It increases protein synthesis in all cells
of the body, mobilizes fatty acids from adipose tissue,
and antagonizes the effects of insulin. Growth hormone
decreases cellular uptake and use of glucose, thereby
increasing the level of blood glucose. The increased
blood glucose level stimulates further insulin secretion
by the beta cells. The secretion of growth hormone
normally is inhibited by insulin and increased levels of
blood glucose. During periods of fasting, when both
blood glucose levels and insulin secretion fall, growth
hormone levels increase. Exercise, such as running and
cycling, and various stresses, including anesthesia, fever,
and trauma, also increase growth hormone levels.
Chronic hypersecretion of growth hormone, such as
occurs in acromegaly (see Chapter 32), can lead to glucose
intolerance and the development of diabetes mellitus. In
people who already have diabetes, moderate elevations in
