INSULIN and GLUCAGON

Insulin
• Insulin is a polypeptide hormone produced by
the β cells of the islets of Langerhans––
clusters of cells that are embedded in the
exocrine portion of the pancreas
• Insulin is the most important hormone
coordinating the use of fuels by tissues.
 A. Structure of insulin
• Insulin is composed of 51 amino acids
arranged in two polypeptide chains,
designated A and B, which are linked together
by two disulfide bridges
 B. Synthesis of insulin
• Biosynthesis involves two inactive precursors,
preproinsulin and proinsulin, which are
sequentially cleaved to form the active
hormone.
• Insulin is degraded by the enzyme insulinase
which is present in the liver and, to a lesser
extent, in the kidneys.
• Insulin has a plasma half-life of approximately
6 minutes. This short duration of action
permits rapid changes in circulating levels of
the hormone.
 Regulation of insulin secretion
• Insulin secretion by the β cells of the islets of
Langerhans of the pancreas is closely
coordinated with the release of glucagon by
pancreatic α cells.
• The relative amounts of insulin and glucagon
released by the pancreas are regulated so that
the rate of hepatic glucose production is kept
equal to the use of glucose by peripheral
tissues.
 Stimulation of insulin secretion
• Glucose:
 Glucose is the most important stimulus for
insulin secretion.
 Glucose also increases expression of the gene
for insulin.
• The β cells are the most important glucose-
sensing cells in the body.

• Ingestion of glucose or a carbohydrate-rich

meal leads to a rise in blood glucose, which is
a signal for increased insulin secretion (as well
as decreased glucagon synthesis and release.)
 Amino acids
• Ingestion of protein causes a transient rise in
plasma amino acid levels, which, in turn,
induces the immediate secretion of insulin.
 Gastrointestinal hormones
• Most gastrointestinal hormones favor insulin
release.
• The intestinal peptides cholecystokinin increase
insulin secretion in response to oral glucose.
• They are released from the small intestine after the
ingestion of food and cause an anticipatory rise in
insulin levels.
• This may account for the fact that the same amount
of glucose given orally induces a much greater
secretion of insulin than if given intravenously.
 Role of Ca+2

Glucose taken into β cells is metabolized followed by production of

ATP.

ATP-sensitive potassium channels close

cause depolarization of the plasma membrane,

activation of voltage-gated calcium channels

influx of calcium into the cell.

Calcium causes vesicles containing insulin to be released from the β

cell.
 Inhibition of insulin secretion
• The synthesis and release of insulin are
decreased when there is
 Deficiency of dietary fuels
 during periods of stress (for example, fever or
infection).
• Epinephrine, (which is secreted by the adrenal medulla in
response to stress, trauma, or extreme exercise has a
direct effect on energy metabolism) causing a rapid
mobilization of energy-yielding fuels, including glucose
from the liver.

• In addition, epinephrine can override the normal glucose-

stimulated release of insulin. Thus, in emergency
situations, the sympathetic nervous system largely
replaces the plasma glucose concentration as the
controlling influence over β-cell secretion.
 Metabolic effects of insulin
1. Effects on carbohydrate metabolism:
• The effects of insulin on glucose metabolism
promote its storage and are most prominent in three
tissues: liver, muscle, and adipose.

 In the liver, insulin decreases the production of

glucose through the inhibition of glycogenolysis and
gluconeogenesis
 In the muscle and adipose, insulin increases
glucose uptake by increasing the number of
glucose transporters in the cell membrane.
The intravenous administration of insulin thus
causes an immediate decrease in the
concentration of blood glucose.

 In the liver and muscle, insulin increases

glycogen synthesis
2. Effects on protein synthesis:
• In most tissues, insulin stimulates the entry of
amino acids into cells, and protein synthesis,
through activation of factors required for
translation.
 3. Effects on lipid metabolism:
Adipose tissue responds within minutes to
administration of insulin, which causes a significant
reduction in the release of fatty acids.

• a. Decreased triacylglycerol degradation:

• Insulin decreases the level of circulating free fatty
acids by inhibiting the activity of hormone- sensitive
lipase that degrades triacylglycerol in adipose tissue.
Insulin acts by promoting the dephosphorylation
and, hence, inactivation of the Enzyme.
• b. Increased triacylglycerol synthesis:
• In liver, insulin promotes the conversion of
glucose to triacylglycerols.
 Mechanism of insulin action

• Insulin binds to specific, high-affinity receptors

in the cell membrane of most tissues,
including liver, muscle, and adipose
 1. Insulin receptor:
• The insulin receptor is synthesized as a single
polypeptide that is glycosylated and cleaved
into α and β subunits.
• The α subunit contains the insulin-binding site.
The β subunit is a tyrosine kinase , which is
activated by insulin.
 Cont…
• Signal transduction occurs when an
signaling molecule activates specific
receptor located on the cell surface or inside
the cell.

• In turn, this receptor triggers a biochemical

chain of events inside the cell, eventually
eliciting a response.
 2. Signal transduction
• The binding of insulin to the α subunits of the
insulin receptor induces conformational
changes.

• This promotes a rapid auto- phosphorylation

on each β subunit
 3. Membrane effects of insulin
• Glucose transport in some tissues, such as
skeletal muscle and adipocytes, increases in
the presence of insulin

• Insulin promotes the recruitment of insulin-

sensitive glucose transporters (GLUT-4) from a
pool located in intracellular vesicles.
 4. Receptor regulation
• Binding of insulin is followed by internalization of
the hormone–receptor complex.
• Once inside the cell, insulin is degraded in the
lysosomes.

• The receptors may be degraded but most are

recycled to the cell surface.
• Elevated levels of insulin promote the degradation of
receptors, thus decreasing the number of surface
receptors. This is one type of “down-regulation.”
 5. Time course of insulin actions
• The binding of insulin provokes a wide range of
actions.
• The most immediate response is an increase in
glucose transport into adipocytes and skeletal
muscle cells that occurs within seconds of insulin
binding to its membrane receptor.
GLUCAGON
• Glucagon is a polypeptide hormone secreted by
the α cells of the pancreatic islets of Langerhans.

• Glucagon, along with epinephrine, cortisol, and

growth hormone (the “counter-regulatory
hormones”), opposes many of the actions of
insulin.

• Most importantly, glucagon acts to maintain blood

glucose levels by activation of hepatic
glycogenolysis and gluconeogenesis.
Structure & Synthesis of Glucagon
• Glucagon is composed of 29 amino acids
arranged in a single polypeptide chain

• Glucagon is synthesized as a large precursor

molecule (preproglucagon) that is converted
to glucagon through a series of selective
proteolytic cleavages, similar to those for
insulin biosynthesis
Stimulation of glucagon secretion
• Glucagon secretion is increased by:

• 1. Low blood glucose: A decrease in plasma

glucose concentration is the primary stimulus for
glucagon release. During an overnight or
prolonged fast, elevated glucagon levels prevent
hypoglycemia
 Cont…
• 2. Amino acids: Amino acids derived from a
meal containing protein stimulate the release of
both glucagon and insulin. The glucagon
effectively prevents hypoglycemia that would
otherwise occur as a result of increased insulin
secretion that occurs after a protein meal.

• 3. Epinephrine: Elevated levels of circulating

epinephrine, or norepinephrine or both,
stimulate the release of glucagon.
• Thus, during periods of stress, trauma, or
severe exercise, the elevated epinephrine
levels can cause increased glucagon release
and increase blood glucose levels.

• In these situations—regardless of the

concentration of blood glucose—glucagon
levels are elevated in anticipation of increased
glucose use. In contrast, insulin levels are
depressed.
 Inhibition of glucagon secretion

• Glucagon secretion is significantly decreased:

• By elevated blood glucose

• By insulin
Metabolic effects of glucagon

• 1. Effects on carbohydrate metabolism: The

intravenous administration of glucagon leads to
an immediate rise in blood glucose. This results
from an increase in the breakdown of liver (not
muscle) glycogen and an increase in
gluconeogenesis.
• 2. Effects on lipid metabolism: Glucagon
activates lipolysis in adipose. The free fatty acids
released are taken up by liver and oxidized to
acetyl coenzyme A.
• 3. Effects on protein metabolism: Glucagon
increases uptake of amino acids by the liver,
resulting in increased availability of carbon
skeletons for gluconeogenesis. As a consequence,
plasma levels of amino acids are decreased.
 Mechanism of action of glucagon
• Binds to high-affinity G protein-coupled
receptors on the cell membrane of
hepatocytes
• Distinct receptors (not found on skeletal
muscle)
MECHANISM OF ACTION
HYPOGLYCEMIA
• Hypoglycemia is characterized by:
– 1) central nervous system (CNS) symptoms
• Confusion
• aberrant behavior
• Coma
– 2) a simultaneous blood glucose level
• equal to or less than 40 mg/dl
– 3) symptoms being resolved within minutes
following the administration of glucose
• medical emergency
• Transient hypoglycemia.…cerebral
dysfunction,
• severe, prolonged hypoglycemia….brain death
 Symptoms of hypoglycemia
• Two categories:
1. Adrenergic symptoms:
– anxiety, palpitation, tremor, and sweating— are
mediated by epinephrine release regulated by the
hypothalamus in response to hypoglycemia
2. neuroglycopenia
– the impaired delivery of glucose to the brain—results in
impairment of brain function, causing headache,
confusion, slurred speech, seizures, coma, and death
– result from a gradual decline in blood glucose, often to
levels below 40 mg/dl
 Glucagon and epinephrine:
• Hypoglycemia is combatted by decreased
release of insulin and increased secretion of
glucagon, epinephrine, cortisol, and growth
hormone
• Glucagon and epinephrine…..most important
in the acute, short-term regulation of blood
glucose levels.
• How glucagon acts:
– stimulates hepatic glycogenolysis and
gluconeogenesis

• How Epinephrine acts:

– promotes glycogenolysis and lipolysis
– inhibits insulin secretion
– inhibits the insulin-mediated uptake of glucose by
peripheral tissues
 Cortisol and growth hormone:
• Less important in the short-term maintenance
of blood glucose concentrations. However,
play a role in the long-term management of
glucose metabolism.