Metabolic effects of Insulin

and Glucagon
• Four major organs play a
dominant role in fuel metabolism:
liver, adipose, muscle, and brain.
These tissues contain unique sets
of enzymes, such that each organ
is specialized for the storage, use, • These tissues do not function in
isolation, but rather form part of a
or generation of specific fuels. network in which one tissue may provide
substrates to another, or process
compounds produced by other organs.
Changes in the circulating levels
of these hormones allow the
body to store energy when food
is available in abundance, or to
make stored energy available, for
example, during “survival crises,”
such as famine, severe injury, and
“fight-or flight” situations.
 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.
• The islets of Langerhans make up only
about 1–2% of the total cells of the
pancreas.

• Insulin is the most important hormone coordinating the use of fuels by tissues. Its
metabolic effects are anabolic, favoring, for example, synthesis of glycogen,
triacylglycerols, and protein.
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.

• The insulin molecule also contains an intramolecular disulfide

bridge between amino acid residues of the A chain.
• Pig (porcine) and beef (bovine) insulin
differ from human insulin at one and
three amino acid positions, respectively.

• When used in humans for the

treatment of diabetes, antibodies to
these foreign proteins develop.
• Use of human recombinant insulin has
eliminated this problem.
• Insulin biosynthesis involves two inactive precursors, preproinsulin and proinsulin, which
are sequentially cleaved to form the active hormone plus the connecting or C-peptide.

• The C-peptide is essential for proper insulin folding. Also, because of its
longer half-life in the plasma, the C-peptide is a good indicator of insulin
production and secretion. Insulin is stored in the cytosol in granules that
are released by exocytosis, given the proper stimulus.
 Intracellular movements of insulin
and its precursors.

Insulin is degraded by the insulin-degrading

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

1. Stimulation 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.
Because of its coordinating role, it is not surprising that the β cell responds to a
variety of stimuli.
 Insulin secretion is increased by:
a. Glucose:
• The β cells are the most important glucose-sensing cells
in the body. Like the liver, β cells contain GLUT-2
transporters and have glucokinase activity, and thus can
phosphorylate glucose in amounts proportional to its
actual concentration in the blood.

• Glucose is the most important stimulus

for insulin secretion.
• Note: Glucose also increases expression
of the gene for insulin.
• 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.
 b. Amino acids:

• Ingestion of protein causes a transient rise in plasma amino acid levels,

which, in turn, induces the immediate secretion of insulin.
• Elevated plasma arginine, for example, stimulates insulin secretion.
c. Gastrointestinal hormones:
• Most gastrointestinal hormones favor insulin release.
The intestinal peptides cholecystokinin, glucagon-
like peptide-1 (GLP-1) and gastric-inhibitory
polypeptide [GIP] (glucose-dependent insulinotropic
peptide) increase insulin secretion in response to oral
glucose, and so are referred to as “incretins.”

• 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.
 2. Inhibition of insulin secretion:
• The synthesis and release of
insulin are decreased when
dietary fuels are scarce, and also
during periods of stress (for
example, fever or infection).
• These effects are mediated primarily
by epinephrine, which is secreted by
the adrenal medulla in response to
stress, trauma, or extreme exercise.
• Under these conditions, the release of
epinephrine is controlled largely by the
nervous system.
• Epinephrine has a direct effect on energy
metabolism, causing a rapid mobilization
of energy-yielding fuels, including glucose
from the liver (produced by glycogenolysis
or gluconeogenesis) and fatty acids from
adipose tissue.
Epinephrine can override the normal glucose-
stimulated release of insulin.
• Thus, in emergencies, 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 and muscle, insulin increases glycogen synthesis.
• In the muscle and adipose, insulin increases glucose uptake
by increasing the number of glucose transporters GLUT-4,
in the cell membrane.
• The intravenous administration of insulin thus causes an
immediate decrease in the concentration of blood glucose.
• In the liver, insulin decreases the production of glucose
through the inhibition of glycogenolysis and
gluconeogenesis.
 2. 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:
• Insulin increases the transport and
metabolism of glucose into adipocytes,
providing the substrate glycerol 3-
phosphate for triacylglycerol synthesis.
• Insulin also increases the lipoprotein
lipase activity of adipose tissue by
increasing the enzyme's synthesis, thus
providing fatty acids for esterification.
• Note: In liver, insulin promotes the conversion of glucose
to triacylglycerols.
 3. Effects on protein synthesis:

• In most tissues, insulin stimulates the entry of amino acids

into cells and protein synthesis.

• Note: Insulin stimulates protein synthesis through

activation of factors required for translation.
 Insulin receptor:

• The insulin receptor is synthesized as a single polypeptide

that is glycosylated and cleaved into α and β subunits,
which are then assembled into a tetramer linked by
disulfide bonds.
 Signal transduction:

• The binding of insulin to the α subunits of the insulin

receptor induces conformational changes that are
transduced to the β subunits. This promotes a rapid auto
phosphorylation of specific tyrosine residues on each β
subunit.
• A hydrophobic domain in each β subunit spans the plasma
membrane.
• The extracellular α subunit contains the insulin-binding
site. The cytosolic domain of the β subunit is a tyrosine
kinase, which is activated by insulin.
• Autophosphorylation initiates a cascade of cell signalling
responses, including phosphorylation of a family of
proteins called insulin receptor substrates (IRS).
• At least four IRS have been identified that show similar
structures but different tissue distributions.
• Phosphorylated IRS proteins interact with other signaling
molecules through specific domains, activating a number
of pathways that affect gene expression, cell metabolism
and growth.
• The actions of insulin are terminated by dephosphorylation
of the receptor.
E. Mechanism of insulin action

• Insulin binds to specific, high-affinity receptors in the cell

membrane of most tissues, including liver, muscle, and
adipose.
• This is the first step in a cascade of reactions ultimately
leading to a diverse array of biologic actions.
 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 of skeletal and cardiac muscle and adipose tissue.
4. Receptor regulation:

• Two alternative processes describe the dephosphorylation of the IR:

(1) The IR can dephosphorylate on the plasma membrane by the
dissociation of insulin;
• (2) The IR can be internalized into the cytoplasm. There, the insulin
is degraded, and the IR is transported back to the plasma membrane.
 The tissues that require insulin for effective uptake of glucose are adipose tissue and resting
skeletal muscle.

Tissues in which glucose uptake is not affected by insulin include:

• Intestinal mucosa
• Red blood cells(erythrocytes)
• β-cells of the pancreas
• Nervous tissue
• Kidney tubules
• Hepatocytes
• Cornea
Long-acting modified forms of medical insulins
 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.
• Insulin-induced changes in enzymic activity in many cell
types occur over minutes to hours, and reflect changes in
the phosphorylation states of existing proteins.
• Insulin also initiates an increase in the amount of many
enzymes, such as glucokinase, liver pyruvate kinase, acetyl
CoA carboxylase, and fatty acid synthase, which requires
hours to days.
 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, opposes
many of the actions of insulin.
• Most importantly, glucagon acts to maintain blood glucose levels
by activation of hepatic glycogenolysis and gluconeogenesis.
• Glucagon is composed of 29 amino acids arranged in a
single polypeptide chain. Unlike insulin, the amino acid
sequence of glucagon is the same in all mammalian species
examined to date.
 In contrast to insulin, preproglucagon is
processed into different products in
different tissues.

• Glucagon is synthesized as a large

precursor molecule (preproglucagon)
that is converted to glucagon through a
series of selective proteolytic cleavages,
similar to those described for insulin
biosynthesis.
 Stimulation of glucagon secretion

• The α cell is responsive to a variety of stimuli that signal

actual or potential hypoglycemia.
 Specifically, 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.
Specifically, glucagon secretion is increased by:

• 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.
 Specifically, glucagon secretion
is increased by:

• Epinephrine: Elevated levels of circulating epinephrine produced by the adrenal medulla, or

norepinephrine produced by sympathetic innervation of the pancreas, or both, stimulate the
release of glucagon.
• During periods of stress, trauma, or severe exercise, the elevated epinephrine levels can
override the effect on the α cell of circulating substrates. 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 and by

insulin.
• Both substances are increased following ingestion of glucose or a
carbohydrate-rich meal.
 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 protein metabolism:

• Glucagon increases the 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.
• 3. Effects on lipid metabolism:
• Glucagon activates lipolysis in adipose. The free
fatty acids released are taken up by the liver and
oxidized to acetyl coenzyme A, which is used in
ketone body synthesis.
• Glucagon binds to high-affinity G protein-coupled receptors on the
cell membrane of hepatocytes. The receptors for glucagon are
distinct from those that bind insulin or epinephrine.
Glucagon receptors are not found on
skeletal muscle. Glucagon binding results
in the activation of adenylyl cyclase in the
plasma membrane.

• This causes a rise in cAMP, which, in turn,

activates cAMP-dependent protein kinase
and increases the phosphorylation of
specific enzymes or other proteins.
• This cascade of increasing enzymic activities
results in the phosphorylation-mediated
activation or inhibition of key regulatory
enzymes involved in carbohydrate and lipid
metabolism.
 HYPOGLYCEMIA

• Hypoglycemia is characterized by:

• 1) central nervous system (CNS) symptoms, including
confusion, aberrant behaviour, or 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.
Glucagon stimulates hepatic glycogenolysis
and
gluconeogenesis.
Epinephrine promotes glycogenolysis and
lipolysis. It inhibits insulin secretion, thereby
preventing GLUT–4–mediated uptake
of glucose by muscle and adipose tissues.

Epinephrine assumes a critical role in

hypoglycemia when glucagon secretion is
deficient, for example, in the late stages of type
1 diabetes mellitus.
The prevention or correction of hypoglycemia
fails when the secretion of both glucagon and
epinephrine is deficient.

Cortisol and growth hormone are less important in the short-

term maintenance of blood glucose concentrations.

They do, however, play a role in the long-term (transcriptional)

management of glucose metabolism.
 Hypoglycemia occurs when blood
glucose levels fall below 4 mmol/L
(72mg/dL).

• Hypoglycemia is a medical emergency because the CNS has an

absolute requirement for a continuous supply of blood-borne
glucose to serve as fuel for energy metabolism.
• Transient hypoglycemia can cause cerebral dysfunction whereas
severe, prolonged hypoglycemia causes brain death. It is, therefore,
not surprising that the body has multiple overlapping mechanisms to
prevent or correct hypoglycemia. The most important hormone
changes in combating hypoglycemia are elevated glucagon and
epinephrine, combined with the diminished release of insulin.
 The symptoms of hypoglycemia can be divided into two categories.

• Adrenergic symptoms— anxiety, palpitation,

tremor, and sweating— are mediated by
epinephrine release regulated by the
hypothalamus in response to hypoglycemia.
• The second category of hypoglycemic symptoms is neuroglycopenic.

• Neuroglycopenia—the impaired delivery of glucose to the brain—results

in impairment of brain function, causing headache, confusion, slurred
speech, seizures, coma and death.
 1. Insulin-induced hypoglycemia:

• Hypoglycemia occurs frequently in

patients with diabetes who are receiving
insulin treatment.
• Mild hypoglycemia in fully conscious
patients is treated by oral administration
of carbohydrates.
• More commonly, patients with
hypoglycemia are unconscious or have lost
the ability to coordinate swallowing.
• In these cases, glucagon, administered
subcutaneously or intramuscularly, is the
treatment of choice.
 2. Postprandial hypoglycemia:

• It is caused by an exaggerated insulin

release following a meal, prompting
transient hypoglycemia with mild
adrenergic symptoms.

• The plasma glucose level returns to

normal even if the patient is not fed.
The only treatment usually required is
that the patient eat frequent small
meals rather than the usual three
large meals.
 3. Fasting hypoglycemia:

• Low blood glucose during fasting is rare but is more likely to present as a serious medical
problem.
• Fasting hypoglycemia, which tends to produce neuroglycopenia symptoms, may result from
a reduction in the rate of glucose production by hepatic glycogenolysis or gluconeogenesis.

• Alternately, fasting hypoglycemia may be the result of an increased rate of glucose use by
the peripheral tissues due to overproduction of insulin
• By Rare pancreatic tumors
• Alcohol is metabolized in the liver by two
oxidation reactions. Ethanol is first converted to
acetaldehyde by alcohol dehydrogenase.

• Acet aldehyde is subsequently oxidized to

acetate by aldehyde dehydrogenase.
• [Note: This enzyme is inhibited by disulfiram, a
drug that has found some use in patients
desiring to stop alcohol ingestion.
• It causes the accumulation of acetaldehyde in
the blood, which results in flushing, tachycardia,
hyperventilation, and nausea].
• Chronic alcohol consumption can also result in alcoholic fatty liver
due to increased synthesis of triacylglycerols: as a result of
decreased fatty acid oxidation due to a fall in the NAD+/NADH ratio,
and increased lipogenesis due to the increased availability of fatty
acids (decreased catabolism) and of glyceraldehyde 3-phosphate (the
dehydrogenase is inhibited by the low NAD+/NADH ratio).
• With continued alcohol consumption, alcoholic fatty liver can
progress first to alcoholic hepatitis, and then to alcoholic cirrhosis.