Download Metabolic effects of insulin & glucagon

Metabolic effects of
insulin & glucagon
ENDO412
Introduction
Fuels are biomolecules (as carbohydrates, lipids & proteins) that can yield
energy in the form of ATP on (catabolism or degradation). This energy (ATP) that can
be used for all biological processes of the cells.
Fuels can be also stored in certain sites of the body in the form of larger molecules
(anabolism or building) to be released in case of demand.
These procedures (catabolism & anabolism) are called energy metabolism.
Energy metabolism occurs mainly in 4 organs; liver, adipose, muscles & brain, in
which energy is stored, produced & released according to needs of the body.
These 4 organs communicate in a way that one of them produces substrates for
another.
Among these 4 organs, energy metabolism is integrated & regulated primarily
by the action of insulin & glucagon
(with catecholamines plays a supporting role).
Organ map during the absorptive state
showing intertissue relationship
Organ map during the fasting state
showing intertissue relationship
Introduction (cont.)
• In conclusion:
In case of well-fed state (directly after ingestion of a meal):
There is a abundance of energy yielding fuels (glucose etc..) more than actual body
needs for energy.
Excess of fuels (energy) is stored by help of INSULIN hormone.
(anabolic pathways)
In case of stress or prolonged fasting (post absorptive):
These is a lack in energy-yielding fuels to give sufficient energy to all body.
Stored fuels are released to be available for used by cells of the body by the help
of GLUCAGON hormone.
Also, epinephrine plays a role in this status.
(catabolic pathways)
Insulin
Generally, insulin hormone is:
• a polypeptide hormone
• produced by b-cells of islets of Langerhands (1-2% of cells of the
pancreas).
• the most important hormone coordinating the use of fuels by tissues.
• of anabolic metabolic effects favoring synthesis of glycogen,
triacylglycerol (storing of energy) & proteins
Structure of insulin
• Insulin is protein composed of 51 amino acids,
• which are arranged in 2 polypeptide chains A & B linked together by 2
disulfide bridges (in addition to intrmolecular disulfide bridges
between amino acids of the A chain)
Synthesis & secretion of insulin
Preproinsulin (inactive precursor)
in ER
Proinsulin (inactive precursor)
Golgi apparatus
Insulin
+
C-peptide
Insulin & C-peptide are stored in cytosol as granules
To be released by certain stimulus by exocytosis to blood
C-peptide has a longer half-life in the plasma more than insulin.
& hence is a good indicator of insulin production & secretion in early cases of DM
Synthesis & secretion of insulin
Regulation of secretion of insulin
• Insulin secretion by b-cells is coordinated with the release of glucagon
by a-cells.
• Relative amounts of insulin & glucagon released from the pancreas are
regulated so that the rate of liver glucose production is equal to use of
glucose by peripheral tissues.
• In short:
Insulin is required for storing of glucose in liver.
Glucagon is required for releasing glucose from its stores in liver.
So, both hormones secretion from pancreas has to be regulated
according to needs of the body.
Regulation of secretion of insulin (cont.)
1- Factors stimulating of insulin secretion:
- Glucose ingestion (or carbohydrate rich meals)
- Amino Acids
- Gastrointestinal hormones (as cystokinines & gastric-inhibitory polypeptides) increase
insulin secretion in response to oral glucose
2- Factors inhibiting insulin secretion:
Decrease of synthesis of insulin occurs when there is a scarcity of diet fuel & during
periods of stress.
These effects are mediated by epinephrine, which causes rapid mobilization of
energy-yielding fuels (including glucose from liver & fatty acids from adipose
tissue).
Epinephrine binds to a-adrenergic receptors on b-cells resulting in decrease of
insulin secretion.
Regulation of secretion of insulin (cont.)
Metabolic effects of insulin
Carbohydrates Metabolism
Promotes storage of glucose
Liver
Muscles
Glycogen
Synthesis
Glycogen
Synthesis
Gluconeogenesis
Intake of
glucose
Glycogenlysis
Lipids Metabolism
TAG
Degrad.
adipose
uptake of
glucose
TAG
Synth
Protein Synthesis
Entry of AA into cells
Protein Synth.
Mechanism of action of insulin
Binding
Of Insulin on a-cells
Phosphorylation
of b-cells
Phosphorylation
of IRS
CHANGES
IN
Gene
Expression
Metabolism
Growth
Mechanism of action of insulin
(Membrane effects of insulin)
Glucose transport in some
tissues as skeletal muscles
& adipocytes increase in
the presence of insulin
Insulin promotes the
recruitment of insulin-sensitive
glucose transporters (GLUT-4)
from a pool located in
intracellular vesicles
N.B. Some tissues do not depend on insulin for glucose transport
As Liver cells, RBCs, neurons, intestinal mucosa, renal tubules & cornea
Time course of action of insulin
Binding of insulin to its receptors on various cells provoke a
wide range of actions that varies in time course.
Some may occur immediately within few seconds, while others need
days
Immediate (within seconds): increased glucose transport into adipose tissue & sk. ms.
(membrane effect)
Within minutes to hours: changes in activity of enzymes.
(phosphorylation of proteins i.e. enzymes)
Within hours to days: increase amounts of many enzymes
(increase in gene expression with increase in mRNA & enzyme synth.)
Down regulation of action of insulin
(Receptor Regulation)
Binding of insulin to its receptors is followed by internalization of hormonereceptor complex.
Once inside cells, insulin is degraded in lysosomes.
Receptors are either degraded or recycled to cell surface.
Elevated levels of insulin promote the degradation of receptors, with a decrease in
the number of surface receptors (a type of down regulation)
Glucagon
• Glucagon is a single polypeptide chain hormone secreted by a-cells of
islets of Langerhands of the pancreas.
• It is one of a group of hormones (glucagon, epinephrine, cortisol &
growth hormone) that oppose many actions of insulin (anti-insulin
hormones or diabetogenic hormones).
• Glucagon mainly acts by maintaining blood glucose level by increasing
glycogenlysis & gluconeogenesis in liver cells.
Stimulation of glucagon actions
a-cells are responsive to a variety of stimuli that signal hypoglycemia (actual or about to occur)
Glucagon secretion is increased by:
1- Low blood glucose in blood:
During an overnight or prolonged fasting, elevated glucagon levels prevent hypoglycemia.
2- Amino acids:
Amino acids released from meals containing protein stimulate both glucagon & insulin.
In this case, glucagon prevents the hypoglycemia that would occur as a result of increased insulin
secretion after a protein meal.
3- Epinephrine:
Epinephrine is released either by adrenal medulla or by sympathetic innervations of pancreas or both)
in cases of stress, trauma or severe exercise.
In these cases, glucagon levels are elevated to be ready for the possibility of increased glucose use.
Inhibition of glucagon actions
Glucagon secretion is significantly decreased by :
- Elevated blood glucose
- Insulin
Both substances are increased following ingestion of glucose or
carbohydrate-rich meal
Stimulation & Inhibition of
glucagon release
Metabolic effects of glucagon
Carbohydrates Metabolism
Increases blood glucose
Liver
Glycogenlysis
Lipids Metabolism
TAG
Degrad.
in adipose tissue
fatty acids
in liver
Gluconeogenesis
ketone bodies
(ketpgenesis)
Protein Metabolism
Uptake of AA by liver
Carbon skeleton for gluco neogenesis
Mechanism of action of glucagon