Seminor on molecular & cellular moa of thyriod harmone and insulin converted

SEMINOR ON MOLECULAR &
CELLULAR MOA OF THYRIOD
HARMONE AND INSULIN
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Department of Pharmacology BVVS COP
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➢ Thyroid hormones are produced & released by thyroid gland.
➢ Thyroid is an important endocrine gland that primarily governs
the rate at which metabolism occurs in the individual cells.
➢ Thyroid hormones profoundly influence. They are chemically
amino acid derivatives, tyrosine based hormones.
❖Types of Thyroid hormones
1. T4 (Thyroxin)
2. T3 (Triiodothyronine).
3. RT3 (Reverse-Triiodothyronine), secreted in small quantity.
4 . Calcitonin
➢ T4, T3, and RT3 are secreted from thyroid follicles and
calcitonin is secreted from the para-follicular cells (C cells) of
thyroid gland.
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Metabolism of iodine
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Thyroid Hormone Synthesis
❖ Steps of Thyroid Hormone Synthesis
➢ The thyroid hormone synthesis involves following
steps:
1. Iodide trapping
2. Conversion of iodide into iodine
3. Thyroglobulin synthesis
4. The coupling reaction
5. Proteolysis of thyroglobulin
6. Secretion of thyroid hormones
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➢ Iodide Trapping:- Thyroid gland takes up iodide by active
mechanisms. The active transport of iodide from circulation into
the colloid of the thyroid follicles is known as iodide trapping or
iodide pump.
➢ Conversion of Iodide into Iodine:- Iodide that is actively
transported into the colloids of thyroid follicles is immediately
converted to iodine by means of oxidation. This oxidation of Iˉ to
I, also known as organification is facilitated by the enzyme
thyroid peroxidise.
➢ Thymoglobulin Synthesis:- It is synthesized in the endoplasmic
reticulum of thyroid cells, packaged in Golgi apparatus and then,
secreted into the colloid by exocytose.
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❖Binding of Iodine to Thymoglobulin:- Once reactive
iodine is formed (by oxidation of iodide to iodine), it
binds immediately with the tyrosine molecule, which is
attached thymoglobulin molecule at 3 position. This
binding of iodine to thymoglobulin is facilitated by
thyroid peroxidise.
❖Coupling Reaction:- Binding of iodine with tyrosine at
3 positions forms mono-iodotyrosine (MIT), which is
again iodinated in the 5 position to form di-iodotyrosine
(DIT). Two DIT molecules undergo oxidative
condensation to form thyroxin (T4). This is called
coupling reaction.
❖ There are two theories of coupling reaction:
intermolecular coupling and intermolecular coupling.
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➢ Proteolysis of thymoglobulin and Secretion of Thyroid
Harmonised.
➢ The lysosomal enzymes digest the peptide bonds
between iodinated residues and thymoglobulin. This is
called proteolysis of thymoglobulin molecule.
➢ This results in formation of free T4, T3, DIT, and MIT in
the cytoplasm. The iodinated tyrosine are de-iodinated
by the microsomal enzyme iodotyrosine deiodinase.
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DAILY SECRETION AND FATE OF THYROXINE
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Metabolism of Degradation
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❖Protein Binding
➢ Thyroid hormone bind with three types of plasma
proteins:
1. Thyroxin binding globulin (TBG).
2. Thyroxin binding pre-albumin (TBPA), also called
transthyretin.
3. Albumin. Normally, T4 binds mainly with TBG and
TBPA, and T3 binds with albumin and TBG.
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Regulation of Secretion
➢ Secretion of thyroid hormones is regulated by a
feedback control mechanism. Hypothalamus secretes
thyrotropin releasing hormone (TRH), which stimulates
thyrotrophs of anterior pituitary to secrete thyroid
stimulating hormones (TSH). TSH stimulates thyroid
gland to secrete T3 and T4.
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MOA OF THYROID HARMONE
1.T3 and T4 enter the cells of the target organs by carrier mediated
(energy dependant) transport.
2. Inside the cell, most of the T4 is converted to T3, which then
binds with the thyroid-hormone receptors (TR) present on
nucleus. The thyroid receptor protein binds to thyroid-hormone
response elements (TRE) in the DNA via zinc fingers.
3. Binding of T3 with thyroid hormone receptor-TRE element
cause translation of DNA that in turn increases the transcription
of mRNA.
4.Increased mRNA causes increased intracellular protein synthesis
that stimulates cellular growth and maturation, increases
intracellular enzyme synthesis, increase mitochondria formation
and respiratory enzyme synthesis, and increases Na+, K+,
ATPase activity.
5. The increased Na+, K+, ATPase activity increases cellular
oxygen consumption and increased mitochondrial activity
increases general metabolism of the cell.
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Mechanisms of increased cardiac output
by thyroid hormones
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Physiologic effects of thyroid hormones
Target system Functions
Metabolism Increase in BMR (↑ O2 consumption in all tissues except
testes, uterus, lymph node, spleen and anterior pituitary)
CVS 1. Tachycardia (increased no. And sensitivity of breceptors)
2. Increased myocardial contractility (increased MHC and
myosin ATPase)
3. Increased SBP (↑ cardiac output)
4. Decreased DBP (↓peripheralresistance)
CNS Brain development
Bone Skeletal development and ↑ growth and endochondral
ossification and maturation of epiphyseal bone.
Muscle ↑ expression of MHC gene, Protein catabolism
Adipose tissue ↑ Lipolysis 16
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GIT Stimulates GI motility, ↑ appetite,
↑Carbohydrate absorption,propulsive activity
of gut is increased.
Reproduction Follicular maturation and ovulation,
Fertility is impaired.
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THYROID HORMONE DEFICIENCY:HYPOTHYROIDISM
➢Early onset: Delayed/incomplete physical and
mental development.
➢Later onset(youth): Impaired physical growth
➢Adult onset (Myxedema): Gradual changes occur.
Tiredness, lethargy, decreased metabolic rate,
slowing of mental function and motor activity, cold
intolerance, weight gain, goitre, hair loss, dry skin.
Eventually may result in coma.
❖Causes:
➢(a) Insufficient iodine.
➢(b) Lack of thyroid gland.
➢(c) Lack of hormone receptors.
➢(d) Lack of TH binding globulin.
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HOW IS HYPOTHYROIDISM RELATED TO
GOITER?
➢ During iodine deficiency, thyroid hormone production
decreases.
➢ This results in increased TSH release (less negative
feedback).
➢ TSH acts on thyroid. Increasing blood flow, and
stimulating follicular cells and increasing colloid
production.
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MIDWEST-THE GOITER BELT
➢ If goitre is due to decreased Iodine, then thyroid gland
enlarges-called endemic or colloidal goitre.
➢ Pituitary gland –TSH stimulate thyroid gland to produce
TH, but the only result is that the follicles accumulate
more and more unusable colloid.
➢ Cells eventually die from over activity and the gland
atrophies.
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THYROID HARMONE
EXCESS:HYPERTHYROIDISM
➢ Emotional symptoms (nervousness, irritability), fatigue,
heat intolerance, elevated metabolic rate, weight loss,
tachycardia, goitre, muscle wasting, apparent bulging of
eyes (exophthalmos), may develop congestive heart
failure.
❖Causes:
➢ (a) Excessive TSH release.
➢ (b) Autoimmune disorders.
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Insulin
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➢ Insulin is secreted from pancreatic Beta cells upon
absorption of digested food products to exert multiple
immediate and long-term effects on the cell and
organism.
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Structure of islet of Langerhan’s
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❖Four type of cells present in the islets:
1. Beta cells (B cells): Secrete insulin.
2. Alpha cells (A cells): Secrete glucagon.
3. Delta cells (D cells): Secrete somatostatin.
4. Gamma cells (PP cells): Secrete pancreatic
polypeptide
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❖ B-cell granules secrete the following substances
1. Insulin: Insulin constitutes about 95% of secretion
from beta-cell.
2. Pro-insulin: Pro-insulin is a 86 amino acid peptide. It
has about 10%of biological activity of insulin. It is
secreted as only about 3% of the amount of secreted
insulin. However, as plasma clearance is slower (half
life 15-30min) than insulin, the plasma concentration
in fasting state is about 10-15% of insulin
concentration.
3. C peptide: It is a 31 amino acid peptide. The amount
of C-peptide secreted is about 7% of the insulin
secreted from the gland:
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Structure of Insulin
➢Insulin is a peptide hormone consisting of two
chains, A and B, which are connected by
disulfide bridges. The molecular weight of
insulin is 6,000.
➢The A chain contains 21 amino acids and B chain
30amino acids.
➢The final structure of insulin is determined by the
N-terminal and C-terminal amino acids of A
chain, and the hydrophobic character of the
amino acids at the C-terminal of B chain.
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Synthesis, Secretion and Metabolism
➢ Insulin is synthesized as preproinsulin, containing 110 amino acids. The
insulin gene is located on the short arm of the chromosome 11. Insulin is
first formed as preproinsulin in the ribosome of rough endoplasmic
reticulum.
➢ The N-terminal signal peptide is immediately cleaved from the
preproinsulin molecule to form the proinsulin, is a 86 amino acid
peptide, which then enters the Golgi apparatus.
➢ In the Golgi apparatus, the disulfide bridges are established that allows
the proinsulin molecule to be folded The A and B chains of insulin are
linked by the connecting peptide (C peptide).
➢ During packaging in the Golgi apparatus into the granules, the
proinsulin is cleaved to form insulin molecules and C peptides are
retained in the granules.
➢ When insulin is secreted, the C peptide is also released in equimolar
concentration with insulin. Insulin is associated with zinc as molecule
matures.
➢ The zinc insulin crystals form the dense central core of the granule with
a clear space around
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MOA OF INSULIN HARMONE
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➢ The binding of insulin to a subunits brings about
conformational change in the B subunits.
➢ The intracellular domain of B subunits possesses tyrosine
kinase activity. Conformational change of the B subunits
activates its tyrosine kinase activity. This produces
auto-phosphorylation of B subunits on tyrosine residues.
➢ Auto-phosphorylation triggers phosphorylation of many
intracellular proteins that alter cell functions. Also,
dephosphorylation of proteins occurs.
➢ The active tyrosine kinase phosphorylates tyrosines on
insulin receptor substrates (IRS 1 and IRS 2):
➢ IRS proteins are docking proteins to which a variety of
downstream proteins bind. Thus IRS phophotyrosines
serve as docking site and activating site for different
protein kinases and protein phosphatases
➢ The IRS also serves as facilitator proteins that link to
membrane G proteins, phospholipases, and ion channels.
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➢ Phosphorylation of IRS causes activation or deactivation of
many target enzymes, translocation of GLUTs (glucose
transport proteins) to the cell membranes and induction or
suppression of genes in the nucleus. This results in
synthesis of different intracellular proteins.
➢ The GLUTs that move to the cell membrane facilitates
glucose entry into the cell. The insertion of different protein
channels on the plasma membrane increases entry of amino
acids, potassium, magnesium, and phosphates into the cell.
➢ Activation of mitogenic proteins increases transcription of
various factors that are essential for stimulation of gene
expression, especially concerned with cell growth.
➢ IRS also activates growth receptor binding protein-2 (GRB
2), which stimulates binding of GTP to Ras oncogene (a
proto-oncogene present in plasma membrane). This
activates the enzyme glycogen Synthase, a key enzyme that
modulate the metabolic effects of insulin.
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Actions on carbohydrate metabolism
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Action On Fat Metabolism in adipose tissue
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Action on Fat Metabolism in liver
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Action on Protein Metabolism
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Other Actions of Insulin
1. Insulin increases entry of phosphate and magnesium into
the cell.
2. It also increases re-absorption of K+, Na+, and phosphate
from the kidney.
3. Insulin decreases food intake. This action is partly
mediated by its inhibitory effect on neuropeptides release
from hypothalamus.
4. Chronic insulin excess increases body weight and adipose
tissue mass. The leptin level in plasma increases that
promotes satiety (decreases food intake).
5. Growth promoting actions: Insulin stimulates synthesis of
macromolecules in cartilage and bone that promotes their
growth. Insulin stimulates transcription of genes for
growth factors such as IGF-I and II. Thus, insulin
facilitates growth of the individual, in addition to its
stimulation of protein synthesis
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Diabetes Mellitus
➢In humans, diabetes occurs usually due to
destruction of B cells of pancreas or due to
decreased sensitivity of insulin receptors to insulin.
➢ A state of starvation in the midst of plenty: In
untreated diabetes, plasma glucose concentration is
always high. In spite of hyperglycaemia, the tissue
cannot utilize glucose either due to insulin
deficiency or due to insulin resistance. In this
condition, cells cannot utilize glucose though they
are surrounded by a high concentration of glucose.
Therefore, diabetes is called a disease of “starvation
in the midst of plenty”.
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Insulin Excess
❖ Insulin excess occurs in insulin secreting tumour of
pancreas (insulinoma). This causes hypoglycaemia:
1. Chronic hypoglycaemia causes in-coordination of
movement and slurring of speech. This is usually
misdiagnosed as drunkenness. It is typically most
common in the morning, as toward the early morning
blood glucose concentration decreases and hepatic
glycogen store is depleted.
2. Hypoglycaemia also occurs in excess administration
of insulin in the treatment of diabetes. But in this
condition hypoglycemia is acute and manifest in the
form of sweating, palpitation, anxiety, and other
autonomic functions. 42
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❖References
➢Willium F. Ganong, Review of medical
physiology, 17th Edition.
➢Gopal Krushna Pal, Comprehensive Textbook of
Medical Physiology, Vol-1
➢Vasudevan-Textbook of biochemistry.
➢K, D Tripathi essential of medical pharmacology.
➢Sonia Najjar, Medical College of Ohio, Toledo,
Ohio, USA artical on Insulin Action: Molecular
Basis of Diabetes.
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THANK YOU
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