16-08-21

Hormones & receptor mediated

regulation
Sulaman Yaqub
(ASCP)

Syllabus

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Introduction
• Word Hormone is derived from the Greek word
hormon meaning urging on or to arouse to
activity
• Hormone can be defined as:
• A chemical substance synthesized in an organ,
gland, or body part and transported through
the blood to another body part, chemically
stimulating that part
– to increase or decrease functional activity or
– to increase or decrease secretion of another
hormone

• Body secretions are secreted by specialized tissue

in different organs called gland to carryout normal
body functions
• Some gland secrete their secretions through ducts
at the site of action
– Such glands are called exocrine glands
– E.g. Salivary glands secrete saliva
• Other glands secrete their secretions directly into
the blood stream
– Endocrine glands or ductless glands
– The secretions of endocrine glands are called hormones
• Hormones are secreted by special system of
ductless glands distributed throughout the body
called endocrine gland system
– Endocrine system is extremely diverse system

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• Major glands in endocrine system are:

– Pituitary
– Thyroid
– Parathyroid
– Adrenal
– Pancreas
– Gonades
• Ovaries (in female only)
• Testes (in male only)
• Other glandular tissues also considered to
secrete hormones are:
– Kidneys
• Angiotensis II is involved in vasodilation & BP regulation
• Erythropoietin is secreted by JG cells of kidneys and
regulates erythropoiesis (RBC maturation)

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– Thymus Gland:
• Produce hormones that affect the formation of lymphocyte
– Pineal Gland:
• Produce hormones that antagonizes ACTH
• Also produces glomerulptrophins that regulates the
aldosterone secretion from adrenal gland
– GI tract:
• Glucagon-like peptide from small intestine
• GI hormones regulates the gastric secretions and proper
digestive function of alimentary canal
• Some hormones are prepared in more than one
tissue
– E.g. skin, liver and kidneys are involved in calcitriol
• Hormones act on their target cells only
– Have particular receptors for that hormone

Classification of Hormones
• Hormones can be classified by a number of
different ways, according to
– Chemical nature
• Steroidal, proteinous, amino acid derivatives etc
– Solubility properties (lipophilicity or hydrophilicity)
• Group I and Group II hormones
– Mechanism of action
• Location of receptors and nature of signal used to
mediate its action within cell
• Intracellular receptor binding or cell surface receptor
binding and second messenger based mechanism etc.

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• Most commonly used system of classification for

hormones is according to their chemical nature
• Chemically hormones can be classified into:
i) Protein hormones (peptide hormones):
– Either large proteins or small peptide chains
– E.g. insulin, glucagon, parathormone & pituitary
hormones etc.
ii) Amino acid derivatives:
– Mostly these are tyrosine derivatives
– E.g. Epinephrine, norepinephrine & thyroid hormone
iii) Steroid hormones:
– Contain steroidal nucleus in their structure
– E.g. Adrenocorticosteroids, endrogens, estrogens &
progesteron etc.

• Classification based on mechanism of action can

be described as:
i) Hormones that bind to the intracellular
receptors:
• Also called group-I hormones; lipophilic in nature
• Transported through carrier proteins via blood
– Bound hormone is inactive while free hormone is
active
• Readily crosses plasma membrane
• Bind to the receptors in cytosol or nucleus of target cells
• Long plasma half-life
• The ligand-receptor complex is the intracellular
messenger in this group

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ii) Hormones that bind to cell surface receptors:

• Water soluble hormones
– Including proteinous and aminoacid derivatives
• Binds to the specific receptors on plasma
membrane of target cells
– Communicate with intracellular metabolic processes
through intermediate molecules called second
messengers
• As their synthesis is triggered by primary hormone
– Second messengers
• Activated by binding of first messengers (hormones) with
the receptors
• Starts a cascade of events that ultimately results in the
response from a cell
• E.g. cAMP, Ca2+ ions, protein kinase, proteins phosphatase

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Group I Group II

Steroids, Polypeptides, Proteins,

Types Iodothyronins, Glycoproteins,
Calcitriol, Retinoids Catecholamines

Solubility Lipophilic Hydrophilic

Transport
Yes No
proteins

Plasma Half-life Long (hours to days) Short (minutes)

Receptor Intracellular Plasma Membrane

cAMP, cGMP, Ca2+,

Receptor- hormone Metabolites of complex
Mediator
complex phosphoinositols, kinase
cascades

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Mechanism of Hormone action

• Many hormone act as inducer or repressor of
genetically controlled synthesis of key enzyme
systems
• The mechanism of hormone actions is well
known today but the exact site of action of any
hormone is still not well understood
• Following mechanisms of action have been
proposed
– Interaction with nuclear chromatin
– Membrane receptor interactions
– Enzyme synthesis at ribosomal level
– Direct action of enzyme system

i) Mechanism of action of steroidal hormone:

• Interaction with nuclear chromatin (nuclear
action)
• Steroid hormones mostly act by changing
transcription rate of specific genes
– Act on specific, soluble, oligomeric receptor protein
• Mobile receptors
– Conformational changes and alteration in the
surface charges of protein receptors
– Receptor –steroid complex moves to chromatin and
binds to hormone responsive element (HME) of DNA
– Changes in the concentration of intracellular mRNA
alters the synthesis of proteins
• Structure, enzymatic, carrier or receptor proteins

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ii) Mechanism of action of Protein hormones:

• Protein hormones being water soluble do not
require any carrier protein
– Binds to the cell surface receptors
– act through second messengers in a cell
• Second messenger are produced as intracellular
signals to carryout cell responses
– cAMP, cGMP, Ca2+ ions, phosphatidylinositides etc.

• G-Protein coupled receptors: (GPCR)

• Also called Serpentine receptors, 7TM receptors
• Many protein hormones bind to the receptor
that are linked to effectors through a guanine
binding protein (G-protein) intermediary
• Structure of serpentine receptor:
– Seven α-helical hydrophobic plasma membrane –
spanning domains
– Often demonstrated as seven
interconnected cylinders extending
through lipid bilayer

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• G-proteins are heterotrimeric proteins consisting of

α, β and γ subunits
– There are 21α, 5β and 8γ subunit genes
– Their combination provide a large number of possible αβγ
complexes
– Depending on protein sequences conservation four major
classes of G-proteins have been identified
• Gs, Gi, Gq and G12
– Each differ by alpha subunit (αs and αi etc.)
• The α-subunits bind guanine nucleotide
– The β and γ subunits are mostly associated as dimer
• The binding of hormone to receptor results in the
receptor mediated activation of G-protein
• The ability of a hormone to stimulate or inhibit
effector depends upon the type of G-protein

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• GTP attached to G-proteins results in the

dissociation of α-subunits from βγ
– α-Subunit attached with GTP is active
– Hydrolysis of GTP to GDP deactivates the α-Subunit
• The α-subunits binds and activates the effector
depending upon α-Subunit type:
– αs activates Adenylyl cyclase, Ca2+, Na+, Cl- Channels
– αi activates K+ channels
– αq activates Phospholipase C
– αt activates cGMP Phophodiesterase
• The βγ subunits can also have direct action on
effector
• G-protein activates enzyme to produce second
messengers that phosphorylate or dephosphorylate
proteins that in turn control gene expression

• Adenylyl Cyclase (AC):

• Cyclic AMP is a nucleotide derived from ATP by the
action of enzyme adenylyl cyclase (AC)
– First intracellular second messenger signal identified in
mammalian cells
• Its level may increase or decrease by hormonal
action depending upon tissue and receptor types
– αs - GTP activates AC and increase the level of cAMP
– αi - GTP inhibits AC and decrease cAMP
• cAMP activates some protein kinase enzymes
allosterically and influences gene expression
– E.g. the activation of protein kinase in glycogen
metabolism
• Phosphodiesterases deactivate cAMP by hydrolysis

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Hormones that stimulate Hormones that inhibit

Adenylyl Cyclase Adenylyl Cyclase
ACTH Acetylcholine
ADH Angiotensin-II
Calcitonin Somatostatin
FSH
Glucagon
LH
MSH
PTH
TSH

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• Phopholipase C:
• Activated G-Protein coupled receptor (GPCR)
can also activates phopholipase C
• Phospholipase C acts on Phosphotidylinositol-
4,5- bisphosphate and produce two second
messengers
– Inositoltriphosphate (IP3)
• Increase the Ca2+ into the cytosol from within cell
• Activates Ca2+ -Calmodulin dependent kinases & other
enzymes
– Diacyl glycerol (DAG)
• Activates Protein kinase C
– These results in the increased phosphorylation of
specific enzyme proteins and modulate their
activities

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• Protein kinase cascade:

• Specialized enzyme(s) activated by second
messengers
– May act as single enzyme or multi-enzyme system
• Protein kinase A (PKA)
• Protein kinase C (PKC)
• Ca2+ – Calmudolin kinase (CaM-Kinase) etc

Hormones of Pituitary Gland

• Also called hypophysis or master gland
– Also directs other glands to secrete hormones
• Pituitary gland is situated at the base of the
brain, directly below hypothalamus
– Behind the bridges of nose
– in an indent in the sphenoid bone called sella turcica
• The word pituitary has its origin in
– Greek: ptuo means “to spit”
– Latin: Pituita means “mucus”
• Mucus was produced by the brain and was
excreted through the nose by the pituitary

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• Pituitary is a pea sized, bean shaped bi-lobed gland,

that are further subdivided into areas called ‘parses’
– Anterior lobe
• Also known as Adenohypophysis
• Consist of about 80% of the gland
– Posterior lobe
• Also called Neurohypophysis
• Anterior lobe has two divisions
– Pars distalis
• Largest
• Hormone producing cells
– Pars tuberalis
• Upward extension to the anterior lobe and attached to pituitary
stalk
• Posterior lobe
– Pars nervosa
• Pars intermedia (Median part connecting two lobes)
– Poorly defined in the human

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• Both lobes secrete differently from eachothers

• Hormones of Anterior pituitary are:
– Growth hormone: Promotes growth
– Adrenocorticotropin (ACTH): Controls adrenal cortex
– Thyroid stimulating hormone (TSH): Controls thyroid
– Prolactin: Development of breasts & milk secretion
– Gonadotropic hormones
• Follicle stimulating hormone (FSH)
• Luteinizing hormone (LH)
– FSH: Stimulates follicle growth in ovaries &
maturation of sperms in testes
– LH: Ovulation, corpus luteum, estrogen &
progesteron secretions from ovaries and stimulate
testosteron synthesis in male

• Hormones of posterier pituitary are:

– Antidiuretic hormone (ADH) (Vassopressin)
• Increase water reabsorption by kidneys
• Cause vasoconstriction
• Increase blood pressure
– Oxytocin
• Milk ejection and uterine contraction during birth
• Melanophore stimulating hormone is secreted
by pars intermedia (median part) of pituitary
• The secretions of pituitary are regulated by
hypothalamus

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• Control of Pituitary Secretions:

i) Nervous mechanism
– Regulatory factors are released from hypothalamus
ii) Hormonal mechanism
– Feedback inhibition controls their release
• Both Nervous & Hormonal control of overall
endocrine system is coordinated by
hypothalamus
• Hypothalamus:
• Specialized center in the brain that functions as
master coordinator of hormonal action
– Connected directly to pituitary stalk

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• Pituitary stalk have a portal system of blood

vessels to maintain the proper secretory activity
• Pituitary is supplied from carotid artery
– Hypophyseal arteries & veins
– 80 to 90% to anterior lobe
– Posterior lobe is rich in unmyelinated nerve supplies
• The neurosecretory cell in hypothalamus
releases regulatory factors through their axons to
the capillary beds in anterior lobe
– Hypothalamic releasing factors or hormones
– Hypothalamic inhibitory factors or hormones
• The regulatory factors of hypothalamus stimulate
pituitary cells to secrete or inhibit hormones

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• Secretory cells in anterior pituitary are:

– Somatotropes: human Growth Hormone (hGH)
– Corticotropes: ACTH
– Thyrotropes: TSH
– Gonadotropes: Gonadotropi hormones (FSH, LH)
– Lactotropes: PRL
• Posterior pituitary hormones are synthesized by
cell bodies of neurosecretory cells in
hypothalamus
• Major hypothalamic releasing and inhibitory
hormones are:
– Thyrotropin Releasing Hormone (TRH): Releases TSH
– Corticotropin Releasing Hormone (CRH): ACTH

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– Gonadotropin Releasing Hormone (GnRH)

• Stimulate the release of gonadotropic hormones (FSH, LH)
– Growth Hormone-releasing Hormone (GHRH)
• Releases growth hormone from anterior pituitary
– Growth Hormone Release-Inhibiting Hormone
(GRIH)
• Inhibit secretion of GH from somatotropes
– Prolactin Release-Inhibiting Hormone (PLRIH)
• Inhibit the release of prolactin
– Melanocyte Stimulating Hormone-Release Hormone
• Release MSH from pars intermedia
– Melanocyte Stimulating Hormone-Release inhibiting
hormone (MSHRIH)
• Inhibit MSH release

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Growth Hormone
• Also called as Somatotropin or somatotropic
Hormone (STH)
• Proteinous hormone produced by somatotropes
– Specialized group of acidophilic cells in anterior
pituitary
Chemistry of GH:
• Single polypeptide of M. Wt. 21500
• Consist of 191 aminoacids
– Two disulfide linkages between adjacent cysteine
residues
• 53 & 165 and 182 & 189

• GH can bring about some action of prolactin (PL)

and human placental lactogen (HPL)
– Due to high degree of amino acid sequence homology
• Release:
• Regulated by feed back mechanism through GRH
and GRIH (Somatostatin)
– Several factors influence its production and release
• Sleep, Stress (Pain, cold etc.), exercise, food intake etc.
– Maximum release occurs after the onset of sleep
• Physiological Role of Growth Hormone:
• Act by binding to membrane bounding receptors on
its target cells
– Exact mechanism of action and second messenger is not
yet known

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• Promotes growth and normal metabolism of

proteins, carbohydrates, lipids and minerals
• i) Effect on growth:
• Growth related effects are mediated via insulin like
growth factor-I (IGF-I)
– Also called somatomedin-C produced by liver
– Prolong the growth of epiphyseal cartilages
• Growth in Epiphyseal plate or Growth plate cause the growth of
long bones
• Promote bone growth by
– Retention of Ca2+ and PO43- that helps in osteogenesis and
ossification
– Enhance incorporation of
• Hydroxy proline into collagen matrix
• Amines to glycosaminoglycans (GAGs)
• Sulfate into matrix proteoglycan like chondroitin sulfate
– Increase synthesis of DNA and RNA in Chondrocytes

• Hyposecretions may cause Stunted growth

• Hypersecretion can lead to acromegaly in adults
– Gigantism in children

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ii) Effect on Protein metabolism:

• Promotes uptake of aminoacid into tissues
• Stimulates overall protein synthesis
• Bring about positive nitrogen balance by
retaining nitrogen
– Increased body mass

iii) Effect on Carbohydrate metabolism

• Growth hormone is diabetogenic hormone
– Antagonizes the effects of insulin
• Reduces insulin sensitivity
• It cause hyperglycemia
– Increase gluconeogenesis
– Decrease glucose utlilization
– Impairs glycolysis
• Increased cardiac and smooth muscles glycogen
– Reduces the glucose uptake by the tissues
• Exhibits glycostatic effects
– Increase liver glycogen

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iv) Effect on Lipids:

• Mobilizes fats from fat depots
– Activates triacylglycerol lipase enzyme
• Promotes lipolysis in adipose tissue
• Increase circulating free fatty acid and their
oxidation
– May lead to ketogenesis particularly in diabetes
v) Effect on mineral metabolism:
• Promotes bone mineralization
– Increased absorption of Ca2+ from intestine
– Retains Na+, K+, Mg2+, Ca2+ and PO43- ions

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• Tropins:
• A tropin or tropic hormone is the one which
influences the activities of other endocrine gland
• Important tropin hormones of pituitary gland are
– Leuteotropic hormone (LTH): also called Prolactin
– Thyrotropin: Thyroid Stimulating hormone (TSH)
– Gonadotropins: FSH, LH
– Corticotropin: ACTH
• Prolactin (Leuteotropic Hormone):
• Also called lactogenic hormone, Leuteotropin,
mammotropin
– Promotes the growth of corpus luteum
– Stimulate secretion of progesteron

• Secreted by lactotroph α-cells of anterior

pituitary
• Similar in aminoacid sequence with growth
hormone
• Physiological Function:
• Act through specific glycoprotein receptors on
plasma membrane of mammary gland cells
– Stimulate mRNA synthesis
• Increase the level of several enzymes involved in
– Carbohydrate metabolism
• Promotes HMP shunt pathway, stimulate lactose
production in mammary glands
– Lipid metabolism
• Increase lipid biosynthesis

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• Primarily concerned with the initiation and

maintenance of lactation in mammals
– Stimulate mammary growth especially during
pregnancy
• Mammotropic action
– Secretion of milk
• lactogenic action
• Increased milk protein synthesis after birth

Thyrotropic Hormone
Thyroid Stimulating Hormone (TSH)
• Produced by basophil cells of anterior pituitary
• Chemistry:
• TSH is a dimer glucoprotein with mol. Wt. 30000
– Consist of two subunits (α and β subunits)
– Alpha subunit
• Consist of 92 amino acids
• The α-subunit of TSH, LH, FSH are nearly identical
– Beta subunit
• Unique from other hormones with 112 amino acids
• Contains biological activity of thyrotropin
– Both α and β subunits have several disulfide bonds

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• It also contains 21% carbohydrates linked to

asparagine residues on both α and β subunits
via N-glycosidic linkage
– Two oligosaccharide chains are attached with α-
subunit
– One attached with β-subunit
• Separately synthesized chains of α and β
subunits by separate structural genes
– Post translational modification and glycosylation
• Regulation of TSH
• Release is controlled by feedback mechanism
– Thyroid hormones (T3, T4) inhibit it
– TRH from hypothalamus stimulates its release

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• Mechanism of Action:
• Act through glycoprotein receptors on thyroid
cell membrane
– Receptor binds to binding site on β-subunit
• Activates adenylyl cyclase
– cAMP is synthesized
• Increased cAMP levels mediate its response
• Function of TSH:
• Stimulates the secretions of all thyroid hormones
at all stages
– Promotes iodide ion (I-) uptake from circulation to
thyroid gland

– Increase the conversion of iodide (I-) to active iodide

(I+) (organification)
• Promotes the release of stored thyroid hormones
– Increase proteolysis of thyroglobulin to release T3 and
T4 into general circulation
• Activates DNA contents
– Increased production of nucleic acid and proteins and
as a result cell size is increased
• Stimulates glycolysis, TCA cycle, HMP and
phospholipids synthesis with or without cAMP
• Activates adipose tissue lipase
– Enhance lipolysis (the release of fatty acids)

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Gonadotropins
• Influence the function and maturation of testes
and ovaries
• These include:
• Follicle Stimulating Hormone (FSH)
• Luteinizing Hormone (LH)
• Human Chorionic Gonadotropin (HCG)
– Not a pituitary hormone but a gonadotropin
• Chemistry:
• All these gonadotropins are glycoproteins in
nature attached with
– Sialic acid, hexose, hexosamine as carbohydrate
moiety (16%)

• Molecular Weight
– FSH: 25,000
– LH: 40,000
– HCG: 100,000
• Consist of α and β subunits
– α subunit of FSH and LH is identical to that of TSH
– β subunit have 118 aminoacids in FSH and 112 in LH
• Each chain have several disulfide linkages
• A large precursor protein molecule for α and β
subunits is synthesized separately in
gonadotroph β cells in anterior pituitary
• Site of synthesis of HCG is syncytiotrophoblast
cells of placenta
– Its level serves as a basis for early detect pregnancy

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• Regulation:
• Release of FSH and LH from anterior pituitary is
regulated by feedback mechanism through
– Gonadotropin releasing Hormone (GnRH) of
hypothalamus
– Controlled by the levels of FSH and LH
• Mechanism of action:
• They bind to specific receptor proteins and
mediate through cAMP second messenger
• Metabolic Role and Biochemical Functions:
• FSH:
• It acts differently in males and females

• In Females:
– Promotes follicular growth
– Increase the weight of ovaries
– Prepare Graafin follicle for the action of LH
– Enhance the production and release of estrogens
from ovaries
• In Males:
– Promotes growth of seminal tubules
– Stimulates testosterone production
– Plays important role in the maturation of
spermatozoa during spermatogenesis
• Spermatogenesis
– The formation of active, motile sperms in
seminiferous tubules is stimulated by TSH

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• Luteinizing Hormone (LH):

• In Females:
– Causes final maturation of Graafian follicle and
stimulates ovulation
• Act synergistically with FSH and facilitate ovulation
• Ovulatory surge is the large amount of LH secreted by
pituitary during the day immediately preceding ovulation
– Stimulate the secretions of estrogen by ovaries
– Helps in the formation & development of corpus
luteum
• Stimulate the secretion of progesteron from corpus luteum
– Stimulate non-germinal elements in ovary to produce
androgen, and testosterons in minute amounts

• In Males:
– In males it is called as interstitial cells stimulating
hormone (ICSH)
– Stimulate interstitial cells to produce testosteron
– Amount of testosteron secreted is proportional to the
amount of LH
– Stimulate androgen secretion
• Development and maintenance of male secondary sex
characters
• Human Chorionic Gonadotropin (HCG)
– Structure closely resembles with LH
– Maintains progesteron secretion from corpus luteum
during early pregnancy

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Adrenocorticotropin
• Also called Adrenocorticotropic Hormone
(ACTH), corticotropin
• Concerned with the growth and functioning of
adrenal cortex
• Chemistry:
– Single polypeptide with 39 aminoacids
• First 23 amino acids from N-terminal contains biological
activity
– Molecular weight 4500
– Occurs in two forms
• α-corticotropin
• β-corticotropin

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• ACTH is synthesized from a glycoprotein called Pro-

opiomelano cortin (POMC) peptide
• POMC is hydrolyzed by different enzymes to form:
– ACTH
– β-Lipotropin
– β-Endorphins
– Melanocyte Stimulating Hormone (MSH) etc.
• Mechanism of Action
• Ca2+ ion dependant activation of cAMP
– Increased transcription and translation
• Growth of adrenal cortex
– Increased phosphorylation and activation of cholesterol
estrase
• Free cholesterol is raised in adrenal cortex

– Increased cAMP activates hormone sensitive lipase

• Increased lypolysis and free fatty acids
• Biochemical Functions:
• Main function of ACTH is the development and
secretions of adrenal cortex
– Increased synthesis of corticosteroids
– Increased release of corticosteroids from adrenal
cortex
• Stimulate synthesis and secretion of
glucocorticoids
– Promote uptake of cholesterol from plasma
lipoproteins into fasciculata cells or adrenal cortex
– Elevates the levels of free cholesterol

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– Promotes binding of cholesterol to cyctochrome P450 and

helps in hydroxylation of cholesterol
• Promotes conversion of cholesterol to pregnenolone in adrenal
cortex
• Activates protein synthesis
• Activates lipase of adipose tissue
– Increases lipolysis and amount of free fatty acids
• Increases ketogenesis
• Activates dehydrogenases of HMP and increased
concentration of NADPH required for hydroxylation
• Excessive production of ACTH cause Cushing’s
syndrome
– Elevated cortisol levels from adrenal cortex
– Hyperpigmentation

Melanocyte Stimulating Hormone

(MSH)
• Secreted by Pars inermedia (intermediate lobe)
of pituitary
• Occurs in three different forms (α, β, and γ
MSH)
• Biosynthesis:
– MSH is the cleavage product of a large precursor
peptide called pro-opiomelano cortin (POMC)
• Protease enzyme cleave POMC into ACTH and β-
lipotropin
• ACTH is further cleaved to form MSH

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• Mechanism:
• Act by binding the G-protein coupled
melanocortin 1 receptor (MC1R) on melanocytes
– Increases cAMP levels through adenylyl cyclase
• Functions of MSH:
• Stimulate the production and release of melanin
from melanocytes in skin & hair (melanogenesis)
– Darkens the skin
• α-MSH acts on hypothalamus
– Suppresses appetite
– Arouse sexually

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Hormones of Posterior Pituitary

• Two hormones are secreted from posterior
pituitary
– Antidiuretic Hormone (ADH) or Vasopressin
– Oxytocin
• Chemistry:
• Both ADH and oxytocin are nonapeptides
– Consist of 9 aminoacids
• Oxytocin differs from vasopressin at 3rd and 8th
amino acid residues
• Disulfide linkage is present between 1st and 6th
cysteine

• Both hormones are synthesized in neuro-

secretory neurons in hypothalamus and stored in
posterior pituitary
– Released independent of each other

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• Regulation of secretion:
• ADH is regulated by osmoreceptor of
hypothalamus and barroreceptors of heart
– Any increase in plasma osmolarity stimulate its
release
• Oxytocin is regulated by neural impulses from
nipples
• Mechanism of Action:
• ADH stimulates the production of cAMP through
adenylyl cyclase
– cAMP promotes water reabsorption
• Inhibitors of adenylyl cyclase (Ca2+) inhibit ADH

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• Oxytocin act through G-protein coupled oxytocin

receptors (OTR) that increase intracellular Ca2+
through phospholypase-C pathway
• Biochemical Functions:
• Antidiuretic Hormone (ADH)/ Vasopressin:
• Primarily concerned with the water balance in the
body
– Water re-absorption leads to the formation of
concentrated (hypertonic) urine
• Low volume
• High specific gravity
• High concentration of Na+, Cl-, PO43- and urea
• Reabsorbed water increase blood volume and in
turn increase blood pressure
– It can also cause vasoconstriction as well as
glycogenolysis by increasing intracellular Ca2+

• The failure of secretion of ADH or defect in the

receptors of target cells is described as diabetes
insipidus
– A situation in which patient urinates excessively just
like in diabetes mellitis (Polyuria)
• Diabetes insipidus is characterized by high
volumes of very dilute urine (20-30L/day)
– This may cause:
• severe dehydration
• Na+ depletion that may lead to electrolyte imbalance
– The overall symptoms may include drowsiness,
irritibility, nausea, vomiting, convulsions, stupor or
coma

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• Oxytocin:
• Primary function of oxytocin is the contraction of
smooth muscles
– Uterine smooth muscles to induce labour
– Myoepithelial smooth muscles to cause milk ejection
• Galactobolic effect
• The number of receptors as well as secretion is
increased by estrogen while decreased by
progesterone

Thyroid Hormones
• Thyroid gland is a bow shaped bi-lobular gland
located below the larynx on each side of trachea

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• Each lobule of thyroid gland consist of a large

number of thyroid follicles
– Structural and functional unit of thyroid gland
• Thyroid follicle are spherical units filled with
colloid and made up of cuboidal cells called
follicular cells
• In between thyroid follicles, small C cells are
also present called parafollicular cells

• It functions under the influence of TSH from

pituitary gland.
• Major hormones secreted by thyroid gland are
– Thyroxine (T4 or Tetra iodo thyronin) and Tri iodo
thyronin (T3) secreted by follicular cells
– Calcitonin secreted by parafollicular cells
• Calcitonin is involved in Ca2+ homeostasis while
other two regulate metabolic rate of the body
Chemistry:
• Chemically thyroid hormones are iodinated
derivatives of tyrosine aminoacid
– Containing more than half of the body’s total iodine

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Biosynthesis & Release of Thyroid Hormones:

• The raw materials required for thyroid hormones
are:
– Thyroglobulin
– Iodine
i) Thyroglobulin:
• Precursor glycoprotein found in follicular cells
and contains about 120 tyrosine residues
– Tyrosine residues serves as substrate for iodine
• Iodinated tyrosine compounds are:
– Mono-iodo tyrosine (MIT) and
– Di-iodo tyrosine (DIT)
• MIT&DIT coupled with each other to form T3 & T4

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ii) Iodine metabolism:

• Iodine is essential for thyroid functioning
• Normally approximately 50mg iodine is present
in the body
– Normal daily intake of iodine is 100 to 200 μg
– 2/3 of iodine is excreted by kidneys and remaining
1/3 is taken up by thyroid gland
• Iodine is incorporated in hormones in 3 steps
a) Uptake of iodine
• Actively taken up by Na+-K+ ATPase pump under the
influence of TSH
b) Organification
• Oxidation of I- to active iodine by thyroperoxidase in the
presence of H2O2
• Iodinium ion (I+) orhypoiodite (HIO) or free iodine radicle (I)

• Active iodine is incorporated into the tyrosine residues to

form MIT and DIT
c) Coupling of iodotyrosines
• MIT and DIT molecules each condenses to form T3 & T4
molecules in the presence of enzyme thyroperoxidase
• 1 MIT and 1DIT combines to form T3 & reverse T3
• 2DIT undergo oxidative condensation to form T4 (Thyroxin)
• Each thyroglobulin contains about 6 to 8
molecules of Thyroxin (T4)
– Ratio of T3 & T4 in thyroglobulin in 1:10
• Prepared hormones are stored in thyroid gland
– Freed hormones are released into blood stream
under the stimulation of pituitary through TSH
– 90% T4 (Thyroxin) and 10% T3

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• In plasma mostly T3 & T4 are transported by

thyroxin binding proteins
– Thyroxine-binding Globulin (TBG)
– Thyroxine binding Pre-Albumin (TBPA)
• After their saturation excessive hormones can bind to
albumin
• The unbound (free) hormones are metabolically
active hormones in the plasma
– Plasma half-life of T3 is about 1 day
– T4: 4 to 7 days
• Thyroid hormones are de-iodinated in the
peripheral tissues by de-iodinase (dehalogenase)
– Iodine removed is recycled and utilized by the gland
again

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Regulation of Thyroid Hormones:

• The synthesis is controlled by feedback
regulation
• T3 is more actively involved in regulation than T4
– TSH from pituitary and TRH from hypothalamus are
inhibited by T3 and to a lesser extent by T4
– Decreased levels of T3 & T4 stimulate TRH and TSH
• Thyroid hormones are stored for several weeks
– It takes months to observe thyroid functional
deficiency
Target sites:
• Liver, Kidneys, Adipose tissue, heart, neurons
(brain etc.
– Carrier mediated (TBG, TBPA) transport to target cells

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Mechanism of Action of Thyroid Hormones:

• Act through binding the intracellular DNA-
binding proteins
– Hormone-responsive transcription factors
– Similar to steroidal hormone receptors
• Crosses the membrane by trans-membrane
carriers
– Binds to receptors in the nucleus
• Hormone receptor complex binds to DNA and
modulate gene expression
– Enhance mRNA synthesis through DNA-dependent
RNA polymerase
– Increase Protein synthesis
– Increased enzyme production

• Functions of Thyroid Hormones:

• Thyroid hormones (T3 & T4) show similar biological
functions however
– Affinity of T3 to thyroid receptors is 10 times greater than
T4
– Biological activity is T3 is 4 times more than T4
– T3 has more rapid onset of action and degradation
kinetics than T4
– About 80% of the T4 is de-iodinated to T3 in the peripheral
tissues
• Effect on BMR:
• They increase the overall metabolic rate of the body
– Increase oxygen consumption in most tissues
– Except Brain, lungs, testes, uterus, lymph nodes etc.

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• This increase heat production and an overall

increase in basal metabolic rate (BMR)
– Increase mitochondrial oxidation
• Induction of Glycerol-3-P-dehydrogenase
– Increase number and activity of Na+-K+ ATPase pumps
• Hydrolyses ATPs to transport Na+ across membrane
• Lack of energy utilization or Na+-K+ ATPase
activity may lead to obesity in some individuals
• Effect on Proteins:
• Promote proteins synthesis
– Cause positive nitrogen balance
• Promote growth and development

• Effects on Carbohydrates:
• Promotes utilization of glucose in the body and
increase blood glucose level (Hyperglycemia)
– Increase absorption from intestine
– Increase gluconeogenesis
– Increase glycogenolysis
• Thyroid hormones act antagonistic to insulin
– DM is aggravated by thyrotoxicosis
• Stimulate oxidative metabolism of carbohydrates
– Stimulate glycolysis, TCA, HMP shunt pathways
• Effects on Lipids:
• Increase lipolysis in adipose tissue
– Increase plasma free fatty acids

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• Increase rate of degradation of cholesterol,

formation of bile acids and bile excretion
• Hypothyroidism increases
– plasma cholesterol
– Plasma lipoproteins (LDL)
• Hyperthyroidism decreases these both of these
– In thyrotoxicosis or thyroid hormone administration
Disorders of Thyroid Gland:
• Among all endocrine glands thyroid is most
susceptible of hypo or hyper function
• Three abnormalities are associated mostly with
thyroid function

– Goiter
– Hyperthyroidism (Thyrotoxicosis)
– Hypothyroidism
i) Goiter:
• Abnormal increase in the size of thyroid is called
goiter
• Failure in the auto-regulation of T3 & T4 synthesis
leads to elevated TSH levels
– Thyroid gland is enlarged to compensate the decrease
synthesis of thyroid hormones
• Main cause of Goiter is deficiency of iodide caused
by Thiocyanates, nitrates and perchlorates
(Goitrogenic factors)
• Certain foods like cabbage, cauliflower and turnip contain
thiocyanate

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• Endemic goiter can be prevented by taking

iodized table salt
– Common salt is mixed with potassium iodide, sodium
iodide or sodium iodate
ii) Hyperthyroidism: (thyrotoxicosis)
• Associated with overproduction of thyroid
hormones
• Caused by Grave’s disease or increased thyroid
hormone intake
• Grave’s disease is due to elevated levels of
thyroid stimulating IgG (Long acting thyroid stimulator)
– Activates TSH that results in the increased hormone
production

• The general symptoms of thyrotoxicosis are:

– Increased BMR
– Nervousness
– Irritibility, anxiety, rapid heartrate
– Loss of weight, increased appetite
– Diarrhea, sweating, weakness
– Sensitivity to heat
– Exophthalmos
• Protrusion of eyeballs
• Hyperthyroidism is treated with
– Antithyroid drugs like thiocarbamides,
aminobenzene etc.
– Surgical removal of thyroid gland

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iii) Hypothyroidism:
• Impaired thyroid function
– Decreased levels of T3 & T4
• Disorder of pituitary or hypothalamus may
contribute to hypothyroidism
• Typical symptoms are:
– Reduced BMR,
– slow heart rate,
– Weight gain,
– Sluggish behavior,
– Sensitivity to cold etc.
• In adults it cause myxoedema
– Bagginess under eyes, puffiness of face and slowness in
physical and mental activities
• In children it causes cretinism
– (Physical & mental retardation)

• Calcitonin (CT):
• Secreted by parafollicular cells of thyroid gland
– Also called C-cells present in thyroid, parathyroid and
thymus glands
• Calcium regulating hormone
– Act antagonistic to parathormone from parathyroid
• Chemistry:
• Single chain lipophilic polypeptide with 32
aminoacids
– Disulfide linkage between two cysteine residues at 1st
and 7th position
– High contents of aspartic acid and threonine is
present

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Mechanism of Action:
• Binds to calcitonin receptors on plasma
membrane of osteoclasts and renal tubular
epithelial cells
– Activates adenylyl cyclase that increase cAMP level
• cAMP mediate hormone action
Functions:
• Acts on bones and kidneys
• Cause Hypocalcaemia (decreased blood calcium)
i) Bones
– Promotes calcification by increasing osteoblast
activity

– Decrease osteoclast activity

• Bone resorption and Ca2+ and PO43- mobilization from
bones to blood
ii) Kidneys:
• Act on DCT and ascending loop of Henle
• Decrease tubular reabsorption of calcium (Ca2+)
and inorganic phosphate (PO43-)
– Increased excretion of Ca2+ (Calcinuria) and PO43-
(phosphaturia)
• Also decrease Ca2+ absorption from intestine

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Parathyroid Hormone
• Two pairs of small oval shaped parathyroid
glands located on the posterior of thyroid gland
• Primarily concerned with Ca2+ and PO43-
homeostasis through its secretion
(parathormone)

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• Parathormone (PTH):
• Secreted by Chief cells of the parathyroid gland
– Most important regulator of calcium and phosphorus
concentration in extracellular fluid
• Chemistry:
• Linear polypeptide hormone with 84 amino acids
– Alanine is present at N-terminal
– Glutamine is present at C-terminal
• Aminoacid sequence 1 to 34 is important for its
biological activity
– Possesses receptor binding properties
• Methionine is necessary for calcium mobilizing
effects

Biosynthesis:
• PTH is originally synthesized as a pro-hormone in
the chief cells
– Initially 115 aminoacid based pre-pro-parathormone
is formed in polysomes
– Pre-pro-PTH is hydrolysed to pro-PTH with 90 AA
• 25 aminoacids are removed during hydrolysis
– Finally further removal of hexapeptide converts pro-
PTH to active parathormone
• Stored in secretory vesicles of golgi bodies
• Release:
– Regulated by –ve feedback regulation of serum Ca2+
– Increase cAMP and low Ca2+ stimulates its release

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Mechanism of Action:
• Act by binding specific receptors on plasma
membrane of bone, kidney and intestinal cells
• Activate cAMP through adenylyl cyclase
• cAMP
– activates protein kinases
– increase intracellular Ca2+ concentration
• Act as another second messenger
• Both cAMP and increased Ca2+ activates
intracellular proteins and generate its response
Physiological functions:
• The prime function of PTH is to elevate serum
calcium levels by acting on bones, kidneys and
intestine independently

i) Action on bones:
• It causes decalcification or demineralization of
bones
– Very significant role in Ca2+ homeostasis
• It increase cAMP in
– Osteoclasts
– Osteoblasts
– Osteocytes
• Here it activates protein kinase enzymes that:
– Stimulate differentiation and maturation of
osteoclasts
– Increase resorption of bones
• Enhance Ca2+ and PO43- mobilization from bones
• Increased overall serum Calcium level

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ii) Action on Kidneys:

• Increase Ca2+ re-absorption from kidney tubules
• Stimulates α-1-hydroxylase in mitochondria of
PCT
– Converts 25-hydroxy cholcalciferol to 1,25-dihydroxy
cholcalciferol
• Increase the intestinal and renal absorption of Ca2+
• Increase excretion of PO43-, K+ and HCO3- by
decreasing their re-absorption
iii) Action on intestine:
• Indirectly increase the Ca2+ absorption by
promoting the synthesis of calcitriol
• Overall action of PTH and calcitonin are
opposite to each other in regulating blood Ca2+

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Disorders of Parathyroid hormones:

• Hyperactivity of parathormone may induce:
– Hypercalcemia, that may lead to
• kidney stones
• High blood pressure
– Osteoporosis due to over demineralization of bones
• General symptoms of hyperparathyroidism are:
– Muscle weakness, fatigue, depression and aches &
pains in joints and bones
– In Severe cases increased thirst and urination is also
observed
• Hypoparathyroidism increase the risk of
– Addison’s disease, cataracts, Parkinson’s disease etc.

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Pancreatic Hormones
• More than 95% of the pancreas consist of exocrine
tissue involved in digestion
• Remaining tissue consist of clusters of endocrine
cells (Islets of Langerhans)
– irregularly shaped patches of endocrine tissue that
produce hormones and regulate:
• Blood Sugar level
• Pancreatic secretions
– Normal pancreas contains about 1 million Islets of
Langerhans
– Four distinct cell types among which 3 produce hormones
• Alpha cells (Glucagon), Beta cells (Insulin), Delta cells
(Somatostatin)
• Fourth cell type is not known to any secretion

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Insulin
• Polypeptide hormone secreted by beta cells of
islet of Langerhans in pancreas
– First hormone to be identified, isolated, purified
and produced by recombinant DNA technology
• Anabolic hormone; influences the metabolism
of
– Carbohydrate
– Fats and
– Proteins

• Chemistry:
• Heterodimeric protein
– Two different polypeptide chains (A & B chains)
linked together by 2 disulfide bonds
• Connecting A7 to B7 and A20 to B19
– A chain:
• 21 amino acids
• An additional disulfide bond A6 and A11
– B chain:
• 30 aminoacids
• Terminal sequences of aminoacids, 3 disulfide
bonds, and 3D stuructures is similar in different
species
– Insulin from one animal is very likely to biologically
active in other species

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Fig: Structure of Insulin (A and B Chains)

[Showing interchain and intrachain disulfide bonds]

• Biosynthesis of Insulin:
• Insulin is synthesized by β-cells of islets of
Langerhans of pancreas
– Pre-pro-insulin (108 AA) is formed, converted to pro-
insulin (86 AA) that is ultimately converted to insulin
• Sequential degradation to insulin and connecting peptide
(C-peptide)
• C-peptide is itself biologically inactive but serves as a useful
index for endogenous insulin production
– Pre-Pro-insulin is synthesized in polysomes, attached
to rough ER in β-cells
• Transferred to lumen of rough ER cisternae
• There Signal peptidase enzyme split 23 AA peptide from N-
terminal of pre-pro-insulin
• Pro-insulin with 86 amino acids is formed

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• Pro-insulin is transferred from ER to golgi bodies

– Trypsin-like-protease hydrolyses it at two sides
– 2 peptides; A-chain (21AA) and B-chain (30AA) and 1
connecting C-peptide (31AA) is formed
• Insulin (and also pro-insulin) combines with two
Zn2+ to form hexamer complex and stored in
cytosol secretory granules
– Released by exocytosis in response to various stimuli
• Regulation of Insulin Release:
• 40-50 Units of insulin is secreted daily
– Normal plasma insulin concentration is 20-30μU/mL
• Various factors stimulate or inhibit the release of
insulin from β-cells

• Factors stimulating insulin secretion are:

– Glucose (most important stimulus)
• Carbohydrate rich meal and elevated BSL
– Aminoacid
• Rise in plasma amino acid concentration
• Arginine, leucine are potent stimulator of insulin release
– GI hormones (Secretin, gastrin etc.)
• Release after the ingestion of food
• Epinephrine from adrenal medulla suppresses
insulin release
– promotes energy metabolism by mobilizing energy-
yielding compounds
• Glucose from liver and fatty acids from adipose tissue

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Target Tissues:
• Major target tissues are Muscles, liver, heart
and adipose tissue
Mechanism of Insulin Action:
• Act by binding to specific insulin receptors
– Tetramer glycoprotein receptors consist of 2 alpha
and 2 beta subunits
• Insulin binds to extracellular alpha subunit
• Beta subunit is a transmembrane tyrosine specific protein
kinase enzyme, activated by insulin molecule
– Up to 20,000 receptors are found on target plasma
membrane
• Being constantly synthesized and degraded daily

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• Signal transduction in insulin receptors:

– Binding to alpha unit induce conformational changes in it
– This activates tyrosin kinase (β-subunit)
• Autophosphorylation of tyrosine residues on β-subunits and
insulin receptor substrate (IRS)
– Phosphorylated IRS promotes activity of other protein
kinases and phosphatases that regulate biological activity
• An overall fall in cAMP and rise in cGMP levels
• Both function in a reciprocal relationship
• Insulin also act by affecting the rate of transcription
of specific genes: Increase proteins and enzymes
– Decrease the synthesis of phosphoenol pyruvate carboxy
kinase (PEPCK) (Key enzyme of gluconeogenesis)
– Induce synthesis of Phosphofructokinase and pyruvate
kinase (Key enzymes of glycolysis)

• Biological Function of Insulin:

• It increases
– carbohydrate metabolism, glycogenesis and glycogen
storage
– FA synthesis, Triglyceride storage
– Aminoacid uptake and protein synthesis
i) Action on carbohydrate metabolism:
• Net effect is
– Lowering blood glucose
– Increase glycogen stores
a) increase glucose uptake
– Directly or by stimulating glucose transporters GLUT4
– Induce synthesis of glucokinase in hepatocytes
• Phosphorylate glucose: lowering intracellular concentration

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b) increase glycolysis
– Induce enzymes phosphofructokinase and pyruvate
kinase
– Increase utilization of glucose for providing energy
c) increase pyruvate to acetyl Co-A conversion
– Activates pyruvate dehydrogenase enzyme
• Increases aerobic oxidative decarboxylations of pyruvate to
acetyl Co-A
d) Promote glycogenesis
– Activates glycogen synthase
• Key and rate limiting enzyme of glycogenesis
e) increase HMP-shunt pathway
– Activates Glucose-6-Phospho Dehydrogenase and 6-
phosphogluconate dehydrogenase
– Stimulate HMP shunt pathway and produce NADPH

f) Decrease Gluconeogenesis
– Decrease rate of transcription of PEP-carboxykinase
(PEPCK)
• Key rate limiting enzyme of gluconeogenesis
– Inactivates fructose-2,6-biphosphatase that
allosterically inhibit fructose-1,6-bi-phosphatase
• Increase concentration of fructose-2,6-bi phosphate in cells
g) Decrease glycogenolysis
– Inactivates glycogen phosphorylase and glucoe-6-
phosphatase enzymes

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ii) Action on Lipids metabolism:

• Overall action of insulin on lipid metabolism is
decreased release of fatty acids from stored fats
– Lowering of free fatty acid levels (↓ FFA level)
– Increase triglyceride stores (↑ TG store)
a) decreases lipolysis in adipose cells
– Activates phosphoprotein phosphatase
• Dephosphorylates triacyl glyceol lipase
– Activates phosphodiesterase enzyme
• Deactivates cAMP, prevents rephosphorylation and
reactivation of TG lipase
b) increases the synthesis of triglycerides from
glucose in adipose tissue

– Provide more raw material

• glycerol-3-phosphate (from glycolysis)
• NADPH (from HMP shunt pathway)
– Induce the synthesis of lipoprotein lipase enzyme
• Increased hydrolysis of VLDL and TG of circulating
chylomicrones to provide FFA for the synthesis of
triglycerides in adipocytes
c) increases fatty acid synthesis (for TG synthesis)
– Provide more acetyl Co-A through various
mechanisms
– Increase activity of acetyl Co-A carboxylase
• Key enzyme in fatty acid synthesis
d) decreases ketogenesis
– Formation of ketone bodies (Ketone group containing
water soluble molecules) from fatty acids by the liver

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• Ketone bodies are formed from acetyl CoA condensation to

acetoacetyl CoA and finally 3-hydroxy-3-methyl glutaryl-
CoA (HMG-CoA)
– Insulin decreases
• FFA level
• β- oxidation of fatty acids to produce acetyl-CoA
• The activity of HMG-CoA synthetase enzyme
– Increases the utilization of acetyl-CoA for
• Oxidation
• Lipogenesis
• The overall effect is the reduced availability of
acetyl-CoA for ketogenesis
iii) Action on Protein Metabolism:
• Net effect is increased protein synthesis and
decreased protein degradation

a) increases aminoacid uptake by the tissues

– Stimulate the synthesis of AA transporter proteins
b) Effect gene transcription at nuclear level
– Regulate specific mRNA synthesis
c) Effect translation at ribosomal level
iv) Action on Mineral metabolism:
• Decrease K+ and inorganic phosphate (Pi)
– Enhanced glycogenesis and phosphorylation of
glucose
v) Action on Growth and cell replication:
• Stimulate cell growth and replication
– Regulated through various growth factors
• Epidermal growth factor (EGF), platelet-derived growth
factor (PDGF), fibroblast growth factor (FGF) etc.

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Diabetes Mellitus (DM)

• DM is a metabolic disease characterized by
severe hyperglycemia
– Persistently high blood glucose level leads to various
long term complications
• Diabetes is broadly divided into
– Insulin dependent diabetes mellitus (IDDM)
– Non-Insulin dependent diabetes mellitus (NIDDM)
i) Insulin dependent diabetes mellitus (IDDM)
• Also called type-I diabetes or juvenile onset
diabetes
– Occurs in childhood (Between 12-15 years age)
– 10-20% of total known DM patients

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• Characterized by total deficiency of insulin

– Destruction of β-cells of islets of Langerhans
caused by
• Autoimmunity
• Drugs
• Viruses
• Obesity
• Due to certain genetic variations β-cells are
identified as foreign cells
– Destroyed by immune mediated injury
• Symptoms appear when 80-90% of cells are
lost
– Pancreas fail to produce insulin in response to
sugar ingestion
• Insulin therapy is needed for the treatment

ii) Non-insulin dependent diabetes mellitus

(NIDDM)
• Also called type-II diabetes or maturity onset
diabetes or adult onset diabetes
• Most common type of DM
– 80 to 90 % of known patients
• Occurs in adults (above 30 to 35 Years of age)
– Less severe than type-I DM
• Causes are genetic, environmental and personal
lifestyle based
– Particularly linked with obesity (diabetogenic factor)
• Decrease in insulin receptors on target cells
• Amount of insulin may either be normal or even elevated

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• Many times weight loss alone is sufficient to

treat it
– Mostly oral hypoglycemic agents are needed to
control blood sugar levels
• Recent studies shows insulin resistance is
caused by
– Increased level of Tumor necrosis factor-α (TNF-α)
– Decreased secretions of adiponectin by adipocytes
of obese people
• Normal glucose levels
• Fasting: >100mg/dL
• Random: >150mg/dL

Signs & Symptoms of uncontrolled DM

• Uncontrolled DM leads to the manifestation of
the following signs & symptoms in patients:
– Hyperglycemia
– Glycosuria (Glucose in urine)
– Polyuria (Increased urination)
– Polydipsia (excessive drinking of water due to thirst)
– Polyphagia (Hyperphagia: increased food intake)
– Ketosis (Ketoacidosis)
– Loss of body weight (increased catabolism of fats & proteins)
– Water & electrolyte imbalance
– Hyperlipidemia (elevated lipids in blood; LDL,VLDL etc.)

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• Severe and persistent hyperglycemia may cause

– Glucose toxicity
• Osmotic effects/hypertonic effects results in polyurea
• β-cell damage due to enhanced oxidative phosphorylation
• Increased glycation of proteins can be linked with Diabetes
associated complications
– Atherosclerosis
– Gangrene
– Neuropathy, Nephropathy and Retinopathy, etc.
– Ketoacidosis
• Increased mobilization of fatty acids
– Overproduction of ketone bodies
– Hypertriglyceridemia and hypercholesterolemia
• Increased level of triglycerides, VLDL, chylomicrons and
choleserol

Treatment of diabetes mellitus:

• Management option of DM includes
– Diet
• Low caloric, low carbohydrates, high protein and fiber rich
diet should be taken
• Fat should be drastically reduced (unsaturated FA)
– Exercise
– Drugs and finally
• Oral hypoglycemic agents are used (Sulfonylureas &
biguinides)
– Insulin (short acting & long acting (modified) insulin)
• Most cases can be controlled only by diet &
exercise or drugs
– Only 20-30% patients need insulin

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• Elevated glucose level should not be used as

index for DM
• DM can be diagnosed on the basis of individual’s
response to oral glucose load
– Oral glucose tolerance test
• 10 Hours fasting blood and urine analysis
• 75g Glucose is administered orally in 1 glass (300mL) water
• Continuous sampling every 30 minutes for 2 hours

• Other indices for DM management are:

– Random and Fasting BSL
• Most significant and easy detection of short term control
can be estimated by Fasting and random BSL
– Glycosuria
• Most commonest cause of glycosuria is DM
– Glycated hemoglobin (HbA1C) (2-3 months control)
• Condensation of N-terminal valine of each β-chain with
glucose
• Conc. of HbA1C can also be used for diagnosis (>7%)

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Glucagon
Hyperglycemic – Glycogenolytic factor (HGF)
• Produced by α-cells of islets of Langerhans of
Pancreas and act antagonistic to insulin
• Involved in
– Rapid mobilization of hepatic glycogen to glucose
• By Glycogenolysis
Chemistry:
• Polypeptide hormone consisting of 29AA
– 15 different types of amino acids are present
• Unlike insulin no cysteine, proline or isoleucine
– But tyrosine, methionine and tryptophan are present
– Amino acid sequence is same in all species
• Molecular wt. of glucagon is approximately 3500 D

• Biosynthesis:
• Synthesized as pro-glucagon in α-cells
• Various peptidases hydrolyse pro-glucagon to
glucagon and different inactive peptides
– Carboxy peptidase B
– Trypsin-like peptidase
• Peptidases act on both C – & N – terminals
• Regulation of Secretion:
• Stimulated by
– low blood glucose level
– Amino acid derived from dietary proteins
– Low levels of epinephrine
• Inhibited by elevated blood glucose level

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• Mechanism of Action:
• Act by binding to G-protein coupled receptor on
the membranes of hepatocytes and adepocytes
– Activates adenylyl cyclase and increases cAMP
– cAMP then activates protein kinases that regulate the
actions of glucagon
• cAMP also induce the synthesis of specific
enzymes by increasing transcription of genes
– E.g. Glucose-6-phosphatase enzyme
Physiological Functions:
• It influences the metabolism of carbohydrates,
proteins and lipids
– Typically acts opposite to insulin

i) Action on carbohydrates metabolism:

• Overall it increases the blood sugar levels
– Cause hyperglycemia
• a) Increases Glycogenolysis in liver only
– Muscle cells lack glucagon receptors
• b) increase gluconeogenesis in liver
– Protein kinase activity leads to the synthesis of new
enzymes involved in gluconeogenesis
• PEP carboxykinase
• Pyruvate carboxylase
• Fructose-1,6-bisphosphatase etc.
• c) increase glucogenic aminoacids pool in liver
– Increased breakdown and decreased synthesis of
proteins

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ii) Action on Lipid metabolism:

• a) Promotes lipolysis
– Increase breakdown of TG
– Increased level of FFA
• FA undergo β-oxidation
– Increased formation of ketone bodies
• Thyroid hormones help in lipolytic action of
glucagon probably by increasing glucagon
receptors on adipocytes
• b) Decreases lipogenesis
– Increased FFA inhibits acetyl-CoA carboxylase
– cAMP phosphorylate acetyl-CoA carboxylase and
inactivates it

iii) Action on Protein metabolism:

• a) Reduces protein synthesis
– Decreases the incorporation of AA into peptide
chains
– Inactivation of ribosomal components by protein
kinases regulated by cAMP
• b) increase amino acid pool in liver for
gluconeogenesis
– Stimulate protein catabolism, specially in liver
– Increased uptake of amino acid by liver
• Lowers plasma amino acids level
iv) Action on Heart:
– Positive ionotropic effect without myocardial
arrhythmias (advantage over nor-epinephrine)
– Increased heart rate and heart contraction

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v) Actions on mineral metabolism:

• Increase K+ release from liver
– May be due to glycogenolytic activity
• Decrease plasma Ca2+ levels
– Increase calcitonin release from thyroid gland
vi) Calorigenic Actions:
• Increased hepatic de-amination of amino acids
– Thyroid activity is increased to utilize these
deaminated residues
– Overall heat of the body increases
• Increase heat production
• Raise basal metabolic rate (BMR)

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Overall comparison of insulin and glucagon

functioning

Important Questions from Past papers

• What are hormones? Discuss in detail the secretion
of thyroid hormone and its disorder. (20 Marks)
[A/2015]
• Write the introduction, Chemistry, physiological
functions, regulation and disorders of parathyroid
hormone (20 Marks) [A/2016]
• Write the introduction, Chemistry, functions,
regulations and disorders of adrenal medullary
hormone (20 Marks) [A/2016]
• Define and classify Hormones (10Marks)[S/2016]
• Write the chemistry, functions, regulation and
disorders of thyroid hormone (20Marks)[S/16,17,
A/2018, 19]

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• Write the introduction, chemistry, physiological

functions, regulation and metabolism of Growth
hormone (10 Marks: S/16,18; 20 Marks: A/2017]
• Write the introduction, chemistry, functions,
regulation and disorders of glucagon (20 Marks:
A/2017,19, S/2018]
• Write the introduction, chemistry, functions,
regulation and disorders of insulin (20 Marks:
S/2017, A/2018]

75