Physiology

for 2nd year medical students

Endocrine
Illustrated with images

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➢ Endocrine glands (ductless glands):
Pituitary: master gland
glands under control of pituitary: glands not under control of pituitary:
thyroid, suprarenal cortex and gonads parathyroid, suprarenal medulla and pancreas
N.B.: organs which possess endocrine function:
- Heart: atrial natriuretic peptide (ANP). - Kidney: erythropoietin
- Liver: somatomedines & 25 hydroxychole- calciferol. - pineal gland: melatonin.
- Skin: calciferol (vitamin D). - GIT hormones as gastrin, CCK, secretin and VIP.
➢ Endocrine Hormones
1) secreted directly into blood in small amounts
2) bind with receptors and initiate many reactions.
3) removal: target cell uptake, metabolic inactivation by liver or excretion by kidney

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❖ classification:
Structure Polypeptide and Protein Steroid Hormones Derivatives of
tyrosine
Secreted by pituitary, pancreas, parathyroid and hypothalamus adrenal cortex, gonads, placenta & thyroid and
vitamin D adrenal medulla
Synthesis - in rough endoplasmic reticulum as inactive - from Cholesterol
preprohormone → cleaved → prohormones. - stores of cholesterol esters rapidly
- Golgi apparatus: packaging into secretory mobilized for synthesis after a
vesicles. stimulus
- enzymes in vesicles cleave prohormones to
active hormones and inactive fragments.
storage vesicles stored in cytoplasm - not stored
Secretion exocytosis highly lipid soluble, once synthesized →
simply diffuse across cell membrane

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➢ Mechanisms of Action of Hormones::
• 1st step: binding with receptor → hormone – receptor complex
• receptors: large proteins specific for a single hormone → determine target tissue
❖ regulation of receptors: number of receptors is not constant:
1. Down regulation: ↑ hormone → ↓ number of receptors (↓ response) by:
(1) ↓ production of receptors.
(2) Temporary sequestration of receptor inside cell.
(3) Inactivation of some of receptor or intracellular protein signaling molecules.
(4) Destruction of receptors by lysosomes after they are internalized.
2. Up-regulation: ↓ hormone → ↑ number of receptors (↑ response).

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 Protein (catecholamines, serotonin, Steroids thyroid
melatonin)
Site of cell membrane (lipid insoluble) Cytoplasm (lipid soluble) Nucleus (small molecules)
receptor
Intracellular • hormone binds to extracellular part of Protein Synthesis & activation of Genes
Signaling receptor → affect target proteins (enzymes - hormone-receptor complex binds with a specific
or ion channels) either directly or through (promoter) sequence of DNA "hormone response
second messenger. element" → either activates or represses transcription of
• Types of receptors: genes → new proteins become controllers of functions.
1) G Protein-Linked: - proteins are enzymes, transport proteins, or structural
serpentine: seven transmembrane segments. thyroid hormones are characterized by:
2) Enzyme-Linked Receptors 1. formation of many intracellular proteins
N.B.: Second messenger: another substance 2. function for days or weeks.
perform intracellular changes of some
hormones. includes:
cAMP, phospholipase C, c GMP and Ca
Transport dissolved in plasma o mainly bound to plasma proteins. (< 10 % free).
o protein-bound hormones:
- cannot diffuse across capillaries to cells (inactive).
- Reservoirs: replenishing concentration of free hormones.
N.B.: Binding to plasma proteins slows clearance from plasma.

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➢ Inter-relation between endocrine and nervous systems
A. nervous system can affect endocrine system:
Hypothalamo Hypothalamo-hypophyseal Direct connection
hypophyseal portal tract between hypothalamus
circulation and suprarenal medulla
hypothalamus affect ADH and oxytocin formed affect secretion of
anterior pituitary by in hypothalamus but secreted epinephrine &
releasing or inhibiting by nerve endings in posterior norepinephrine
hormones pituitary

B. endocrine system can affect nervous system:

1. Parathyroid glands control Ca++ in blood → affects excitability of nerves.
2. thyroid hormones affect the excitability of the nervous system.

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 ➢ Regulation of Hormone Secretion
1. Hypothalamic pitutary axix

2. Feedback Control
a) Negative feedback (prevents over activity of hormone systems):
- ensures proper level of hormone.
- By hormone (or its products) to prevent over-secretion.
- at all levels, including gene transcription and translation involved in synthesis
of hormones or releasing stored hormones.
b) positive feedback (Rare).
o action of hormone → additional secretion of hormone. example:
- LH acts on ovaries → secretion of estrogen → increase LH secretion.

3. Cyclical variations (circadian rhythm):

periodic variations in hormone release influenced by stages of development,
aging, diurnal (daily) cycle, and sleep

Pituitary Gland (hypophysis)

• Physiologically, gland is divisible into:
1. anterior pituitary (adenohypophysis)
2. posterior pituitary (neurohypophysis)
3. pars intermedia: inbetween, a small, relatively avascular zone (absent in human)
➢ Synthesis of anterior pituitary hormones: one cell type for each hormone:
1. Somatotropes (30 to 40 %): growth hormone (hGH)
2. Corticotropes (20 %): adrenocorticotropin (ACTH)
3. Thyrotropes (3 - 5 %): thyroid-stimulating hormone (TSH)
4. Gonadotropes (3 - 5 %) : gonadotropic hormones, (LH) and (FSH)
5. Lactotropes (3 - 5 %): prolactin (PRL)
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➢ Control of secretion of anterior pituitary:
I - Hypothalamic control = Releasing and inhibiting hormones:
o Characters:
1. small polypeptides. 2. Nonspecific.
3. Work through cAMP system.
o Site of release: Median eminence.
o Mode of delivery: Hypothalamo-hypophysial portal circulation.

releasing hormones inhibiting hormones

GHRH GHIH = “somatostatin”.
PIH (prolactin inhibiting)
1. TRH “thyrotropin releasing hormone”.
2. CRH “corticotropin releasing hormone”
3. Gn-RH

II- Feed back control:

1) Long loop (negative feed back):
o hormones of target endocrine glands on the pituitary or hypothalamus.
o always inhibitory except: Estrogen & luteinizing hormone (LH)
2) Short loop: pituitary hormones on hypothalamus. always inhibitory.
3) Ultra short (short-short): releasing hormones on themselves (autocrines).

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 Growth Hormone (Somatotropin)
• hGH: protein hormone having 191 amino acids.
• secreted in a pulsatile pattern (normally higher in children)

➢ Mechanism of action = “JAK – STAT”

• One hormone molecule binds to 2 receptors forming homodimer → activates
JAK (Janus family of tyrosine kinase enzymes) → phosphorylate tyrosine in:
1) themselves (autophosphorylation)
2) membrane protein kinase C (PKC) & phosholipase C (PLC).
3) “IRS” insulin receptor substrate: intermediary product in many cellular
metabolic pathways induced by insulin.
4) (STAT) signal transducer and activator of transcription proteins →
nuclear responses through transcription of genes → protein synthesis.

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➢ Actions: only anterior pituitary hormone functioning directly (not through a gland):
I- Metabolic effects:
Protein metabolism Carbohydrate metabolism Fat metabolism
anabolic: Diabetogenic: lipolytic Ketogenic (in fasting & stress):
increase synthesis → ↑ size and ↑ blood glucose ↑ fat utilization for energy production.
number of cells. - anti-insulin: ↓ glucose uptake by - lipolysis (↑mobilization of fatty acids from
- ↑ amino acid uptake through cell inhibiting "hexokinase" or adipose tissue, ↑ fatty acid in blood) →
membrane. “glucokinase” in skeletal muscles hyperlipidemia.
- ↑ transcription of DNA. and fat cells. - Ketogenic: ↑ uptake of fatty acids by liver:
- ↑ RNA translation by ribosomes → - ↓ glucose utilization (glycolysis and ketone bodies & acetyl CoA formation.
protein synthesis oxidation of glucose). - Ketosis: ↑ growth hormone → large
- “protein sparer”: uses fatty acid - ↑ glucose production by liver. quantities of acetoacetic acid formed by
for energy decreasing protein - ↑ glycogenesis: promotes glycogen liver → body fluids
catabolism deposition due to polymerization - N.B.: excessive mobilization of fat from
of glucose adipose tissue may cause a fatty liver.
N.B.: (diabetes mellitus if increased)

NB: excessive GH results in:

• insulin resistance: Decreased affinity of insulin receptors
• Hyperglycemia: increased blood glucose stimulates insulin secretion
• Hyperlipidemia: muscle infiltration with fatty acids impairs insulin action

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II- Effect on growth: increases protein synthesis, cell division and proliferation
a) on soft tissues: growth, erythropoiesis and positive nitrogen balance.
b) on bone and cartilage: growth of skeletal frame. effects:
1) reproduction of chondrocytic and osteogenic cells.
2) converting chondrocytes into osteogenic cells → new bone.
3) ↑ deposition of protein by these cells.
• principal mechanisms of bone growth:
1- ↑ length: in Long bones grow at epiphyseal cartilages:
- deposition of new cartilage → conversion into new bone, elongating shaft
- indirectly through somatomedins = Insulin-like growth factors "IGFs".
Proof: Chondrocytes exposed to growth hormone outside body → not affected
- After adolescence: fusion between shaft and epiphysis: no further lengthening.
2-↑ thickness: Osteoblasts in periosteum deposit new bone on surfaces:
(throughout life especially membranous bones).
❖ Somatomedins or Insulin-like growth factors "IGFs":
- secreted by liver & chnodrocytes under stimulation of growth hormone
- effects on growth are similar to insulin
- four but most important is “somatomedin C” or IGF-1
- called sulfation factor: cause Chondrocytes to increase synthesis of collagen
and chondriotin sulphate (matrix of cartilage).
Growth hormone somatomedin C
duration of action Short prolonged
attachment to plasma proteins weakly strongly
release from blood rapidly slowly
half-time less than 20 minutes 20 hours

❖ N.B.: growth hormone & insulin:

o Insulin was proved to be necessary for the growth-promoting action of GH due
to insulin's ability to enhance the transport of some amino acids into cells.
o GH fails to cause growth in an animal that lacks a pancreas
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➢ Control & Regulation of growth hormone secretion:
1- Hypothalamic control (Hypothalamo- hypophyseal portal circulation):
median eminence secretes GHIH, GHRH
2- Feed back control:
a. Long loop: IGF-1 stimulates hypothalamus to secrete GHIH = inhibits GH.
b. Short loop: (always negative): GH inhibits GHRH and GHIH.
c. Ultra short (short- short): GHRH on itself.

3- Factors affecting:
↑ secretion ↓ secretion
1. Growth hormone-releasing hormone. GHIH (somatostatin)
2. Starvation or severe protein deficiency. obesity
3. Hypoglycemia, fasting or low fatty acids in increase glucose or fatty
blood acids
4. Stress (Exercise, Trauma) and excitement. cortisol
5. first 2 hours of deep sleep (stages II &IV) exogenous GH
6. Sex hormones: estrogens & testosterone. aging
(puberty)

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➢ Disturbances of GH function - Primary: pituitary in origin. - Secondary: hypothalamic in origin.
I- Effects of hypofunction: “Pituitary Dwarfism”:
causes characters
1. GHRH (growth hormone releasing hormone) deficiency. • growth arrested (short stature 100-120 cm)
2. GH deficiency. • well proportioned i.e. span = height and
3. Laron dwarfism = GH insensitivity: mutation of GH receptor gene vertex to symphisis = symphisis to heel
4. Lévi-Lorain dwarf: hereditary inability to form somatomedin C. • normal mentally & sexually. (Some are
5. Deficient local secretion of IGF-1 by chondrocytes intelligent but unstable psychologically)

• N.B. Pituitary infantilism:

• pituitary dwarfism, associated with hypogonadism.
• Cause: deficiency of gonadotrophic hormones in addition to GH.
❖ Differential Diagnosis:
Achondroplasia (most common) Thyroid dwarf (cretin)
cause autosomal dominant mutation of gene fibroblast deficiency of thyroid hormones during infancy
growth factor receptor3 "FGFR3"
manifestations trunk normal: head, neck, chest & pelvis; limbs - Physically, mentally and sexually retarded.
short (disproportion). - disproportionate in viscera (big tongue, liver, abdomen).
N.B.: good candidates in circus & shows
❖ Treatment: h GH synthesized by Escherichia coli (recombinant DNA technology)

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II- Effects of hyperfunction (Causes: acidophilic adenoma).
Gigantism (Giantism) Acromegaly
timing before adolescence after puberty: after union of epiphyses of long bones
Specific Bones Symmetrical over growth of bones - ↑ in thickness (no linear): clearer in terminal portions (acro= periphery)
manifestations (height 200- 210 cm) = normal hands, feet, fingers become large (megaly = enlarged)
proportions (span = height, and vertex - acromegalic facies : skull box shaped with prominent cheeks, super
to symphisis = symphisis to heel). ciliary ridges and a protruded lower jaw (prognathism) with widely
separated teeth (do not overgrow).
- Kyphosis: Bending of spine, due to overweight "ape like" posture. may
produce osteoarthritic changes.
Common 1. Overgrowth of Soft tissues:
manifestations a) viscera: splanchnomegaly
b) muscles: very strong → becomes weak. due to: overstretch & inadequate development relative to bones
c) bulldog facies: skin & soft tissues (nose & lips) overgrow → wrinkling
d) increased hyroxy proline in urine: indicator of increased soft tissue
2. Endocrinal:
- Hyperglycemia, glucosuria & secondary diabetes mellitus (10%)
- thyroid gland is enlarged (goiter): increased production of T3 > T4.
- gynecomastia (breast enlargement) in males: similarity between GH & prolactin
3. Pressure symptoms (Pituitary enlargement):
- on optic chiasma: (bitemporal hemianopia): tubular field.
- on gonadotropes: Hypogonadism
- panhypopituitarism → death (destruction of all cells of pituitary).
• Treatment: microsurgical removal of tumor or irradiation of pituitary gland.

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 Prolactin hormone: PRL = Mammotropine = Lactotropine
• polypeptide: 199 AA, with a great similarity to GH.
• N.B.: also secreted by endometrium & placenta (during pregnancy).
• level in plasma: 5ng/ml in males & 8ng/ml in females.
➢ Mechanism of action: “JAK – STAT” (PRL receptors resemble GH
receptors)

➢ Actions:
A – In females:
1) Milk secretion: production of casein & lactalbumin after breasts priming by
estrogen & progesterone
2) Prevention of ovulation= anovulation: inhibits effect of gonadotrophic
hormones on ovaries → infertility & amenorrhea during lactation.
B – In males: no physiologic effect.

➢ Regulation: hypothalamus controls PRL secretion by:

- Prolactin inhibiting hormone: dopamine.
- Prolactin stimulating hormone: not definitely present.
• not in balance; more inhibition
• prolactin increases dopamine (indirect feedback).

➢ Physiological variations:
1) Pregnancy: it rises gradually & peaks at parturition.
2) Suckling: surge (sharp rise) with each lactation.
- surges gradually decline after 3 months of lactation
- N.B.: In non-pregnant: massage of nipple causes a mild rise in PRL.
3) Sleep: it rises at its onset & then persists at a plateau.
4) Stress: physical or mental (crying baby) increases secretion.

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➢ Disturbance of PRL Secretion:
Hypoprolactinemia Hyperprolactinemia
cause pituitary damage mostly adenoma (tumor)
In females inability to lactate1) amenorrhea (absent menstruation):
antagonize gonadotrophic hormones
2) galactorrhea (milk production) in
non-lactation period.
In males hypogonadism & sterility: antagonizes
gonadotrophic hormones
both sexes decreased libido (sexual desire)
Treatment Dopamine blockers Dopamine agonists (bromocriptine):
(chlorpromazine) decrease PRL

Panhypopituitarism
• Simmond's disease or Sheehan's syndrome (after post partum hemorrhage).
• atrophy of adenohypophysis → ↓ all pituitary hormones (gonadotropines,
thyrotropine, corticotropine, somatotropine & prolactin).
➢ Manifestations:
A. General = progeria: premature Secondary: generalized endocrine
& rapidly progressing senility hypofunction of
- General emaciation (decrease of - thyroid: decreased (BEE) &
body weight). anemia.
- Premature graying of scalp hairs - suprarenal cortex: hypoglycemia,
with loss of body hairs. hypotension & weakness
- Dry & wrinkled skin. - gonadotrophic hormones:
- Shrunken hands & feet. o amenorrhea (female)
o impotence with sterility (male)

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 Posterior pituitary gland = Neurohypophysis
1. Vasopressin= anti diuretic hormone = ADH = pressophysin:
arginine-vasopressin (in some species it is lysine-vasopressin or a mixture).
2. Pitocin= Oxytocin= oxyphysin: (Nonapeptide)

• Synthesis: in hypothalamic magnocellular neurons (supra-optic &

paraventricular nuclei)
• packaged in granules as pre-pro-pressophysin & pre-pro-oxyphysin.
• migrate in neural axons to posterior pituitary → cleavage into:
1. Pressophysin & neurophysin II (from pro-pressophysin).
2. Oxyphysin & neurophysin I (from pro-oxyphysin).

• Function of neurophysins: carrying & storing proteins.

❖ Release: neurons action potentials: Ca2+ - dependent exocytosis.

Vasopressin= anti diuretic hormone= ADH

• nonapeptide (9 AA). secreted from:
A- Supraoptic nucleus: mainly, released into systemic circulation
B- Paraventricular nuclei : less degree ; released into :
- brain third ventricle (function unknown).
- median eminence (with CRH): to corticotropes by adenohypophyseal vessels.

➢ Types of ADH receptors (all G coupled protein coupled):

2nd messenger
V1 (V1A) ionsitol phosphate increase in intracellular Ca2+
V2 ↑ cAMP
V3 (V1B) on phospholipase produce prostaglandin

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➢ Functions:
I – Renal:
A- In tubular system:
1- ↑ water reabsorbtion (V2 receptors: 2nd messenger: cAMP):
- On late DCT (principal cells), cortical & medullary duct.
- ↑ water channels (aquaporin 2) from endosomes to membrane:
passage of water from tubule lumen → inside cell → interstitium according to
osmotic gradient producing decreased urine volume (antidiuresis).
2- ↑ K secretion:
- In cortical collecting tubule: H2O reabsorption under ADH effect →
↑ urinary K concentration → antagonize K secretion.
- ADH stimulates K secretion to balance this effect.
3- increases urea reabsorbtion:
- In medullary collecting tubule
- insertion of urea transporters (UT1): ↑ flow of urea into interstitium:
↑ solutes in renal interstitium → more water reabsorption.

B- In renal vascular system (V3 receptors):

- in glomeruli: ↑ production of a dilator (PGE2).
- -ve feed back: antagonizes VC → maintains renal perfusion.

II – Extrarenal:
1. In vascular system (V1 receptors):
- ↑ intracellular Ca2+ → VC → ↑ dropped ABP in hemorrhage (vasopressor).
- minor effect: RAS & sympathetic are the primary regulators of arterial BP.
2. In cases of stress (as pain & trauma) (V3 receptors):
- ADH & CRH are co-secreted from paraventricular nuclei.
- stimulated corticotropes → ACTH → cortisol secretion.

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➢ Control of ADH Secretion: supraoptic nuclei are affected by:

↑ ↓
1. ↑ plasma osmolarity (hyper-osmolarity: 1%): 1. hypo-
• retain water through kidneys → readjust osmolarity. osmolarity
• Mechanism:
- Hyperosmolarity → outflow of water from
osmoreceptors → shrunken cells activate stretch-
inactivated cation channels → depolarization → ADH
secretion & synthesis
2. Hypovolemia (10% ↓ blood volume → affects ABP): 2. Hypervolemia
- carotid baroreceptors ↑ ADH from paraventricular n.
- low pressure receptors in atria & big veins through Vagi
↑ ADH secretion (weak in humans).
3. Stress: CRH-ADH. (for days After surgery) 3. α- agonists
4. Drugs: morphine, nicotine, some tranquilizers & 4. Ethyl alcohol
anesthetics

➢ Disturbance of ADH Secretion= Diabetes insipidus:

• ↑ water loss in urine
• Urine (diabetes) large in volume & solutes very dilute (tasteless: insipidus)
• Manifestations: polyurea, polydepsia and dehydration
• Types:
1. Central: lesion in supraoptic nucleus.
- lesion below (in posterior pituitary): no D. insipidus (ADH reach circulation)
2. Nephrogenic: congenital defects of renal V2 receptors.
1) X-linked mutation of V2 recceptors: ↓ production of cAMP.
2) autosomal mutation → loss of function of aquaporins.

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 Oxytocin
➢ secretion: neurohormonal reflex:

Stimulus Functions
1) Genital stimulation: of • Afferents: spinal cord to 1. During sexual intercourse: orgasm:
male & female. hypothalamic nuclei. a- In males: contraction of smooth muscle in vas
• Efferent: hypothalamic nuclei deferens → ejaculate semen.
release oxytocin from posterior b- In females: contraction of myometrium
pituitary followed by relaxation → ↓ intra uterine pressure
→ semen into the uterus after intercourse.
• Mechanism: receptors coupled
2) Dilatation of cervix: during to a G protein→ ↑ Ca2+ → ↑ 2. During labor: strong contractions of uterus
labor by head of fetus. muscles contraction expel baby & placenta.

3) Massage of nipple: by 3. During suckling: squeezing of milk from

suckling or sexual playing. breast alveoli into ducts then nipple.

➢ N.B.: lactation reflex is termed “milk letting” = “milk ejection reflex”, may be:
a. Unconditioned: receptor stimulation.
b. Conditioned: no receptor stimulation: higher center stimulation e.g. seeing, hearing cry, or Thinking about baby

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 Thyroid gland
➢ Hormones of thyroid gland
1. Thyroid hormones: thyroxin T4 & tri-iodothyronine T3 by thyroid follicle
2. Thyrocalcitonin: from parafollicular cells (lie in between follicles).
➢ Iodine requirements: 500 µg /day: absorbed & carried in blood as iodide (I-).
o four fifth rapidly excreted by kidney.
o one fifth trapped by thyroid for T3 and T4 synthesis.
- after metabolisation, Iodine of thyroid is excreted in urine and stools.
- Iodide intake & supply to gland is variable from day to day.
- thyroid cell contains small amount of reserve sufficient for minutes or hours

➢ Formation of thyroid hormones.

1- Thyroglobulin synthesis = colloid formation:
- glycoprotein rich in tyrosine (molecule contains 123 tyrosine residues).
- secreted together with peroxidase enzyme into cavity of follicle.
2- Iodide trapping (pump): cells negative relative to interstitium & colloid
a. Na/K pump creates a low Na+ inside
b. co-transporter (secondary active transport) carries Na+ & I- inside cells.
N,B.: I- (iodide): carried against concentration & electric gradients
N.B.: also occurs in: mammary & salivary glands, gastric mucosa, placenta.

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3- Oxidation & Iodination: peroxidase enzyme:
1) oxidizes (I-) into iodine (I).
2) binds iodine (I) to tyrosine in 3 & 5 positions: mono & di-iodo tyrosine (MIT
& DIT).
4- Coupling: binding of tyrosine molecules.
- Two DIT → tetra - iodothyronine : T4 (2DIT → T4)
- One DIT & one MIT → tri–iodothyronine : T3 (DIT + MIT →T3)
- One MIT & one DIT → reverse tri – iodothyronine: rT3 (MIT + DIT → rT3)
- T4 : T3 : rT3 is 40: 2: 1.
5- Release:
o microvilli ingest portions of colloid into pinocytic vesicles
o vesicles traverse cells merge with lysosomes where:
- Proteinase enzyme liberates T4, T3, and DIT & MIT from thyroglobulin.
- T4 & T3 diffuse to nearby capillaries.
- de-iodinase enzyme removes (I) from DIT and MIT: recycled again.
6- Storage: extra amounts in follicle bound to thyroglobulin (2 – 3 m).

➢ Level of thyroid hormones in blood:

T4 T3
Total 8-12 g/dl 0.15 g/dl
Bound 99.98 % 99.8 %

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➢ Transport:
• More than 99% Bound to plasma proteins: albumin, thyroxine binding
prealbumin (TBPA), thyroxine binding globulin (TBG).
- N.B.: Affinity of globulins is higher: carry 2/3 of T4 and ½ of T3.
➢ Mechanism of action:
• hormones diffuse inside cells to bind receptors: 4 types: 1, 2, 1 and 2
- T3 binds:  1,  1 and  2.
- T4 binds: all:  1,  2,  1 and  2.
• T3 is more active than T4 because it is:
1. More free (less bound to plasma proteins).
2. More affine to thyroid receptors (10-15 fold).
N.B.: rT3 is non active because it does not bind to the thyroid receptors.
• Types of receptors:
1. Extranuclear receptors "non genomic ": at plasma membrane,
cytoskeleton and mitochondria. e.g. sugar transport, pyruvate kinase, …..
2. Nuclear receptors: close or bound to DNA.

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➢ Actions of thyroid hormones:
I- on metabolism:
1. Basal metabolic rate (BMR= BEE: basal energy expenditure):
a. normal BEE of 40Calories / hr / m2
b. normal weight, appetite, food intake & energy balance
2. Cell metabolic activity: calorigenesis & increase O2consumption by:
a. mitochondria:
- ↑ size & number (in most cells) → ↑ ATP formation.
- ↑ uncoupling of oxidative phosphorylation: small increase ATP & a greater
loss of heat
b. ↑ ions transport: as Na/K pump of all cells → ↑ energy consumption
3. Carbohydrate metabolism: ↑ all aspects: insulin secretion, glucose
absorption, glucose uptake by cell, glycolysis & gluconeogenesis
4. Protein metabolism: anabolic: ↑ protein synthesis all over body.
5. Fat metabolism: ↑ all aspects: mobilization of lipid from fatty tissues
(lipolysis), free fatty acid oxidation → depletion of fat stores
- N.B.: on plasma lipids: ↓ plasma cholesterol due to:
1) ↑ secretion of cholesterol in bile and stools
2) ↑ number of LDL receptors on liver cells: rapid removal.
3) ↑ oxidation of cholesterol.
6. vitamins: ↑ in enzymes activity → ↑ needs for vitamins: coenzymes.

II- Effects on growth:

a – Mental (Brain):
- important during fetal & first few years for normal mental development.
- induces neuronal, axonal & nerves ending formation.
b - Physical: Bones affected more than soft tissues.
c – Sexual: (with sex hormones) responsible for sexual growth.

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III- Effects on body systems:
a- Primary effect: majority of systems stimulated directly.
b- Secondary effect: some systems by increased metabolism: calorigenic action.

❖ O2 consumption:
increased most tissues e.g. CVS , respiratory , GIT , muscular , endocrine
not increased adult brain, lymph nodes, spleen, testes & uterus
decreased anterior pituitary

N.B.: thyroid hormones are essential for:

• Normal development: physical, mental & sexual in young.
• Normal functions: physical, mental and sexual in adults.

➢ Regulation:
1. Thyrotopin Releasing Hormone "TRH" by hypothalamus:
- carried by blood to anterior pituitary: thyrotropes.
- binds to receptors: membrane bound G proteins → activate phospholipase →
↑ Ca2+ & diacyl glycerol → TSH release

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2. Thyroid stimulating hormone "TSH" = thyrotropin:
- binds to receptors on membrane of thyroid gland cells → activation of membrane
bound G proteins → ↑ cAMP → activates protein kinase
- effects:
A - Within 30 min: ↑ proteolysis of thyroglobulin, increasing T3 &T4
B - within hours, days, and weeks:
1) ↑ iodide pump → intracellular to extracellular iodide 8: 1.
2) ↑ iodination of tyrosine → ↑ formation of thyroid hormones.
3) ↑ size, secretory activity and number of thyroid cells.
3. Feedback effect of thyroid hormones:
1) direct on pituitary → ↓ TSH (T4 is converted to T3).
2) Secondary weak effect on hypothalamus: → ↓ TRH.
➢ Disturbances:
• Primary: thyroid in origin.
• Secondary: pituitary in origin.
• Tertiary: hypothalamic in origin.

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 Hypothyroidism Hyperthyroidism: thyrotoxicosis
↓ secretion or effects of thyroid hormones ↑ secretion of thyroid hormones
Causes 1. Thyroidal: 1. Thyroid overactivity:
1) Congenital: absence of thyroid or defects in synthesis 1) Acute thyroiditis.
2) Maternally transmitted: mothers taking antithyroid or 2) Tumor or nodules
excessive iodides → depress thyroid gland of fetus. 3) Grave's disease: auto antibodies against TSH
3) Chronic iodine deficiency: rare (due to supplementation receptors: TSH-R [stim] Ab: not controlled by TRH.
of table salt with iodides.) 2. Suprathyroid overactivity:
4) Iatrogenic: excessive antithyroid drugs, surgically, or 1) pituitary tumor.
over destroy by radioactive iodine. 2) Resistance of receptors in pituitary (gene
5) Chronic thyroiditis: viruses or antibodies (autoimmune). mutation): TSH unopposed by negative feed back
2. Suprathyroidal : 3. Extrathyroidal activity:
- Pituitary - Hypothalamic 1) Ectopic tissue, produce extra amounts of T3 & T4.
2) Excessive administration of thyroid hormones
Symptoms 1. General:
and effects 1) ↓ BEE: ↓ calorigenesis, body temperature → cold 1) ↑ BEE (+ 60% to + 100%): ↑ calorigenesis, body
intolerence. temperature → hot weather intolerence
2) Skin: coarse & dry. 2) skin: warm, flushed and sweaty
3) ↑ body weight (non-pitting edema: accumulation of 3) ↓ body weight: hyperphagia
subcutaneous mucoproteins).
4) General decrease in activity of all systems: 4) General increase in activity of all systems:
o cardiovascular (↓ HR & C.O.) A. nervous system:
o CNS: sleepiness, delayed reactions irritable, nervousness & fine tremors of extended and
o respiratory (bradypnea) abducted fingers, due to sensitivity of reticular
o gastrointestinal (decreased motility & constipation) activating system (RAS) to catecholamines.

A.F. 2025 27
 2. Specific (age dependent): B. C.V.S.:
A. Cretinism: since birth or during early childhood a. ↑ Heart rate and CO. due to:
▪ Cretin= hypothyroid child: delayed growth: 1. Direct stimulation of SAN.
a. mentally (Idiot): difficult learning (IQ is very low), 2. sensitizes SAN to catecholamines.
inability to sit, stand, walk, speak, control his urine & 3. increased metabolism leads to increased venous
stools. return and reflex tachycardia (Bainbridge
b. physically (Dwarf): late fontanel’s close & teeth erupt reflex).
1- facial: wide nasal bridge, enlarged lips & protruded b. ABP:
tongue 1) ↑ systolic: ↑ stroke volume & CO.
2- body: abdominal bulging with umbilical hernia & a 2) ↓ diastolic: due to peripheral vasodilatation.
supraclavicular pad of fat 3) ↑ pulse pressure
c. sexually (infantile: impotent & sterile)

B. Myxodema: adult: - N.B.: Exophthalmos: protrusion of eyeballs

▪ Mental functions depressed: apathetic & drowsy with a - present in some patients.
prolonged reaction time. - autoantibodies attack and cause hypertrophy of
▪ husky voice & absent outer 1/3 of eye brows. extraocular muscles and retro-orbital connective
▪ Sexual functions depressed due to atrophy of gonads tissues.
- In late conditions: press on optic nerve → optic
atrophy and blindness

Laboratory o Low T3 & T4 with high TSH (thyroid origin). a. High T3 & T4 with low TSH: Thyroidal or
o Low T3 & T4 with low TSH (Suprathyroidal). extrathyroidal
o Increased cholesterol in plasma b. High T3 & T4 with high TSH: Suprathyroidal

A.F. 2025 28
A.F. 2025 29
 Ca homeostasis
❖ Functions of calcium:-
I – Role of Ca2+ (ions): "non bony functions":
1. Blood clotting: activation of clotting factors.
2. Second messenger: for some hormones.
3. Membrane excitability: of neurons & muscles.
4. Muscle contraction: induces excitation contraction coupling of all muscles.
5. Cardiac function: maintains contractility & rhythmicity.
6. Exocrine, endocrine & neurosecretion: release of chemicals from vesicles.

II – Role of calcium salts:

1. Constitution of tissues: hard tissues as bone & teeth and fluid tissue as: milk.
2. Storage.

❖ Calcium distribution (1000 – 1100 gm):

1. Bony skeleton: (more than 99%):

▪ bones of a 70 kg adult person contains about 1100 gm of calcium
▪ two pools:
a. Small pool: labile pool (readily exchangeable) (less than 1%):
- calcium phosphate present in equilibrium with plasma.
- N.B.: liver & intestine can also exchange Ca rapidly.
b. Large calcium pool: stable pool (not readily exchangeable) (more than 99%):
- calcium hydroxyapatite in mature bone.

2. Plasma: Ca conc. is 10 mg/dl, in three forms:

a. diffusible (53%): can pass into & outside intravascular space
1) Ionized: free calcium: Ca2+: 47 %.
2) Complexed: with phosphate, HCO3, & citrate: 6 %
b. non diffusible: Bound to plasma proteins (primarily albumin):47%

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❖ Absorption of calcium in GIT:
• 30-80% by upper small intestine, by passive diffusion & active transport
• affected by Local GIT factors: (affect solubility: Salts in solution absorbed, in
precipitate do not):
1) Acidity: of upper GIT secretions dissolve calcium salts.
2) Protein meals: make soluble complexes with calcium.
3) Acidic food: lactic acid from lactose or yogurt, or citrates facilitate solubility.
4) Active vit. D3: ↑ absorption.
5) Ingested phosphates & oxalates: form insoluble calcium salts.

❖ Phosphorous: 500 - 800gm: (plasma conc. 12 mg/dl)

- 85 to 90% in skeleton.
- In Many compounds as ATP, cAMP 2,3DPG and many proteins.

❖ Physico-chemical characters of Ca2+ & PO4--

• In solution of an ionizable salt, contains cations & anions in conc.: solubility
product = [C+] X [A-].
• rise of conc. raise value above solubility product → precipitation of salt.
• Ca2+ and PO4-- exist in ECF in conc. above solubility product
• "pyrophosphate" = inhibitor of precipitation → so solution of calcium phosphate
is supersaturated, but without precipitation.

• Precipitation occurs:
a. Physiologically: a cell (osteoblast) secretes an inhibitor to pyrophosphate.
b. Pathologically: subendothelial (atherosclerosis) or degenerated cells (metastasis)

A.F. 2025 31
❖ Bone Physiology
• functions: protection of organs, support of body against gravity, movement & storage of calcium.
• structure: -
1. Matrix: type I collagen protein 2. Crystals: hydroxyapatite: Ca phosphate & Ca hydroxide.
3. Cells:
Osteoblasts Osteoclastes Osteocyts
Function (bone building): (bone eating): exchange Ca with
1. secrete collagen and other bone proteins. 1) secrete H+ by "H+ ATPase" to ECF through
2. secrete alkaline phosphatase enzyme which hydrolyzes dissolve hydroxyapatite osteocytic
plasma phosphate esters for calcium phosphate formation. 2) secrete acid protease: dissolves membrane system
3. precipitation of calcium by pyrophosphate inhibitor. collagen.
N.B.: Bone remodeling:
- at a rate of 4% for compact and 20% for trabecular bone per year.
- remodeling unit: group of osteoclasts absorb bone and a group of osteoblasts lay new bone (2 millions in human skeleton)

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 Calcium Homeostasis = Control of plasma Calcium
• total amount of ECF calcium is 1g.
• liable to a rapid decrease in diarrhea or to a rapid increase in excessive calcium absorption with overdose of vitamin D.
• Plasma Ca must be maintained constant 9.4-10 mg/dL.
I- First line of defense:
1) exchangeable calcium phosphate (small Ca pool) rapidly shifts from bone fluid to plasma or the reverse.
2) Ca2+ rapidly flows from and to mitochondria of liver & intestinal cells.

A.F. 2025 33
II- Second line of defense: Hormonal control: on a prolonged course
Parathormone (PTH) = Parathrin Thyrocalcitonin Active vit.D3:
source parathyroid gland (4 in poles of thyroid gland) parafollicular cells of thyroid
nature polypeptide (84 aa) polypeptide (32 aa) steroid
actions
A –On ↑ Mobilization of Ca2+ , two phases: ↓ Ca2+mobilization: depend on Ca2+ & PO4—conc.:
bone 1. Rapid = Osteolysis: ( minutes to hours) • stimulates osteoblasts: ↓ • high Ca2+ & PO4 : stimulates
• activation of receptors in osteocytes which form Ca2+, PO4-- release. osteoblastic activity.
osteocytic membrane: ↑ permeability to Ca . 2+
• ↓ Ca pump of
2+
• low Ca2+ & PO4: PTH
• intracellular Ca2+ is pumped by calcium pumps into osteocytic membrane. stimulates:
extracellular fluid under effect of 1,25 DHCC. • ↓ number & activity of 1) osteolysis by osteocytic
2. Slow phase (days or weeks): osteoclasts → ↓ bone membrane.
• stimulates osteoblasts to produce IL-6 & RANKL: resorption. 2) osteoclastic activity indirectly
stimulates osteoclasts (osteoclasts have no receptors for PTH) through osteoblasts.
• osteoclasts resorb bone matrix, releasing into ECF: Ca ,
2+

PO4-- , hydroxyproline
B –On 1) PTH & decreased phosphate activate 1  hydroxlase to • ↓ 1α hydroxylase activity • ↑ Ca2+ absorption in DCT
Kidneys produce: 1, 25 (OH)2 D3. (in PCT) of PCT. (by calbindin D)
2+
2) PTH & 1, 25 (OH) 2 D3: reabsorb Ca in DCT • ↑ excretion of both Ca 2+ • ↑ phosphates reabsorption
3) ↓ reabsorption of phosphate from: ↑ phosphate & PO 4— by proximal tubule (in PCT)
excretion: phosphaturic action. (in PCT)
4) increase Mg2++ & H+ reabsorption.
C –On PTH & 1,25 (OH)2 D3: ↑ calcium & phosphate absorption. • transports Ca2+ from brush to
intestine basolateral border to ISF (by
calbindin D)
• stimulates Ca2+ ATPase &
ALP

A.F. 2025 34
Mechanism ❖ Types of PTH receptors: • After binding to cytoplasmic
of action 1- PTH/PTHrP receptors: in osteoblasts, osteocytes receptor, hormone-receptor
• parathyroid hormone-related protein "PTHrP": complex exposes DNA →
- Functions: PTH action, growth factor in skin, hair transcription of mRNA →
follicles, breasts & chondrocytes. formation of: Calbindin D
2- PTH2- R: in placenta, brain & pancreas. • receptors in:
3- CPTH-R: C terminal of PTH molecule binds to it. - intestine, kidney & bone
❖ G protein linked receptors, either: - anterior pituitary, skin, breast,
• Gs : activates adenyl cyclase and increases cAMP skeletal & cardiac muscles,
• Gq  activates PLC: ↑ Ca2+ & DAG which activates lymphocytes, (functions not
protein kinase C definite).
Regulation mainly feedback mechanisms (not under pituitary control)
2+
1. plasma Ca conc.: 1. plasma Ca2+ conc. 1. plasma Ca2+ conc:
a. ↓ plasma Ca → ↑ PTH
2+
• ↑ plasma Ca → ↑
2+ a. ↓ plasma Ca2+ → ↑
b. ↑ plasma Ca → ↓ PTH.
2+
• ↓ plasma Ca2+ → ↓ b. ↑ plasma Ca2+ → ↓
N.B.: Ca-sensing receptor (Ca SR) = ‘calciostat’:
G protein-coupled receptor in parathyroid, 2. Beta adrenergic 2. 1, 25 -DHCC feeds back:
calcitonin-secreting cells, kidneys: Activated by ↑ Ca2
agonists, estrogen, a) negatively on 1
prolactin & dopamine: hydroxylase: ↓ 1, 25 -DHCC.
2. ↑ PO4-- → ↓ Ca : ↑ PTH.
2+
↑ b) positively on convertase:
N.B.: rise in PO4- increases fibroblast growth factor-23 3. GIT hormones: gastrin, inactivation of 1, 25 -DHCC
(FGF23) in plasma binds to receptor (FGFR): CCK: ↑ (to prevent post- by its transformation into 24,
1)in renal PCT: ↓ PO4- reabsorption and activation of pradndial 25 –DHCC.
25-HCC into 1-25 DHCC. hyperecalcemia).
2)in parathyroid: ↑ PTH.
3. 1,25 (OH)2 D3 inhibits formation of PTH
4. increase cAMP as - agonists increase PTH.

A.F. 2025 35
❖ N.B.:
• Final results of parathormone: (Hypercalcemia , hypercalciuria) & (hypophosphatemia, hyperphosphaturia)
• chronic excessive PTH: hypercalciuria
• calcitonin is antagonistic to PTH as regards Ca (hypocalcemic) but similar on PO4-
❖ Synthesis of active vit D [1, 25(OH)2 cholecalciforal: 1,25 (OH)2 D3]:
1) In skin keratinocytes 7-dehydrocholesterol by action of ultraviolet rays of sunlight, is converted to a provitamin,
spontaneously converted within three days to vitamin D3 (cholecalciferol), under effect of sunshine thermal energy.
2) Cholecalciferol converted in liver to 25 hydroxy cholecalciferol "25 HCC": stored.
3) 25 HCC converted in PCT of kidney to 1,25 dihydroxy cholecalciferol = 1,25 -DHCC := 1,25 (OH)2 D3 , by 1 α
hydroxylase enzyme .
❖ transport of active vit D: on a plasma globulin : vitamin D binding protein : DBP
➢ Hyperparathyroidism:
Primary Secondary Tertiary
Cause tumor of parathyroid hyperplasia of parathyroid in response to ↓ calcium: independent nodule
a. Decreased intestinal calcium absorption: secreting excessive
- Vitamin D deficiency: <20 ng/ml - ↓ calcium intake parathyroid after a
- Bariatric surgery - Malabsorption long period of
b. Renal insufficiency (Renal osteodystrophy) secondary
Phosphate retention in chronic renal diseases  secondary hyperparathyroidism
decrease in plasma Ca2+
Characters Hypercalcemia → ↓ ↑ PTH with normal or low levels of serum calcium
neuromuscular excitability

A.F. 2025 36
➢ Tetany: ↑ neuro-muscular excitability caused by ↓ plasma ionized Ca.
❖ Mechanism:
- ↓ plasma Ca2+ → activate voltage gated sodium channels.
- slight stimuli or spontaneously → nerve impulses: spasmodic contraction.
❖ Causes:
1. Hypoparathyroidism:
a. Most: accidental removal of parathyroid during thyroidectomy
b. Less: autoimmune destruction of parathyroid.
2. imbalance of calcium intake to body needs: infants and pregnants.
3. ↓ intestinal absorption of calcium: vitamin D deficiency, or increased alkalinity
of intestinal contents or oxalates.
4. Alkalosis: ↓ solubility product of Ca2+ and PO4--. (total plasma calcium may be
normal but ionized calcium is reduced e.g. hyperventilation and vomiting).
5. Phosphate retention: in advanced renal disease. secondary drop of Ca2+.
❖ Types:
A - Latent (hidden) tetany { plasma calcium is (9.4 - 7mg/dL)}:
• manifestations appear during exercise, stress or ischemia. or by tests:
Chovestek sign Trousseau sign Erb sign
stimulus Tapping face Ischemia of muscles of upper Galvanic stimulation
over facial limb: occluding circulation for of upper limb
nerve in front few minutes with a blood nerves: over medial
of ear pressure cuff above systolic BP side of forearm
Normal feeling of a tap feeling of ischemia pain • contraction at
make & break
• muscles relaxed
during current
Latent Hyperexcitable Hyperexcitable upper limb Hyperexcitable
tetany facial nerve: nerves: pain, with involuntary upper limb nerves:
feeling tap with spasm (flexion of wrist and involuntary carpal
involuntary metacarpophalingeal joints, with spasm during whole
twitching of extension of all interphalingeal period of current
facial muscles joints and adduction of thumb) flow
"carpal spasm or accoucheur
hand "

A.F. 2025 37
B - Manifest tetany {plasma Ca2+ drops below 7 mg/dL}:
• occurs during rest
• patient presented with carpopedal spasm → spasm of laryngeal (laryngeal
strider) → spasm of respiratory muscles (cyanosis or asphyxia then death).
❖ Treatment:
1. Immediately: calcium gluconate I.V. slowly. "Run to bring, but sit to inject".
2. diet rich in calcium and vitamin D.
3. vitamin D injections.
4. Treatment of cause, e.g. renal failure, alkalosis, etc... .

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 Adrenal Glands
• essential for life: death follows complete removal
• Each gland consists of two endocrine organs:
1- Adrenal Medulla (not essential for life): (central 20%):
- secretes catecholamines (epinephrine, norepinephrine, and dopamine).

2- Adrenal Cortex: (outer 80%): three zones:

Zona Glomerulosa Fasciculata Reticularis
outermost very thin middle widest innermost
secretes mineralocorticoids glucocorticoids mainly sex hormones
N.B.: Mineralocorticocoids and glucocorticoids are necessary for survival.

❖ Synthesis of Adrenocortical hormones:

- steroids formed mainly from cholesterol.
- Cell membrane has receptors for LDL (high concentrations of cholesterol).
- Attachment of LDL to membrane: transfer of cholesterol by endocytosis → moved
to cytoplasmic vacuoles → esterified and stored.
- Small amounts of cholesterol formed within cells from acetyl coenzyme A.

- Under basal conditions: free cholesterol from plasma is the major source.
- under ACTH stimulation: stored esterified cholesterol becomes most important.

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 Glucocorticoids
• formed in zona fasciculata with a small contribution from zona reticularis:
- Cortisol: (hydrocortisone): 95%.
- Corticosterone: less potent (4% of total glucocorticoid activity)

➢ Synthesis:
• Cholesterol ester is hydrolyzed → free cholesterol is transported across outer
mitochondrial membrane → inner mitochondrial membrane→ converted to
pregnenolone → endoplasmic reticulum → converted to 11-deoxycortisol →
back to mitochondria: hydroxylated in 11 position: cortisol.
• Cortisol is not stored: need for increased amounts requires rapid activation of
entire synthetic pathway.

➢ Transport:
1- 75%: bound to corticosteroid binding globulin (CBG) “transcortin”:
- synthesized in liver (decreased in hepatic cirrhosis and nephrosis)
- estrogen stimulates its production (elevated during pregnancy).
2- 15% bound to albumin.
3- Only 10% is unbound (free): active.
N.B.: Because of protein binding: little free cortisol in urine.

➢ Metabolism and excretion:

- in liver: Most reduced and conjugated to glucuronic acid and excreted in urine.
- depressed in liver disease, during surgery and stresses (free cortisol rises).

➢ Actions: Cortisol is essential for life:

A. Permissive Actions: (small amounts) allows certain processes to occur:
(glucocorticoids do not initiate action):
1. glycogenolysis produced by glucagon.
2. lipolytic effect of catecholamines and growth hormone
3. vasoconstrictor response to catecholamines and angiotensin II.

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B. Physiological Actions: (normal amounts)
I- Effect on Metabolism: catabolic → mobilization of fuels.
a) Carbohydrate (Hyperglycemic &Diabetogenic):
1. ↓ utilization of glucose by muscle and adipose tissue: Anti-insulin action.
i. ↓ affinity of insulin receptors to insulin.
ii. ↓ glucose uptake: reducing mobility of glucose transporters.
N.B.: brain and heart spared anti-insulin action = extra glucose to these vital organs.
2. Stimulation of gluconeogenesis by liver:
i. protein catabolism extrahepatic → amino acids
ii. Stimulates hepatic uptake of amino acids and conversion into glucose:
- ↑ intrahepatic glycogen storage (glycogenesis).
- ↑ hepatic release of glucose in blood.
b) protein metabolism (Catabolic):
1- ↓ proteins in cells except liver:
- Increased catabolism of proteins. - Decreased protein synthesis.
2- ↓ amino acid transport into extrahepatic cells: ↑ plasma level.
3- ↑ amino acid transport into liver cells
c) Fat Metabolism (lipolytic & Ketogenic):
1- Lipolytic: stimulates hormone – sensitive lipase that breaks down stored
triglycerides into glycerol and fatty acids: source of energy.
2- Ketogenic: increases ketone body formation

II- CNS:
1- modulates excitability, behavior and mood.
2- ↓ sleep time & REM sleep, but ↑ slow-wave sleep.

III- C.V.S.: maintenance of ABP:

1- inotropic action on heart
2- ↑ Na+- K+ ATPase, and B-adrenergic receptors.
3- ↓ vasodilator prostaglandins.
4- maintain blood volume by ↓ permeability of vascular endothelium.

A.F. 2025 41
IV- kidney:
1- ↑ glomerular plasma flow and GFR.
2- rapid excretion of free water
3- ↑ ammonium from glutamate in response to acids.
4- ↓ PO4 absorption in PCT = ↑ urinary PO4 excretion.
V- Skeletal Muscle: ↑ acetylcholine → neuromuscular transmission and contractility

VI- blood cells:

1. ↑ neutrophils, platelets and red blood cells.
N.B.: depress function of neutrophils.
2. ↓ number of:
a. eosinophils: apoptosis and sequestration in spleen and lungs.
b. T lymphocytes by inhibiting lymphocyte mitosis.

VII- Stress:
• stresses: trauma, pain, infection, surgery, anxiety, shock, etc.
• effect: ↑ ACTH → ↑ cortisol & activate sympathetic:
1) ↑ FFAs as an energy source
2) ↑ glucose to ensure glucose to vital organs.
3) ↑ amino acids for gluconeogenesis and proteins formation by damaged tissues
• N.B.: Permissive action for catecholamines to exert pressor and lipolytic actions

VIII- Appetite: normal effect is equivocal

1- ↑ appetite by:
- ↑ neuropeptide Y (orexiogenic) in hypothalamus
- ↓ CRH (anorexigenic).
2- ↓ appetite by: ↑ leptin in adipocytes: negative feedback effect on appetite center.

IX- Others:
1 - very slight mineralocorticoid activity.
2- During fetal life: maturation of surfactant in lungs.

A.F. 2025 42
C. Pharmacological Actions: (large amounts): high doses or in hypersecretion:
I- Connective tissue:
1- ↓ collagen synthesis: - thinning of skin and hairs
- - fragility of capillaries: easy rupture and hemorrhage.
1- ↓ fibroblasts proliferation and function.
N.B.: effect antagonizes growth: problem for pediatricians.
II- bone: osteoporosis (↓ bone mass)
a. ↓ bone formation by:
1- ↓ type I collagen (main component of bone matrix).
2- ↓ formation of osteoblasts.
3- ↓ absorption of Ca++ and PO4--- from intestine by anti-vitamin D action & ↑
renal excretion → ↓ calcium.
b. ↑ bone resorption.
III. Anti-Inflammatory Effects:
• Inflammation: tissue responses to injury (redness, heat, swelling, pain).
• large amounts of cortisol decreases synthesis, secretion and actions of IL-1:
a- Blocks early stages of inflammation.
b- promotes rapid resolution.
IV. Anti Allergy:
• Certain antibodies + antigens → histamine and leukotrienes from mast cells.
• prevent histamine release and formation of leuko-trienes: relieves asthma.
• N.B.: do not affect combination of antigen with antibody
V. Anti Immunity and lymphoid tissue:
1- ↓ humoral immunity (B-lymphocytes): ↓ antibody production.
2- ↓ cellular immunity (T-lymphocytes): ↓ IL-2, proliferation & production of
interferon: ↓ destruction of virus infected cells and tumor cells.
• N.B.: large doses of glucocorticoids causes significant atrophy of all lymphoid
tissue, double edged weapon:
1. prevention of immunological rejection of transplanted organs.
2. fulminating infection and death from diseases e.g. tuberculosis..

A.F. 2025 43
 ➢ Control of Glucocorticoid secretion:
I. CRH from hypothalamus

II. ACTH:
• maintains normal secretory activity of zona fasiculata and reticularis: ↑ size &
number of cells
• binds to its receptor on membrane of cortisol secreting cells:
- Gs protein → formation of cAMP: activates protein kinase A:
phosphorylates cholesteryl ester hydrolase enzyme increasing its activity:
cholesterol esters → free cholesterol.

• N.B.:
- not important regulator of aldosterone (required for optimal secretion).
- Melanocyte Stimulating Hormone (MSH) activity: similar amino acids

A.F. 2025 44
III. Free Cortisol negative feedback to:
1- Hypothalamus → ↓ CRH secretion.
2- Corticotropes in anterior pituitary → ↓ ACTH secretion.
• degree of ACTH inhibition is proportionate to cortisol level in blood.
• In adrenal insufficiency → ↑ ACTH secretion.

IV. Circadian (diurnal) Rhythm: CRH, ACTH and cortisol in plasma are not
constant:
- high rate of secretion in early morning and is lowest in evening.
- effect results from a 24-hour cyclic alteration in signals from hypothalamus.

V. Stress: act on hypothalamus → ↑ CRH

VI. vasopressin, serotonin and VIP (Large doses): directly stimulate adrenal cortex.

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 MINERALOCORTICOIDS
❖ Types:
o Aldosterone: Very potent: 90% of activity.
o Desoxycorticosterone: 1/50 potency of aldosterone.
o Corticosterone: slight activity.
o Cortisol: Very slight.
❖ Transport:
- 60% bound to aldosterone binding globulin, transcortin, and albumin.
- Binding is weaker than cortisol: half-life in plasma is 20 – 3 0 minutes.
❖ Metabolism: 90% cleared by liver in a single passage: reduced and conjugated
with glucuronic acid that is excreted in urine.
❖ Actions: maintains ECF volume by conserving body sodium:
A. reabsorption of Na+ and secretion of K+ in: sweat, saliva, stomach and colon.
B. In kidney:
1- reabsorption of Na+ and secretion of K+ (P cells) of DCT and collecting duct.
- H2O is passively reabsorbed with Na+: little increase in plasma Na+ conc.
- ECF expands in an isotonic manner.
2- secretion of H+ (mild alkalosis and ↑ in urine acidity) by:
a. exchange with Na+
b. ↑ H+-ATPase proton pump in luminal membrane of (I cells) of collecting duct
N.B.: Cellular Mechanism of Aldosterone Action:
• Aldosterone diffuses inside membranes → combines with cytoplasmic receptor
forming aldosterone-receptor (A – R) complex: diffuses into nucleus and
induces DNA to form mRNA→ synthesis of proteins:
(a) Na+ channel proteins: Na+ diffuse from tubular lumen into inside of cells
(b) Enzymes:
1) Na+ - K+ ATPase: pumps Na+ out of cells in exchange for K+ at basolateral
membranes
2) mitochondrial enzymes: increases energy production.
• 30 minutes required before new proteins appear, 45 before rate of Na+ transport
increase; maximal effect is reached after several hours

A.F. 2025 46
❖ Control of aldosterone secretion:
1- Activation of renin-angiotensin system: "feedback manner":
• juxtaglomerular cells of kidney secrete renin→ acts on angiotensinogen
(globulin of hepatic origin): angiotensin I (inactive) → angiotensin II (AII) by
angiotensin converting enzyme (ACE) in lungs.
• Angiotensin II binds to receptors on zona glomerulosa and stimulates
aldosterone synthesis and secretion:
1) early: convert cholesterol to pregnenolone
2) late: convert corticosterone to aldosterone.
• Renin secretion stimulated by ↓ ECF, plasma volume, RBF:
1) ↓ Na+ as by dietary restriction.
2) Hemorrhage.
3) upright posture for several hours.
4) sympathetic: on B-adrenergic receptors in JG cells.
o Atrial natriuretic peptide (ANP): ↓ renin and aldosterone synthesis by ↓
response of zona glomerulosa to AII.

2- Plasma K+ level: ↑ by 1 mEq/L (as after a meal rich in K+) stimulates:

a- Synthesis: conversion of cholesterol to pregnenolone, and conversion of
corticosterone to aldosterone.
b- Release: by depolarizing adrenal cell → opens voltage gated Ca++ channels

3- Plasma Na+ level: either:

a- Acute ↓ in plasma Na+ of 20 meq/L.
b- Dietary Na+ restriction (slow decline):
1) Initially: ↓ tubular fluid Na+ sensed by macula densa: ↑ renin.
2) Secondly: ↓ ECF volume through renin-angiotensin system.

4- ACTH: “tonic role”:

not important regulator of aldosterone production, but required for optimal
secretion. (when ACTH is deficient; response of zona glomerulosa is decreased)

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➢ Actions of Adrenal Androgens & Estrogens
• Adrenal androgens (DHEA & androstenedione):
- under ACTH control.
- function due to peripheral conversion to potent androgen testosterone.
- In females: pubic and axillary hair, and RBCs production & have no
masculinizing effect in their normal amounts.
- In males: no importance (testosterone by testes is sufficient).
• Adrenal Estrogens:
- either directly from adrenal cortex or conversion of adrenal androgens.
- important source of estrogen in both men and postmenopausal women.

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 HYPERSECRETION OF ADRENOCORTICAL HORMONES
Hyperaldosteronism Cushing’s syndrome = ↑ cortisol Adrenal Androgens
Primary (Conn’s Secondary depend on age and sex:
syndrome)
Cause tumors heart failure, liver 1. Tumors (ACTH independent:↓ by 1- adult males:
cirrhosis, feedback). masculinizing effects
nephrosis: 2. Bilateral hyperplasia of adrenal cortex: are obscured
↑ renin & (ACTH dependent): ↑ ACTH.
angiotensin II → ↑ 3. exogenous cortisone. 2- adult females:
aldosterone "Adreno genital
Feature 1. ↓ K : (hypokalemia):
+
I- Cortisol excess → (metabolic effects): Syndrome":
s 1) Nephropathy: damage of kidneys with A. Excess protein catabolism: masculinization:
loss of concentrating ability: polyuria. 1- Thin Hair, skin, fragile capillaries (bruises).
2) Muscle weakness due to ↓ excitability of 2- Poor wound healing. - deep voice, acne.
nerve and muscle fibers 3- Atrophy and weakness of muscles. - muscles develop
(hyperpolarization). 4- Osteoporosis → bone fractures. obviously.
3) ↓ glucose tolerance (utilization): ↓ 5- in lymphoid tissues: suppressed immunity
insulin - distribution of hair on
B. Fat Metabolism: body and pubis: beard,
2. ↑ Na : Hypertension: ↑ ECF volume is
+
1- Trunkal obesity: Fat collects in face (moon baldness
with water retention face), upper back (Buffalo hump), abdomen
2- Purple striae: ↑ fat deposition in abdominal - Enlargement of clitoris
3. ↓ H: Metabolic alkalosis: → ↓ plasma wall → rupture of subdermal tissues and - irregular menses
ionized calcium: tetany either latent or stretch of thin skin → blood vessels are seen. - atrophy of breast.
manifest 3- Hyperlipemia and ketosis

A.F. 2025 49
 4. No edema: Edema: No Escape C. Carbohydrate Metabolism: 3- prepubertal male:
Escape phenomenon: 1- Hyperglycemia due to: "precocious
phenomenon: expansion of ECF a) ↑ gluconeogenesis. pseudopuberty"
• No Na+ and water volume b) ↓ utilization of glucose a. Early development of
retention: ↑ CVP: 2- diabetes mellitus (if genetically secondary sexual
↑ ANP: predisposed). characteristics.
1) ↓ response of zona b. Rapid development of
glomerulosa. D. CNS: Accelerate basic EEG, ↑ appetite male sexual organs.
2) ↓ renin. (insomnia and euphoria). c. No testes growth
3) actions opposite to 4- intrauterine life:
angiotensin II: ↓ II- Mineralocorticoid Effect: "Female
of Na+ Hypertension (85% of patients): pseudoherma-
reabsorption by 1) significant mineralocorticoid effect. phrodite"
renal tubules → ↑ 2) others: ↑ deoxycorticosterone & females with
excretion of Na+ angiotensinogen, and a direct masculinized genitalia
& H2O in urine. glucocorticoid effect on arterioles. = ovaries with male
external genitalia.
III- Androgen Excess: ↑ face hair & acne N.B.: 17-ketosteroids are
IV- ACTH Excess: (In ACTH dependent): excreted in large amounts
pigmentation of skin (MSH activity) in urine

N.B.: Glucocorticoid – remediable aldosteronism (GRA):

- Cause: A genetic error → zona glomerulosa sensitive to ACTH: excessive amounts of all steroids including aldosterone.
- Ttt: remedied (corrected) by glucocorticoids → suppress ACTH secretion (-ve feed back).

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➢ Hyposecretion of adrenocortical hormones = Addison’s syndrome:
destruction of adrenals is incomplete. (Total adrenal insufficiency is rapidly fatal)
❖ Causes:
1- autoimmune disease.
2- Destruction of adrenal glands (tuberculosis or cancer).
❖ Effects:
↓ Cortisol ↓ Aldosterone ↓ Adrenal Androgen
a. Hypoglycemia: a. Hyponatremia: ↓ ECFV, 1. Loss of pubic and
- ↓ fasting blood glucose level due to ↓ gluconeogenesis. dehydration, hypotension, and ↓ axillary hairs in
- Sometimes post prandial hypoglycemia due to increased cardiac output. females.
insulin sensitivity. N.B.: Patient dies in shock if untreated. 2. Anemia (decreased
b. ↓ of many metabolic functions: b. Polyuria: due to ↑ loss of Na+, Cl- red cell production)
↓ mobilization of proteins and fats → ↓energy substrates and H2O in urine.
→ anorexia, weight loss, fatigue, and muscle weakness. c. K+ retention (hyperkalemia): cardiac
c. ↑ eosinophils and lymphocytes and ↓ neutrophils. arrhythmias and weakness of cardiac
d. Pigmentation of mucous membranes (gums), pressure contractility.
areas of skin areola & nipple due to ↑ ACTH secretion d. H+ retention: mild metabolic
(–ve feedback of cortisol is ↓). acidosis.
e. ↓ resistance to stress.

❖ Addisonian Crisis:
• during stress: fail to respond by increase in glucocorticoids → collapse, shock, hyperkalemia and hypoglycemia.
• Emergency treatment: I.V. cortisol and isotonic NaCl infusion.

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A.F.2025 52
 Pancreas
❖ two types of tissues:
1- Exocrine (Pancreatic acini): 80% secrete digestive juices into duodenum.

2- Endocrine (Islets of Langerhans):

- 1 – 2 million islets form 2% of pancreas (ducts and blood vessels form rest).
- 4 cell types in islets:
1) (α) A cells: 25% secrete glucagon.
2) (β) B cells: 60% secrete insulin (located in the center of each islet).
3) (δ) D cells: 10% secrete somatostatin.
4) F cells: 5% secrete pancreatic polypeptide (PP) concerned with GIT functions
N.B.: Glucagon, somatostatin, and (PP) are also secreted by cells in GIT mucosa

Insulin
❖ Mechanism of release:
• Glucose enters β cells through a special glucose transporter GLUT2.
• Glucose is oxidized generating ATP → closes ATP-sensitive K+
channels → decreased K+ efflux → depolarization → opens voltage-
gated Ca++ channels → influxes Ca++ → Ca++-dependent kinases →
insulin release by exocytosis.
• N.B.: insulin and equimolar amount of C-peptide (90 – 97%) (rest is proinsulin
with little activity)

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❖ Carriage and breakdown:
• free in plasma: half-life is 5 minutes.
• Insulin binds to receptors: internalized by receptor-mediated endocytosis
• destroyed in endosomes by insulinase in liver, muscle, kidney, and others.
• Normally, little or no insulin is found in urine.

➢ Mechanism of action:
❖ Insulin receptors:
• on many cells even cells in which insulin does not increase glucose uptake.
• IGF-I is similar in structure to insulin (compete for receptor)
• receptor is a tetramer (4 subunits) held by disulfide linkages: 2 alpha subunits
outside cell membrane & 2 beta penetrate membrane (protrude in cytoplasm)

- insulin binding to alpha subunit → B subunits activated = tyrosine kinase:

1) autophosphorylation
2) phosphorylate and dephosphorylate some cytoplasmic proteins
3) phosphorylation of insulin receptor substrates (IRS-1, IRS-2, IRS-3 and IRS-4).

❖ Modulation of insulin receptor:

Number affinity
Increases ↓ insulin: starvation (up regulation) adrenal insufficiency and
starvation
Decreases ↑ insulin: obesity and acromegaly excess glucocorticoids
(down regulation)

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❖ Cellular effects of insulin stimulation:
1. Rapid (seconds): ↑ permeabilty to:
- Glucose: translocation of glucose transporters from endosomes to cell membrane.

- Amino acids, K+, and PO 4 --.

2. Intermediate (minutes): activity of enzymes
3. Delayed: (hours): DNA synthesis, mRNA formation & proteins synthesis.

❖ Relation of insulin to potassium

1- Insulin → K+ to enter cells (↑ activity of Na+ - K+ ATPase):
- Clinically: Infusion of insulin and glucose is used for relief of hyperkalemia.

2- ↓ K+ depletion → ↓ insulin secretion:

- K+ - depleted patients (primary hyperaldosteronism) → (diabetic glucose
tolerance curves) restored to normal by K+ repletion.
- Diabetic taking thiazide diuretics → K+ depleted → worsen diabetes.

❖ Actions of Insulin:

I. On Carbohydrate Metabolism (Hypoglycemic):

• stimulates glucose uptake only in: muscle, adipose tissue and liver.

A. On muscle :
1. Between meals (insulin is low): muscle depends on fatty acids.
2. Following a meal:
• insulin: accelerates transport of glucose ↑ GLUT4
• Muscles is 50% of body → major lowering of blood glucose.
• 20% - 50% of glucose entering muscles undergoes oxidation, and remainder
stored as glycogen, because insulin activates glycogen synthase.
• Insulin inhibits lipoprotein lipase: FFA uptake and oxidation are inhibited.

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 B. On Liver:
• Glucose is transported freely into liver through GLUT2 (insulin – insensitive)
• uptake of glucose or its release from liver depends on conc. of free glucose.
• Insulin:
1- ↑ activity of glucokinase: ↑ G-6-P: low free glucose.
2- ↑ glycogenesis: ↑ activity of glycogen synthase.
3- ↓ glycogenolysis: inhibits liver phosphorylase
4- ↓ gluconeogenesis by Inhibiting protein catabolism: ↓ amino acids release.
C. On Adipose tissue:
• stimulates transport of glucose into fat cells by ↑ GLUT4.
• glucose form glycerol combines with fatty acids → triglycerides.
II. On Fat Metabolism (Lipogenic & antiketogenic): “fat sparer”.
1. FA synthesis liver: conversion of glucose into FFAs → triglycerides in VLDL.
2. storage of fat in adipose tissue: (lipogenesis):
a) activates lipoprotein lipase → splits triglycerides into FFAs, and helps
their transfer into adipose cells.
b) FFAs combine with glycerol → stored as triglycerides.
3. inhibits release of stored fat from adipose tissue = Inhibits lipolysis:
a. inhibits hormone-sensitive lipase → inhibit release of FFAs.
b. stimulates use of ketoacids by peripheral tissues: major antiketogenic
III- on Protein Metabolism:
1. ↑ transport of amino acids into cells: ↓ plasma level.
2. ↑ formation of DNA, mRNA: ↑ protein synthesis (mostly enzymes required for
storage of carbohydrates, fats and proteins).
3. on ribosomes ↑ synthesis of rRNA: formation of new proteins
4. ↓ protein catabolism (proteolysis) in muscle.
IV- On Growth: Growth = anabolic state mainly in cartilage, bone and muscle,
1. synthesis of macromolecules (proteins, fats & carbohydrates) in tissues.
2. stimulates transcription of gene of IGF-I, and inhibits gene for one of IGF-I-
binding proteins: more IGF-I is free in plasma. (indirectly affects growth).

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 Glucagon
• polypeptide (29 AA) produced by A cells of pancreatic islets and upper GIT.
• preproglucagon is in A cells and L cells (lower GIT &brain): different processing
❖ Actions:
1. On carbohydrate metabolism "the hyperglycemic hormone":
• Injection of 1 g/kg → ↑ blood glucose about 20mg % in 20 minutes. through:
a) Breakdown of liver glycogen (glycogenolysis), not in muscle.
b) Increased gluconeogenesis in liver.
• Mechanism: Glucagon binds to:
a- Gs receptors on liver cells activate adenyl cyclase → ↑ cAMP, activating
protein kinase A, activating phosphorylase.
b- different receptor activates phospholipase C → ↑ cytoplasmic Ca++.
2. On protein metabolism: ↑ enzymes for .A.A. uptake: gluconeogenesis
3. On fat metabolism (In high concentrations):
• lipolysis in adipose tissues by activating hormone-sensitive lipase:
increases fatty acids → ketogenesis.
• inhibits triglycerides storage in liver → more fats to other tissues.
4. Calorigenic: ↑ deamination of A.A. and ↑ gluconeogenesis.
5. +ve Inotropic: Large doses of exogenous glucagon → ↑ cAMP
6. ↑ secretion of insulin, growth hormone, and pancreatic somatostatin.

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 Somatostatin
• All factors related to food ingestion stimulate its secretion:
1) ↑ blood glucose, A.A., and fatty acids.
2) ↑ GIT hormones as CCK.
• main function: decrease nutrient utilization → food available for longer period
• acts locally (paracrine): secreted by D cells of:
a) pancreatic islets: ↓ insulin, glucagon and pancreatic polypeptides.
b) GIT: ↓ motility (stomach, duodenum, & gall bladder) secretion and absorption.

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❖ Control of Insulin & glucagon Secretion
Insulin glucagon
1) Feedback • most important: • ↑ by hypoglycemia as during starvation,
effect of blood glucose insulin (on 3rd day = maximal gluconeogenesis)
blood fasting (80 – 90 mg %) minimal • ↓ by Hyperglycemia: GABA from B
glucose increased increases cells: acts on A cells → activating
at 300 mg% maximum GABAA receptors → Cl - influx →
hyperpolarizes & inhibits A cells.
• two stages:
1. rapid: within (3-5 min) & lasts 15 min (preformed)
2. delayed: (15 min - 2h) (preformed and newly formed)
• important feedback for regulating blood glucose:
↑ glucose → ↑ insulin → ↑ transport of glucose into muscle,
adipose tissue and liver → ↓ blood glucose to normal

2) Amino • ↑ by some A.A. (e.g. arginine and lysine) from digestion • ↑ especially glucogenic
Acids of protein (to increase uptake of amino acids by cells) N.B.: after protein meal: glucagon
• potentiate glucose stimulus. balances hypoglycemia of insulin

3) GIT Oral glucose → ↑ insulin secretion > glucose I.V. due to: • CCK and Gastrin ↑
Hormones a. glucagon-like polypeptide- I (GLP-I) and GIP • Secretin ↓
(incretins), gastrin, secretin and CCK (insulinogogues).
b. AA, potentiate glucose –stimulated insulin secretion
4) Islet Cell a. Glucagon ↑ Somatostatin and insulin ↓
Hormones b. Somatostatin ↓

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5) Other 1) Cortisol, growth hormone, estrogen-progesterone, human
Hormones placental lactogen, and thyroid hormones:
o directly or indirectly → hyperplasia of B cells with ↑ insulin
o antagonize insulin action on peripheral tissues.
o Prolonged secretion → B cells exhaustion → diabetes
mellitus.

2) Insulin has a negative feedback → ↓ insulin.

3) Leptin released from fat adipocytes act on:

▪ hypothalamus to decrease food intake.
▪ B cells → ↓ insulin release.

6) Autonomic a. Vagus: ↑ insulin: a. Vagal stimulation: ↑glucagon

acetylcholine on M4 receptors coupled via G proteins →
phospho-lipase C → IP3 and → Ca2+ release. b. Sympathetic : net effect ↑ insulin
o α2- receptors ↓
b. Sympathetic: net effect ↓insulin: o β receptors ↑ (by increase cAMP)
o α2- receptors ↓
o β receptors ↑.

7) others ↑ cAMP (B-adrenergic agonists, glucagon, theophylline and GIP): Exercise & Stress: ↑ glucagon due to:
↑ insulin (increasing intracellular Ca++) 1) increased glucose utilization.
2) sympathetic stimulation

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 Regulation of Blood Glucose Level
• importance:
- only nutrient under normal conditions by brain, retina and germinal epithelium.
- hyperglycemia has many harmful effects

❖ normal glucose:
- In fasting: blood glucose level is 80-90 mg %.
- first hour after a meal: increases to 120 -140 mg %
- within 2 hours after last absorption of carbohydrates: back to control level.

- in between meals: glycogenolysis then gluconeogenesis (no insulin → glucose

not utilized by muscles).
- During starvation: gluconeogenesis to maintain fasting blood glucose level.

❖ Control mechanisms and its components:

I- Glucostatic Function of Liver:
a. At absorption (after meal): ↑ glucose & insulin (2/3 stored in liver as glycogen)
b. postabsorptive: blood glucose level falls and liver releases glucose

II- Hormonal Mechanism:

1. insulin and glucagon:

- Hyperglycemia → insulin → ↓blood glucose
- Hypoglycemia → glucagon → ↑ blood glucose
N.B.: In normal conditions, insulin feedback mechanism is more important,
Glucagon feedback is valuable in starvation, exercise and stress

2. Epinephrine: Severe hypoglycemia stimulates hypothalamus → Epinephrine:

1) ↑ glucose production from liver through glycogenolysis
2) ↓ glucose utilization by tissues
3) ↑ FFA in plasma to enhance utilization of fat.

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3. growth hormone & cortisol: if Hypoglycemia prolonged for hours & stress

Growth hormone Cortisol

- Glycogenolysis - Gluconeogenesis,
- ↓ number of insulin receptors - ↓ affinity of insulin receptors
decrease in glucose utilization by peripheral tissues
lipolysis and ketogenesis.
N.B. permissive cortisol action for glucose utilization is needed in normal conditions.

4. Glucagon like peptide one (GLP-1)

• 30 aa peptide produced in intestinal L-cells. in response to meal intake. actions:
1. ↑insulin (incretin hormone).
2. ↓ glucagon: limit postprandial glucose excursions
3. ↓ gastrointestinal motility and secretion.
4. physiological regulator of appetite and food intake
- inactivated by dipeptidyl peptidase IV: blockers of enzyme prolong its actions.
- GLP-1 or GLP-1 receptor agonists → therapy of type 2 diabetes.
- ↓ GLP-1 → obesity - ↑ GLP-1 →postprandial reactive hypoglycemia.

5. Glucose-dependent insulinotropic polypeptide: GIP

• secreted by K-cells (more in duodenum and jejunum but present in all small
intestine): by nutrients as glucose, amino acids, and FFAs
- K-cells sense the presence of glucose using a variant of (SGLT-1).
• Actions:
1. weak inhibitor of acid secretion.
2. Potent stimulator of insulin post meals.

N.B.: incretin effect:

- higher insulin secretion with oral glucose than intravenous.
- GIP is the most potent incretin (with GLP-1 → 25 to 70% of postprandial insulin).

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 Diabetes Mellitus
❖ Factors predispose to diabetes:-
1) Heredity: Type 2 (genetic defects in insulin molecule, receptor, IRS, GLUT4).
2) Obesity:
• Down-regulation of insulin → insulin (even if excessive) is less effective .
• ↑ FFA inhibits enzyme responsible for translocation of GLUT-4 to cell membrane.
❖ Abnormalities = effects of insulin lack:
A. Hyperglycemia: Decreased utilization of glucose
B. Abnormal Fat Metabolism:
• lipolysis and plasma level of FFA.
• ↑ plasma cholesterol: deposition in arterial walls → atherosclerosis
C. protein catabolism

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