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Physiology of thyroid and pancreas

Int. Sunder Chapagain

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Thyroid gland• Thyroid (greek thyroes, shield, plus eidos,

form)• Weight: 12-20 g• Thyroid hormone synthesis normally begins by

11 weeks of gestation

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Thyroid hormone synthesis

•Iodide trapping•Organification of thyroglobulin•Coupling

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Thyroid hormone synthesis

•Iodide trapping•Organification of thyroglobulin•Coupling

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Thyroid hormone synthesis

•Iodide trapping

•Organification of thyroglobulin•Coupling

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Thyroid hormone synthesis

•Iodide trapping•Organification of thyroglobulin

•Coupling

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Mechanism of action of various antithyroid drugs

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• Daily rate of secretion: 80µg T4 , 4µg T3, 2µg of RT3• Plasma level:

– FT4=2 ng/dl– FT3= 0.3 ng/dl– Total T4= 8 µg/dl– Total T3= 0.14 µg/dl

• 99% of total thyroid hormone is protein bound – Thyroid binding albumin (T ½ = 13 d)– Thyroid binding pre-albumin (transthyretin) (T ½ = 2 d)– Thyroid binding globulin (TBG) (T ½ = 5 d)

• So, there is slow release of these hormones to tissues

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• T ½ T4 = 6 days • T ½ T3 = 1 day• T ½ TSH = 50 minutes• Thyroid hormones have

slow onset and long duration of action – T4 latent period – 2-3

days and maximum activity: 10-12 days

– Action of T 3 is 4 times rapid than T4

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Wolff chaikoff effect • In normal individuals, large doses of iodide act

directly on the thyroid to produce a mild and transient inhibition of organic binding of iodide and hence of hormone synthesis. This inhibition is known as the Wolff–Chaikoff effect.

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Jod basedow effect• Hyperthyroidism following administration of

iodine or iodide(dietary, contrast medium, amiodarone).

• Ususally in patient with endemic goitre, graves disease, toxic multinodular goitre or thyroid adenomas.

• Not in normal thyroid.

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Metabolism of thyroid hormones• About half of circulating T4 is converted to T3

• Three types of deiodinases (contains selenocysteine) : D1 D2 D3

• D1 (deiodinate both rings): liver,kidneys, thyroid and pituitary• D2 (deiodinate outer ring 5’C): brain, pituitary, heart, skeletal

muscles and brown fat• D3 (deiodinate inner ring 5C): brain except pituitary, placenta,

fetal and reproductive tissues• D3 is main source of RT3• Some T3, T4 are also conjugated in liver and excreted in bile

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Significance of RT3

• RT3 is inert.• In cardiomyopathy, D3 in heart increases to decrease

energy turnover and oxygen consumption• Selenium deficiency, starvation, burns, major trauma,

advanced cancer, cirrhosis, renal failure, MI and febrile states: suppresses deiodinases(D2) decreased T3, Normal T4, increased RT3 :: LOW T3 SYNDROME

• Overfeeding : increases T3 and decreases RT3

Thyrotropes

Hypothalamus

Thyroid Gland

(TRH)

(+)

(SS, Dopamine)

(-)

(TSH)

(+)T3/ T4

T3/ T4

T3/ T4

(-)

(-)

(-)(-)

Shor

t loo

p fe

edba

ck Ultr

a sh

ort

loop

Long

loop

feed

back

Thermal & Caloric signals

Regulation of Thyroid Hormones

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Cellular Mechanism of Action of TSH on Thyrocytes

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Effects of Thyroid Hormones

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Physiological effects of thyroid hormone

1. Increased metabolic rate2. Growth and development3. Metabolic4. Cardiovascular5. Gastrointestinal6. Permissive action

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Increased metabolic rate

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Effect secondary to increased metabolism

• Increased excretion of nitrogen• Endogenous protein and body fat stores catabolism• Precipitate weight loss• Vitamin deficiency syndromes can be precipitated.• Carotenemia: thyroid hormone is required for

conversion of carotene to vitamin A.

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Growth and Development• Physical:– Bone growth– Early epiphyseal closure– Secretion of growth

hormone– Potentiate effect of

growth hormone in tissues

• Nervous:– Cerebral cortex– Basal ganglia– Cochlea– Decreases time of

stretch reflexes (quick)– Hyperthyroidism: lack of

sleep, fine tremors

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Metabolic effect• Stimulates metabolism

of:– Fat

• Increases free fatty acids• Decreases cholesterol,

phospholipids, triglycerides• Increases rate of

cholesterol secretion in bile

• Increases number of LDL receptors on liver

– Protein• Increased catabolism• Muscle

weakness(thyrotoxic myopathy)

– Carbohydrate• Uptake, glycolysis,

gluconeogenesis, absorption from GIT, increases insulin secretion

Cardiovascular Effects

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Gastrointestinal effects

• Increases appetite• Increases motility• Increases GI secretions• Hyperthyroidism: diarrhoea• Hypothyroidism:

constipation

Permissive action

• Increase expression of adrenergic receptors in tissues increased sympathetic activity tachycardia, palpitations, tremors, sweating..

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Calcitonin• Parafollicular cells (C-cells)• Stimulated by increased

plasma calcium concentration.

• Action just opposite to that of parathyroid hormone.

• Decreases the absorptive activity of osteoclasts (immediate)

• Decrease formation of new osteoclasts ultimately decreased osteoblasts also (prolonged effect)

• Kidney and intestine

Functional Anatomy of Pancreas -an exocrine and endocrine gland.

1 to 2 % endocrine cells 80% exocrine, 18 to 19% ducts & blood vessels

-insulin secretion begins at 10th week of gestation.

The ENDOCRINE PORTION of the pancreas are the pancreatic islets.

Four cell types:A (alpha ) cells20-30% glucagon(T ½ = 3-6 min)B (beta) cells 60-75% insulin (T ½ =5-8 min)D (delta) cells 5-10% gastrin, somatostatinF cells very few pancreatic polypeptide

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INSULIN

Mechanism & Regulation of Insulin release.

Stimuli that regulate insulin synthesis & release.Increased by Decreased by

Glucose, galactose, Glyceraldehyde. Argenine, Lysine,

Leucine, Alanine. Ketoacids, FFA,

Triglycerides. Hormones: Glucagon, GH, CCK,

GLP-I, cortisol, gastrin, secretin Ions: Ca+2 & K+

Vagal Activity.

Fasting. Exercise & endurance

training. Hormones: somatostatin,

Leptin, Prostaglandin E2. α -adrenergic activity.

β -adrenergic activity.

Relationship between plasma glucose and insulin secretion

PREFORMED INSULIN

SYNTHESISED INSULIN

Actions of lnsulin

Blood Glucose, FFA, Amino acids, Ketoacids

Glut-2Glucose

Glut-4Glut-4

Glucose

Stimuli for Glucagon secretion

Action of Glucagon

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INSULIN VS GLUCAGON

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Effects of hypoglycemia

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Somatostatin (T ½=3 min)

Stimulated by:• glucose• amino acids• fatty acids• several upper

gastrointestinal hormones secreted in response to food

Effects : • insulin and glucagon• motility of stomach,

duodenum and gall• secretion and absorption

in gastrointestinal tract

DELTA CELLS

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EXOCRINE PANCREAS• ~1-2 L of secretion/day into

the lumen of the duodenum

• The centroacinar and ductal cells secrete the aqueous HCO3

--containing component of the pancreatic secretion.

• Acinar : proenzymes

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•Enzymes:• Proteolytic:

Trypsinogen, Chymotrypsinogen, Procarboxypeptid-ase B, Elastase• Amylolytic:

Amylase-P• Lipolytic: Lipase-P,

Colipase, Cholesterol esterase, Phospholipase A2

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Effect of Flow Rate on Composition of Pancreatic Juice

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“Fail Safe” mechanism of pancreas• Enzymes secreted in inactive form• Proenzymes are sequestered in membrane bound

zymogen granules• Activation of proenzymes requires conversion of

trypsinogen to trypsin• Trypsin inhibitors(SPINK 1) also secreted by acinar and

ductal cells• Most enzymes have acidic optima.

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REFERENCES• Textbook of medical physiology 12e, Guyton• Ganong’s review of medical physiology 23e• Lippincott’s biochemistry 5e• Lippincott’s pharmacology 4e• Physiology, Linda 3e• Netter’s physiology atlas• Medscape

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