endocrine pancreas

ENDOCRINE PANCREAS

DR AMBIKA JAWALKAR

PANCREAS

• A TRIANGULAR GLAND, WHICH HAS BOTH

EXOCRINE AND ENDOCRINE CELLS, LOCATED

BEHIND THE STOMACH

• ACINAR CELLS PRODUCE AN ENZYME-RICH

JUICE USED FOR DIGESTION (EXOCRINE

PRODUCT)

• PANCREATIC ISLETS (ISLETS OF LANGERHANS)

PRODUCE HORMONES INVOLVED IN

REGULATING FUEL STORAGE AND USE.

ISLETS OF LANGERHANS

• PAUL LANGERHANS – German medical

student, 1st discovered in dogs in 1869

• 1-2% of the pancreatic mass

• 1- 2 million islets in humans

• Beta (β) cells produce INSULIN

• Alpha (α) cells produce GLUCAGON

•Delta (δ) cells produce SOMATOSTATIN

• F cells produce PANCREATIC POLYPEPTIDE

INSULIN

Frederick G. Banting and John

Macleod were awarded the Nobel

Prize in Physiology or Medicine in 1923 "for the discovery of insulin."

SOURCE- http://www.nobelprize.org/educational/medicine/insulin/discovery-insulin.html

INSULIN STRUCTURE• Large polypeptide 51 AA (MW 6000)

• Two chains linked by disulfide bonds.

• A chain (21AA)

• B chain (30 AA)

• The hydrophobic character of the amino acids

at the C-terminal of B-chain is important for

biological activity of Insulin

INSULIN STRUCTURE

Insulin Synthesis• Insulin gene is located on the short arm of the

chromosome 11

• Synthesized as Preprohormone containing 110

amino acids

DNA (chromosome 11) in β cells

mRNA

Preproinsulin – 110 aa (signal peptide, A chain,

B chain, and peptide C)

Proinsulin – 86 aa

Insulin – 51 aa

• Insulin gene encodes a large

precursor of insulin (preproinsulin)

•During translation, the signal

peptide is cleaved (proinsulin)

•During packaging in granules by

golgi, proinsulin is cleaved into

insulin and C peptide

C - PEPTIDE

Connects A & B chains

Facilitates folding of A & B chains

Retained in granules

No biological activity, but secreted in equimolar

ratio with Insulin

Hence its concentration in plasma directly

reflects β–cells activity

Regulation of insulin secretion

Mainly regulated by feed back control signal

provided by nutrients level in plasma

“ Hormone of Abundancy”

PLASMA GLUCOSE

MECHANISM OF GLUCOSE INDUCED INSULIN

SECRETION

METABOLISM OF INSULIN

• Insulin circulates freely in plasma

• Its half life is 5-8 min.

•Metabolic clearance is 800ml/min

• Basal insulin release to the circulation is about

0.5-1 unit/hr

• Total release into peripheral circulation in a day is

30 units

•Metabolized mainly in Liver & Kidney

MECHANISM OF ACTION

INSULIN RECEPTOR

• A glycoprotein tetramer having 2 α

and 2 β subunits

• Gene located on chromosome 19

• Insulin binds with α subunit resulting in

conformational change of receptor

• The HR complex is then internalized by

endocytosis

MECHANISM OF ACTION

Binding of Insulin to α subunit

Conformational change in Receptor (β subunit)

Activation of tyrosine kinase activity of β

subunit

Autophosphorylation of β subunit on tyrosine

residues

Phosphorylation of intracellular proteins that

brings about alteration in cell functions

MECHANISM OF ACTIONThe active tyrosine kinase phosphorylates tyrosines on

Insulin Receptor Substrates (IRS1 & IRS2)

IRSs are docking proteins to which a variety of

downstream proteins bind

Phosphorylation of IRS causes translocation of GLUTs

(Glucose Transport Proteins) to the cell membrane

GLUTS facilitate glucose entry into the cell

Different protein channels are also inserted into the

plasma membrane leading to increased entry of amino

acids, K+, Mg+ & P+

GLUCOSE TRANSPORTERS

MECHANISM OF ACTION

PHYSIOLOGICAL ACTIONS OF

INSULIN

27

Ganong Review of Medical Physiology 1985 12th ed #258

INSULIN ACTION ON CARBOHYDRATE METABOLISM

LIVER

• Stimulates glucose oxidation

• Promotes glucose storage as glycogen

• Inhibits glycogenolysis

• Inhibits gluconeogenesis

MUSCLE

• Stimulates glucose uptake (GLUT4)

• Promotes glucose storage as glycogen

INSULIN ACTION ON CARBOHYDRATE METABOLISM

ADIPOSE TISSUE

• Stimulates glucose transport into

adipocytes

• Promotes the conversion of glucose into

triglycerides and fatty acids

“ANTI-DIABETOGENIC”

INSULIN ACTION ON PROTEIN METABOLISM

• Facilitates amino acids entry into muscle

cells

• Facilitates protein synthesis in ribosomes

by induction of gene transcription

• Inhibits proteolysis by decreasing

lysosomal activity

“ANABOLIC HORMONE”

INSULIN ACTION ON FAT METABOLISM

LIVER

• Anti ketogenic & Lipogenic

• Stimulates HMG-CoA reductase

ADIPOSE TISSUE

• Promotes storage of fat

• Inhibits lipolysis by inhibiting Hormone

sensitive lipase

• Promotes lipogenesis by stimulating

lipoprotein lipase

“ANTI-KETOGENIC”

INSULIN ACTION ON PLASMA K+CONCENTRATION

• Facilitates rapid entry of K+ into cell by

simulating Na-K ATPase activity

• Thus decreases plasma concentration of

K+

• APPLIED: Insulin is given along with

glucose in the treatment of Hyperkalemia

that occurs in Acute Renal Failure

“PHYSIOLGICAL REGULATOR OF PLASMA

K+ CONCENTRATION”

INSULIN ACTION (SUMMARY):

• GLUCOSE UPTAKE IN MOST

CELLS

• GLUCOSE USE & STORAGE

• PROTEIN SYNTHESIS

• FAT SYNTHESIS

Dominates in Fed State Metabolism

Anti-DiabetogenicAnabolic Anti-ketogenicLipogenic

GLUCAGON

• A 29-amino-acid polypeptide hormone that is a

potent hyperglycemic agent

• Produced by α cells in the pancreas

• Its major target is the liver, where it promotes:

•Glycogenolysis – the breakdown of glycogen to

glucose

•Gluconeogenesis – synthesis of glucose from

lactic acid and non carbohydrates

• Release of glucose to the blood from liver cells

DNA in α cells

mRNA

Preproglucagon

Proglucagon

Glucagon

PHYSIOLOGICAL ACTIONS OF GLUCAGON

•Stimulates glycogenolysis, gluconeogenesis

& inhibits glycogenesis

•Promotes lipolysis & ketogenesis

• Increases calorigenesis

“Prodiabetogenic and Ketogenic”

INSULIN-GLUCAGON RATIO

• Insulin is hormone of energy storage

•Glucagon is hormone of energy release

• A balance should be maintained for normal

metabolic functions

• After a normal balance diet is 3

• After overnight fasting decreases to 1, may

decrease to as low as 0.4 after prolonged fasting

• Physiological significance – during neonatal

period a low I/G ratio is critical for survival of the

neonate

INSULIN & GLUCAGON REGULATE METABOLISM

NORMAL PLASMA GLUCOSE LEVELS

•Fasting : 70 – 100mg%

•Postprandial : 100 – 140mg%

•RBS : 80 – 120mg%

PLASMA GLUCOSE

( BLOOD GLUCOSE)

- INSULIN -

GLUCAGON

( BLOOD GLUCOSE) -

EPINEPHRINE

- GROWTH

HORMONE

GLUCOSE HOMEOSTASIS

GLUCOSE HOMEOSTASIS

SOMATOSTATIN

•Secreted from D

cells of pancreas

•Also secreted in

hypothalamus & GIT

•A peptide hormone

with 2 forms, one

with 14 AAs & the

other with 28 AAs

Functions:

• Inhibits secretion of

insulin & glucagon

• Inhibits GI motility* & GI

secretions

•Regulates feedback

control of gastric

emptying

PANCREATIC POLYPEPTIDE

•Secreted from F cells of pancreas

•Polypeptide with 36 amino acids

•Structurally similar to Neuropeptide Y

secreted from hypothalamus

•Secreted in response to food intake

• Inhibits exocrine pancreatic secretion

•Slows the absorption of food from the GI

tract

APPLIED PHYSIOLOGY

INSULIN DEFICIENCY – DIABETES MELLITUS

INSULIN EXCESS – INSULINOMA

GLUCAGON EXCESS – GLUCAGONOMA

SOMATOSTATIN EXCESS –

SOMATOSTATINOMA

CARCINOMA OF PANCREAS

DIABETES MELLITUS

•A serious disorder of carbohydrate

metabolism

•Most common endocrine disorder

•Results from hyposecretion or hypoactivity

of insulin

•The three cardinal signs of DM are:

•Polyuria – huge urine output

•Polydipsia – excessive thirst

•

Classification of DM

Type 1 or IDDM - Insulin Dependent Diabetes

Mellitus

Type 2 or NIDDM - Non-Insulin Dependent

Diabetes Mellitus

Other Types of Diabetes Mellitus – MODY, pancreatic diseases, drug induced (corticosteroids, thiazide diuretics, phenytoin)

GDM - Gestational Diabetes Mellitus

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Polyphagia – decreased activity of

satiety center removes its inhibitory

effect on feeding center in brain

Polyuria – is due to osmotic diuresis

Polydipsia – dehydration due to

polyuria stimulates thirst

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Glycosuria - because when insulin is

not present, glucose is not taken up

out of the blood at the target cells.

So blood glucose is very highly

increased → increased glucose is

filtered and excreted in the urine

(exceeds transport maximum)

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Ketosis -

Fats and proteins are metabolized excessively, and byproducts known as ketone bodies are produced. These are released into the bloodstream and cause:Decreased pH (so increased acidity)

Compensations for metabolic acidosis

Acetone given off in breath

55

Weight loss - patient eats, but nutrients are not taken up by the cells and/or are not metabolized properly

“Disease of Starvation midst of Plenty”

DIAGNOSIS

•Demonstrating persistent hyperglycemia &

glycosuria

•Glucose Tolerance Test (GTT) – oral is

preferred

•Estimation of Fasting Blood Glucose (FBS)

•FBS more than 126mg% in more than two

occasions confirms DM

TREATMENT

• Insulin therapy

•Oral hypoglycemic agents

•Life style modifications

COMPLICATIONS

•Microvascular – diabetic retinopathy,

diabetic nephropathy

•Macrovascular – Myocardial Infarction &

Stroke

•Diabetic neuropathy

•Chronic ulcer & gangrene formation due to

decreased resistance to infection