endocrine pancreas
TRANSCRIPT
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
53
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