endocrine pancreas

1. ENDOCRINE
PANCREAS
DR AMBIKA JAWALKAR

2. 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

4. 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

5. INSULIN

6. 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

8. 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

9. INSULIN STRUCTURE

10. Insulin Synthesis
• Insulin gene is located on the short arm of the
chromosome 11
• Synthesized as Preprohormone containing 110
amino acids

11. DNA (chromosome 11) in β cells
mRNA
Preproinsulin – 110 aa (signal peptide, A
chain,
B chain, and peptide C)
Proinsulin – 86 aa

12. • 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

14. 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

15. Regulation of insulin secretion
 Mainly regulated by feed back control signal
provided by nutrients level in plasma
“ Hormone of Abundancy”

17. PLASMA GLUCOSE

18. MECHANISM OF GLUCOSE
INDUCED INSULIN
SECRETION

20. 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

21. 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

22. 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

23. MECHANISM OF ACTION
 The 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+

24. GLUCOSE TRANSPORTERS

25. MECHANISM OF ACTION

26. PHYSIOLOGICAL
ACTIONS OF
INSULIN

27. 27
Ganong Review of Medical Physiology 1985 12th ed #258

28. 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

29. INSULIN ACTION ON
CARBOHYDRATE METABOLISM
ADIPOSE TISSUE
• Stimulates glucose transport into
adipocytes
• Promotes the conversion of glucose into
triglycerides and fatty acids
“ANTI-DIABETOGENIC”

30. 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”

31. 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

32. 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

33. INSULIN ACTION (SUMMARY):
•  GLUCOSE UPTAKE IN MOST
CELLS
•  GLUCOSE USE & STORAGE
•  PROTEIN SYNTHESIS
•  FAT SYNTHESIS
Dominates in Fed State Metabolism
Anti-
Diabetogenic
Anabolic
Anti-ketogenic
Lipogenic

34. GLUCAGON

35. • 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

36. DNA in α cells
mRNA
Preproglucagon
Proglucagon
Glucagon

38. PHYSIOLOGICAL ACTIONS OF
GLUCAGON
•Stimulates glycogenolysis, gluconeogenesis
& inhibits glycogenesis
•Promotes lipolysis & ketogenesis
•Increases calorigenesis
“Prodiabetogenic and Ketogenic”

39. 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

40. INSULIN & GLUCAGON REGULATE
METABOLISM

41. NORMAL PLASMA GLUCOSE LEVELS
•Fasting : 70 – 100mg%
•Postprandial : 100 – 140mg%
•RBS : 80 – 120mg%

42. PLASMA GLUCOSE
( BLOOD GLUCOSE)
- INSULIN -
GLUCAGON
( BLOOD GLUCOSE) -
EPINEPHRINE
- GROWTH

43. GLUCOSE
HOMEOSTASIS

44. GLUCOSE
HOMEOSTASIS

45. 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

46. 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

47. APPLIED PHYSIOLOGY
INSULIN DEFICIENCY – DIABETES MELLITUS
INSULIN EXCESS – INSULINOMA
GLUCAGON EXCESS – GLUCAGONOMA
SOMATOSTATIN EXCESS –
SOMATOSTATINOMA
CARCINOMA OF PANCREAS

48. 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

49. 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)

52. 52
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. 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)

54. 54
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. 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”

57. 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

58. TREATMENT
• Insulin therapy
• Oral hypoglycemic agents
• Life style modifications

59. COMPLICATIO
NS
• Microvascular – diabetic retinopathy,
diabetic nephropathy
• Macrovascular – Myocardial Infarction &
Stroke
• Diabetic neuropathy
• Chronic ulcer & gangrene formation due to
decreased resistance to infection