2. Pancreatic Hormones

3. Two types of secretions from pancreas
Exocrine function
Acinar cells
Secretion into acini, ductules
Digestive enzymes
Used for digestion of food n intestine
Endocrine function
Islets of Langerhans
Secretion into ECF, blood
Hormones
Regulation of metabolism

4. The Endocrine Pancreas

5. Islets of Langerhans 1-2 million islets of Langerhans
0.3 mm diameter of the islets
3 major types of cells
Alpha cells – 25% - Glucagon
Beta cells - 60% - Insulin and amylin
Delta cells – 10% - Somatostatin
PP cells – small number - Pancreatic polypeptide

6. Islets of Langerhans in Pancreas

7. Insulin First isolated in 1922 by Banting and Best
After that tremendous progress in the treatment of Diabetes Mellitus
Insulin affects not only carbohydrates metabolism but also has very important effects on protein and fat metabolism
Probably , in diabetes mellitus, deranged fat and protein metabolism has more marked and grave effects than the disturbance of carbohydrate metabolism

8. Insulin secretion
Insulin secretion is associated with energy abundance
Availability of energy giving nutrient cause insulin secretion
Insulin stores the available extra energy giving substances
Glucose in the form of glycogen
Amino acids in the form of proteins
Fatty acids in the form of triglycerides

9. Chemistry of insulin A small protein MW = 5808
Two amino acid chains linked by disulphide linkages
Split linkages, two separated polypeptides have no hormonal activity
Insulin synthesized, transcription, translation process as preprohormone

10. Structure of insulin

11. Chemistry of insulin Preprohormone MW = 11500
Cleaved in ER to form proinsulin MW 9000
Finally insulin formed in Golgi apparatus and packaged into secretory granules
1/6 hormone still in the form of proinsulin
Plasma half life of insulin is only 6 minutes
Enzyme Insulinase is responsible for degradation of insulin

12. Mechanism of action Insulin receptor MW = 300,000 Consisting of
2 alpha subunits – lying outside the CM
2 beta subunits - penetrating through the CM
Insulin combines with alpha subunits
Beta subunits protruding into the cytoplasm is phosphorylated
Activation of cytoplasmic tyrosine kinase
Activation of Insulin-receptor substrates (IRS) and many other enzymes
Some enzymes are inactivated
Altered enzyme system affects the metabolism of carbohydrates, fats and proteins

13. Mechanism of action

14. Mechanism of action
Cell membrane of 80 % of the cells increase the transport of glucose across
This transport is by a carrier protein – facilitated diffusion
CM becomes more permeable to amino acids
Slowly many metabolic enzymes are altered
Alteration of translation of m RNA and transcription of DNA takes place much slowly

15. Effects of carbohydrate metabolism
After meals
Glucose absorbed into the blood from GIT
Stimulation of insulin production
Insulin→ ↑uptake, utilization and storage of glucose
Specially in muscles, adipose tissue and liver
Between meals
↓ glucose level
↓ insulin
Utilization of fatty acids for energy instead of glucose

16. Glucose uptake
Muscle and adipose tissue CM is impermeable to glucose without insulin
Resting muscles use fatty acids for energy between meals
Muscle use glucose for energy
During moderate to heavy exercise
In the presence of insulin (which is usually is the case after meals)
Insulin →↑uptake of glucose by the adipose and muscle cells

17. Glucose uptake

18. Storage of glycogen in the muscles
In resting muscle glucose entering into it converted into glycogen
This glycogen can be used for energy later
Muscle glycogen cannot be converted into free glucose to enter into blood in hypoglycemic conditions
Muscles lack the enzyme glucose phosphatase

19. Liver uptake of glucose
Glucose from GIT stored as glycogen by insulin
Between meals glycogen reconverted to glucose to be supplied to all the body tissues
Liver cell membrane freely permeable to glucose
Insulin →↑glucokinase →↑Phosphorylation of glucose (glucose trapped inside)
Insulin→ ↓liver phosphorylase→ ↓glycogenolysis
Insulin →↑glycogen synthetase →↑glycogen storage
Liver glycogen can be stored up to 5-6 % liver cell mass

20. Release of glucose from liver
Between meals ↓blood glucose → ↓insulin →↓ storage of glucose
↓insulin →↑ phosphorylase→ ↑glycogenolysis
↓insulin →↑glucose phosphatase → split PO4 to form free glucose
Liver cell membrane freely permeable to glucose
Glucose from glycogenolysis enters into the blood
60 % of glucose in diet is stored as glycogen an later used to maintain glucose level in the blood

21. Excess glucose in the liver
Glycogen stores up to 5-6 % of liver cell mass
Insulin →↑conversion of glucose into FA
These FA packaged as triglycerides → transported in blood as VLDL to adipose tissue→ storage in adipose tissue
Insulin →↓gluconeogenesis by ↓ enzymes

22. Lack of Insulin effects on neurons
Brain neuronal cell use only glucose for energy
Use of other substrates occurs with great difficulty
Brain neuronal cell membrane freely permeable to glucose without insulin
Brain neurons don’t require insulin for supply and utilization of glucose
Hypoglycemia → energy crises in neurons → hypoglycemic shock
A critical level of glucose is necessary for neuronal cells

23. Carbohydrate metabolism in other tissues
↑ transport of glucose into the cell
↑ glycolysis
Provision of glycerol for storage of fats in the adipose tissue
↑deposition of triglycerides in adipose tissue

24. Effects on fat metabolism
Insulin promotes fat storage in the fat cells
Insulin →↑use of glucose for energy and fats are spared
Insulin → FA synthesis in the liver cells
Insulin →↑transport of glucose into liver cells→ formation of glycogen up to 5-6 %
Extra glucose converted to pyruvate then into Acetyl-CoA
Acetyl-CoA converted into FA

25. Effects on fat metabolism
Insulin →↑Glycolysis→ ↑↑citrate and isocitrate ions→ activation of Acetyl- CoA- corboxylase to form melonyl-CoA
Most of the FA are synthesized in the liver
Converted t into triglycerides
Transported in VLDL to adipose tissue
Insulin →↑lipoprotein lipase is capillary walls of adipose tissue→ conversion of blood triglycerides into FA → absorption into adipose cells→ reconverted into triglycerides

26. Effects on fat metabolism
Insulin →↓ hormone sensitive lipase→ ↓ hydrolysis of triglycerides
Insulin →↑ transport and glycolysis and FA synthesis
Insulin →↑ glycolysis → α-glycerophosphate to provide glycerol nucleus for triglyceride synthesis
↓insulin → ↓storage of fats

27. Insulin deficiency and fat metabolism
↓insulin → ↑ hormone sensitive lipase →↑ hydolysis of triglycrides (mobilization of FA) → ↑FFA
↓insulin →↑β-oxidation of FA
↓insulin → ↑FFA→ conversion into cholesterol and phospholipids → ↑ blood lipoproteins cholesterol and phospholipids
↓insulin →↑ cholesterol → ↑ atherosclerosis

28. Diabetic Ketoacidosis
↓insulin → ↑FFA →↑carnitine transport system for FA into mitochondria→↑β-oxidation of FA → ↑↑Acetyl-CoA
↑↑Acetyl-CoA→ ↑acetoacetic acid. β-hydroxybutric acid and acetone
↓insulin → Ketosis
Ketosis → acidosis
Direct
Indirect through excretion of Na+ and retention of H+ in the kidney tubules

29. Effects of removing the pancreas

30. Effects on Proteins
Insulin →↑ protein deposition (effect similar to GH)
↑transport of amino acids into the cells (valine, leucine, isoleucine, tyrosine and phenylalanine)
↑ translation of RNA in the ribosomes
↑ trascription of RNA from DNA
↓ catabolism of protein
In the liver Insulin →↓ gluconeogenesis from amino acids
Both insulin and GH are required for proper growth of the body

31. Lack of insulin and protein metabolism
↓synthesis of proteins
Stoppage of growth
↑ conversion of amino acids into glucose (gluconeogenesis)
↑catabolism of protein
↑degradation of amino acids
↑excretion of urea
Generalized protein wasting
Deranged organ and metabolic functions

32. Insulin and GH required for growth

33. Mechanism of insulin secretion
Beta cells membrane has glucose transporter protein
Glucose enters the beta cells
Glucose -6 phosphate formed
Utilized to produce ATP
ATP inhibits ATP- sensitive Potassium channels
Depolarization of cell membrane
Voltage gated calcium channels open
Calcium enters into beta cells
Amino acids have similar mechanism of stimulation of insulin secretion

34. Mechanism of insulin secretion

35. Regulation of insulin secretion

36. Factors causing increased insulin secretion
Hyperglycemia
Increased amino acid level in the blood
GIT hormones
Gastrin
Secretin
CCK
GIP
Glucagon, GH, Cortisol
Parasympathetic stimulation, acetylcholine
β-adrenergic stimulation

37. Factors causing decreased insulin secretion
Hypoglycemia
Fasting
Somatostatin
α-adrenergic stimulation

38. Hyperglycemia
Hyperglycemia is the most powerful stimulus for beta cells for insulin secretion
At fasting Blood glucose level of 80 mg/100ml insulin secretion is 25 ng/min/kg body weight
Increasing blood glucose concentration stimulates the secretion
Sustained hyperglycemia → ↑insulin secretion proportionate to level of blood glucose
This increase rate of secretion is in phases

39. Phasic increase in insulin secretion
10 fold increase within 3-5 minutes after elevation of blood glucose
Due to release of preformed/ stored insulin
This increase in not sustained
Returns half way down within 5-10 minutes
Gradual increase after minutes of hyperglycemia
Reaches a new plateau within2-3 hours
The level is higher than the initial rise
Results from additional release and new synthesis
Further slow elevation in days
Due to hypertrophy of beta cells

40. Phasic increase in insulin secretion

41. Feed back regulation
Insulin secretion increases in direct proportion to increase in the blood glucose level
Above 100 mg/100ml blood glucose level → very rapid rise in insulin secretion
mg/100ml blood glucose level →10-25 times the basal level
Reduction in blood glucose level → rapid reduction in secretion
Blood glucose level is very rapidly controlled by this feed back mechanism

42. Insulin secretion at different blood glucose levels

43. Mechanism of insulin secretion
Glucagon, acetylcholine and gastric inhibitory peptide increase intra cellular calcium by some other mechanism
Somatostatin and nor-epinephrine activate -adrenergic receptors and inhibit secretion of insulin
Sulphonylurea (e.g. Daonil) drugs stimulate insulin secretion by combining with ATP-sensitive Potassium channels to block them and to produce depolarization to open calcium channels to secrete insulin

44. Mechanism of insulin secretion

45. Amino acids Elevated amino acid level also stimulates the beta cells
Amino acid Lysine is most potent stimulus among amino acids
Very weak stimulus in absence of simultaneous hyperglycemia
Very strong effect in the presence of hyperglycemia
Effect of hyperglycemia is potentiated by increase in amino acid level
Feed back control of amino acids and insulin

46. GIT hormones Gastrin Secretin Cholecystokinin GIP
All increase insulin secretion moderately
Anticipatory elevation of insulin
Even before elevation of blood glucose or amino acid level

47. Other hormones Glucagon Growth hormone Cortisol Progesterone Estrogen
All of these elevate the blood glucose level and stimulate insulin secretion
Uncontrolled oversecretion of any one of these → burning out of the beta cells → diabetes mellitus

48. Autonomic nervous system
Parasympathetic stimulation causes in crease secretion of insulin
β-adrenergic stimulation also increase insulin secretion

49. Switching between CHO & fats metabolism
↑Insulin (present at times of availability of glucose) →
Utilization of glucose
Fats spared
Protein spared
Absence of insulin (state of hypoglycemia) →
Excessive fat utilization
Glucose spared
Other hormones affecting the switch GH
Glucagon
Cortisol
Epinephrine

50. Regarding action of insulin on target cells, the correct statement is:
a) Insulin receptor has one alpha an 2 beta subunits
b) Beta subunits lie entirely outside the cell membrane
c) Insulin receptor is voltage gated
d) Autophosphorylation of beta subunits activate tyrosine kinase
e) Dephosphorylation of insulin receptor substrates occur

51. ACTH and MSH