1. INSULIN Dr. Ayisha Qureshi Assistant Professor MBBS, Mphil

2. PANCREAS Pancreas is a mixed gland that performs both exocrine & endocrine functions Pancreas is an elongated organ with one end broad (shaped like a hook) & the other end narrowing to a tail. This organ lies sideways, the hook on the right side and turned downwards. It lies behind & below the stomach fitted in the C- shaped concavity of the loop of duodenum (small intestine)

4. FUNCTIONAL ANATOMY OF PANCREAS: EXOCRINE TISSUES Larger part Grape-like clusters of secretory cells forming sacs called ACINI Which empty into the pancreatic ducts that eventually empty into the duodenum The secretion is called the Pancreatic juice!— What does the pancreatic juice contain? ENDOCRINE TISSUES Smaller part Consists of isolated islands of endocrine tissues called as ISLETS OF LANGERHANS dispersed throughout & forming only 1% of total pancreatic mass. These secrete HORMONES!

6. ISLETS OF LANGERHANS: A or Alpha cells (25%) secrete Glucagon B or Beta cells (60%) secrete Insulin & Amylin D or delta cells (10%) secrete Somatostatin F or PP cells (very few) Secrete Pancreatic polypeptide

7. HORMONES OF PANCREAS Enlist the hormones of Pancreas: Insulin (also Proinsulin & C-peptide) Glucagon Amylin Somatostatin Pancreatic Polypeptide

8. INSULIN & CARBOHYDRATE METABOLISM The principal product of carbohydrate digestion & the principal circulating sugar is GLUCOSE. The terms used in CHO metabolism include: Glycolysis Gluconeogenesis Glycogenolysis Glycogenesis The breakdown of glucose to pyruvate or lactate (or both) is called Glycolysis. The conversion of non-glucose molecules to glucose is called Gluconeogenesis. Glycogenesis: The process of glycogen formation is glycogenesis. Glycogenolysis: The process of glycogen breakdown is glycogenolysis.

9. INSULIN

10. It is a Peptide hormone. It consists of 2 amino acid (51AA) chains that are joined together by disulphide linkages. If the 2 AA chains are split apart then the functional activity of insulin is lost. It has a molecular weight of 5808. Plasma half-life: 6 minutes Cleared from the circulation in 10-15 minutes

11. Synthesis of Insulin Insulin is initially produced as Preprohormone (mw: 11,500) which is cleaved in the ER to yield Proinsulin (mw: 9,000). Proinsulin is further cleaved in Golgi apparatus to yield Insulin and its peptide fragment which is also called the C-peptide (connecting peptide) These both are then packaged in secretory vesicles & released when the stimulus arrives. Preprohormone (ER) (11,500) ↓ Proinsulin (Golgi Apparatus) (9,000) ↓ Insulin + C-peptide (stored in secretory vesicles) ↓ Secreted into blood ↓ After use degraded by the enzyme called as Insulinase in the liver & to a lesser extent in the kidneys & muscles

13. Insulin secretion Insulin release is not continuous even after a meal but oscillates with a period of 3-6 minutes: spurts of insulin release. This oscillation is important to consider when administering insulin-stimulating medication as oscillation is the target & not a constant high concentration.

14. Role of Glucose Transporters The transport of glucose from blood into different tissue cells is accomplished by the GLUCOSE TRANSPORTERS (GLUT) Insulin cannot enter the cells without these transporters (proteins). GLUT 1-7 have been characterized. Each GLUT has been evolved for a different task & a different tissue. GLUT 1,2 & 3 are NOT affected by insulin: - GLUT-1: transports glucose across blood brain barrier - GLUT-2: kidney cells - GLUT-3: neurons Therefore, in all these tissues the glucose entry is insulin independent. Only GLUT-4 is insulin-dependant & occurs in the muscles & adipocytes. These cells maintain a pool of GLUT-4 molecules in vesicles in their cell cytoplasm.

15. Glucose Transporters

16. Glucose entry into the LIVER Glucose does not depend on GLUT-4 for entry into the LIVER.

17. Lack of effect of Insulin on Glucose uptake by BRAIN Brain uses only Glucose as its energy source, therefore, it is important that blood glucose levels be maintained above a critical level. Brain is PEREMEABLE to Glucose & can use it even without the intermediation of Insulin. When blood glucose levels fall too low ( 20- 50mg/ 100ml), symptoms of hypoglycemic shock develop. Hypoglycemic shock is characterized by progressive nervous irritability that leads to fainting, seizures & even coma.

18. ACTIONS OF INSULIN:

19. ACTIONS OF INSULIN WHAT IS THE OBJECTIVE OF INSULIN? ↓ It is to maintain blood glucose homeostasis! INSULIN IS THE ONLY HORMONE CAPABLE OF LOWERING THE BLOOD GLUCOSE LEVEL. Insulin is an ANABOLIC hormone Insulin has important effects on: - CHO - Fats - Proteins It LOWERS blood glucose levels of: - Glucose - fatty acids - amino acids It is a hormone associated with ENERGY ABUNDANCE & the FED STATE.

20. Normally, circulating glucose conc. Are determined by:

23. I: Action on CHO metabolism 1.Insulin stimulates Glucose uptake by the cells ( thru GLUT-4!!!) 2.Insulin stimulates Glycogenesis in both the Liver & the skeletal muscles. 3.It inhibits Glycogenolysis 4.It inhibits Gluconeogenesis 5.It promotes liver uptake, use & storage of Glucose

24. MUSCLES Throughout the day the muscles use Fatty Acids. This is because under resting conditions, the cells are dependent on GLUT-4 for glucose uptake But, With moderate or severe exercise, special GLUT- 4 vesicles (present only in muscles) move into cell membrane in response to exercise only & do not require Insulin ↓ That is why EXERCISE LOWERS BLOOD SUGAR!

25. LIVER Insulin inhibits Gluconeogenesis by altering the quantity & activity of Liver enzymes required for the reaction Insulin inhibits Glycogenolysis by inactivating Liver phosphorylase: GLYCOGEN__________→ GLUCOSE (catalyzed by Liver phosphorylase) Glycogen stored in the liver is not broken down into Glucose for further use. Insulin enhances Glycogenesis by increasing the activity of Glycogen synthase & phosphofruktokinase enzyme. –Net effect is increased synthesis of Glycogen in the liver Insulin promotes conversion of excess Glucose into Fatty acids –When the Glycogen content exceeds 5-6% of the liver mass (about 100gms), then the excess glucose entering the liver cells is converted into Fatty acids. ↓ Triglycerides, which is taken to the adipocytes & stored there Glucose is released from the Liver between meals.

26. II: Action on Protein metabolism It increases the translation of mRNA forming new proteins & the transcription of DNA. Insulin inhibits protein catabolism & decreases the rate of amino acids released from the cells. In the liver, it decreases the rate of gluconeogenesis & thus conserves amino acids for protein synthesis. THUS, INSULIN PROMOTES PROTEIN ANABOLISM AND INHIBITS PROTEIN CATABOLISM. It is, thus, essential for growth. Insulin & Growth hormone act synergistically to promote growth.

27. III: Action on Fat metabolism INSULIN PROMOTES FAT SYNTHESIS & STORAGE: Insulin increases Glycogenesis but when 5-6% of liver mass is Glycogen, then additional Glucose entering the liver is converted to Fat. FA synthesized by liver cells are used by them for TG synthesis. Insulin inhibits lipolysis by inhibiting action of hormone-sensitive lipase. Thus, TG present in the fat cells are not metabolized to yield FA. Insulin promotes glucose transport into the fat cells- this glucose is used to synthesize FA & more importantly to form large quantities of alpha glycerolphosphate. This supplies the glycerol that forms the TG after combining with FA in the fat cells. Glycerol+ FA----------Triglycerides

28. SUMMARY OF INSULIN ACTIONS Insulin PROMOTES uptake of Glucose by different cells of the body. In doing so it lowers the blood glucose levels post meal. Insulin increases Glycogenesis, Lipogenesis & protein formation. Insulin inhibits Glycolysis, Gluconeogensis, Lipolysis & protein breakdown. It promotes growth.

29. Factors affecting Insulin secretion Factors Stimulating Insulin Release Glucose Amino acids Free fatty acids Gastrointestinal hormones: gastrin, secretin, GIP Parasympathetic stimulation: Ach Sulfonylurea drugs Factors Inhibiting Insulin Release Decreased blood Glucose Fasting Somatostatin Sympathetic stimulation: epinephrine Leptin

30. Actions of Insulin

31. EFFECTS OF INSULIN DEFICIENCY:

32. 1.Hyperglycemia

33. EFFECTS OF INSULIN DEFICIENCY: 2. Glycosuria

34. EFFECTS OF INSULIN DEFICIENCY: 3. Polyuria

35. EFFECTS OF INSULIN DEFICIENCY: 4. Polydipsia & Polyphagia

36. EFFECTS OF INSULIN DEFICIENCY: 5. Weight Loss

37. EFFECTS OF INSULIN DEFICIENCY: 6. Increase in plasma Cholesterol & Phospholipid conc.

38. Effects of Insulin Deficiency Hyperglycemia Glycosuria Polyuria Polydipsia & Polyphagia Weight loss Increase in plasma cholesterol & phospholipid conc.

39. EFFECTS OF INSULIN DEFICIENCY: THE NET EFFECT OF INSULIN LACK IS A SEVERE REDUCTION IN THE ABILITY TO STORE GLCOSE, FAT & PROTEIN

40. GLUCAGON

41. Glucagon: “Glucose is GONE” Peptide hormone made of 29 amino acids. MW: 3485 Has several functions that are dramatically opposite to Insulin One injection of purified glucagon can have profound Hyperglycemic effects! Therefore, it is also called the HYPERGLYCEMIC HORMONE! SYNTHESIS: in the alpha cells Preproglucagon (158 AA) ↓ Glucagon + Major proglucagon fragment (in the alpha cells)

42. ACTIONS OF GLUCAGON The physiological role of Glucagon is to stimulate hepatic production & secretion of glucose. It accomplishes this by: 1.Glycogenolysis 2.Increased Gluconeogenesis

45. The Balance b/w insulin & Glucagon: Over-riding concern is glucose homeostasis : – must maintain sufficient levels for use by brain – other tissues adjust to other energy sources as necessary. Integration of pathways and tissues is achieved by the action of two major hormones: InsulinGlucagon

46. Insulin Dominates in Fed State Metabolism  glucose uptake in most cells  glucose use & storage  protein synthesis  fat synthesis

47. Glucagon Dominates in Fasting State Metabolism Figure 21-14: Endocrine response to hypoglycemia