Insulin secretion and it's role .pptx

Insulin

1. INSULIN : Secretion and its role AIIMS Raipur

2. History On July 27, 1921, Dr. Frederick Banting, a Canadian surgeon and Charles Best, a medical student, successfully isolated the hormone insulin for the first time.   On January 11, 1922, 14-year-old Leonard Thompson became the first person to receive an insulin injection as treatment for diabetes. The Nobel Prize in Physiology or Medicine 1923 was awarded jointly to Frederick Grant Banting and JJR Macleod “for the discovery of insulin.”  AIIMS Raipur

3. Introduction Insulin is a polypeptide containing 51 Amino acid . Two chains of amino acids, A chain ( 21 Amino acids ) and B chain (30 Amino acids), linked by disulphide bridges. It is secreted from beta cells of Pancreas ( Molecular weight of 5808Da). AIIMS Raipur

4. Pancreatic beta cells co-secrete islet amyloid polypeptide (IAPP ) or amylin , a 37-amino-acid peptide. The IAPP is the major component of the amyloid fibrils found in the islets of patients with type 2 diabetes, and an analogue is sometimes used in treating type 1 and type 2 DM. Human insulin is produced by recombinant DNA technology . AIIMS Raipur

5. Insulin circulates almost entirely in an unbound form. It has a plasma half- life of about 6 minutes , it is mainly cleared from the circulation within 10 to 15 minutes. It is degraded by the enzyme insulinase mainly in the liver, to a lesser extent in the kidneys and muscles. AIIMS Raipur

6. Insulin- Chemistry and Synthesis Synthesized in beta cells , by translation of RNA ( in ribosomes attached to the endoplasmic reticulum ) to form preproinsulin , (86-AA ),( molecular weight : 11,500 Da). Processed by removing the amino-terminal peptide, in the endoplasmic reticulum to form a proinsulin ( molecular weight : 9000 Da ), consisting of 3 chains of peptides, A, B, and C. AIIMS Raipur

7. P roinsulin : cleaved in the Golgi apparatus to form insulin , : A and B chains connected by disulfide linkages, and the C chain peptide, called connecting peptide (C peptide). The insulin and C peptide are packaged in secretory granules . The proinsulin and C peptide have virtually no insulin activity. AIIMS Raipur

8. Significance in Diagnosis and Assessment C-peptide is cleared more slowly than insulin, measured by radioimmunoassay in insulin- treated diabetic patients. Useful marker of insulin secretion : discrimination of endogenous and exogenous sources of insulin Patients with type 1 diabetes will have decreased levels of C peptide. Elevated levels of serum proinsulin are indicative of beta cell dysfunction . AIIMS Raipur

9. Insulin secretion Glucose : key regulator of insulin secretion by the pancreatic beta cell . Glucose levels >3.9 mmol/L (70 mg/dL) stimulate insulin synthesis. Begins with glucose transport into the beta cell by a facilitative glucose transporter . Glucose phosphorylation by glucokinase : rate-limiting step that controls glucose-regulated insulin secretion. Further metabolism via glycolysis generates ATP , which inhibits the activity of an ATP-sensitive K+ channel. AIIMS Raipur

10. This channel consists of two separate proteins :one is the binding site for certain oral hypoglycemics (e.g., sulfonylureas, meglitinides); the other is an inwardly rectifying K+ channel protein (Kir6.2 ). Inhibition of this K+ channel induces beta cell membrane depolarization , which opens voltage-dependent calcium channels (leading to an influx of calcium) and stimulates insulin secretion . AIIMS Raipur

11. pulsatile pattern of hormone release, Small secretory bursts: every 10 min, Greater amplitude oscillations of about 80–150 min . Insulin is produced @ 0.2 – 0.5 U/ kg / day . AIIMS Raipur

12. Glucagon-like peptide-1 ( GLP-1 ) and glucose-dependent insulinotropic peptide ( GIP ) are incretin hormones . Bind specific receptors on the beta cell to stimulate insulin secretion through cyclic AMP production , but have this effect only when the blood glucose is above the fasting level . Incretin hormones also suppress glucagon production and secretion. Incretin analogues or pharmacologic agents that prolong the activity of endogenous GLP-1 are used therapeutically in type 2 DM. AIIMS Raipur

13. AIIMS Raipur

14. Activation of target cell receptors by insulin and the resulting cellular effects Insulin must first bind with and activate a membrane receptor protein ( molecular weight 300,000 Da). The insulin receptor is a combination of four subunits held together by disulfide linkages: 2 alpha subunits : ( outside membrane ) 2 beta subunits : that penetrate through into the cell cytoplasm. AIIMS Raipur

15. Insulin binds with the alpha subunits, causing beta subunits to become autophosphorylated. Insulin receptor is an enzyme-linked receptor. Autophosphorylation of the beta subunits activates tyrosine kinase,   which causes phosphorylation of multiple other intracellular enzymes, including a group called insulin- receptor substrates ( IRS ). In this way, insulin directs the intracellular metabolic machinery to produce the desired effects on carbohydrate, fat, and protein metabolism. AIIMS Raipur

16. Effects of Insulin stimulation - Within seconds after insulin binds with its membrane receptors, cells markedly increase their uptake of glucose. This action is especially true of muscle cells and adipose cells, it is not true of most neurons in the brain. The increased glucose transported into the cells is immediately phosphorylated and becomes a substrate for all the usual carbohydrate metabolic functions. AIIMS Raipur

17. The cell membrane becomes more permeable to many of the amino acids, potassium ions, and phosphate ions, causing increased transport of these substances into the cell. Slower effects (10 to 15 minutes ) to change the activity of many more intracellular metabolic enzymes . Much slower effects occur for hours and even several days. These result from changed rates of translation of messenger RNA s to form new proteins . Still slower effects from changed rates of transcription of DNA in the cell nucleus. - AIIMS Raipur

18. Effect of Insulin on Carbohydrate Metabolism - Immediately after a high- carbohydrate meal, there is rapid secretion of insulin. Insulin Promotes Muscle Glucose Uptake and Metabolism . During much of the day, muscle tissue depends on fatty acids for its energy.
This is because the normal resting muscle membrane  is only slightly permeable to glucose , except when the muscle fiber is stimulated by insulin. AIIMS Raipur

19. However, under two conditions the muscles do use large amounts of glucose. During moderate or heavy exercise . This does not require large amounts of insulin because muscle contraction increases translocation of glucose transporter 4 ( GLUT 4 ) to the cell membrane, which, facilitates diffusion of glucose into the cell. 2. During the few hours after a meal . At this time the blood glucose concentration is high and the pancreas is secreting large quantities of insulin. It causes the muscle cell to use glucose preferentially over fatty acids. AIIMS Raipur

20. Quantitative Effect of Insulin to Facilitate Glucose Transport Through the Muscle Cell Membrane Curve “control” shows that the intracellular glucose concentration remained almost zero despite increased extracellular glucose concentration up to as high as 750 mg/100 ml. Curve labeled “insulin” show that the intracellular glucose concentration rose to as high as 400 mg/100 ml when insulin was added. AIIMS Raipur

21. Thus, insulin can increase the rate of transport of glucose by at least 15- fold.  One of the most important effects of insulin is to store absorbed glucose in the liver in the form of glycogen . Then, between meals, when the blood glucose concentration begins to fall, insulin secretion decreases rapidly and the liver glycogen is split back into glucose, which is released back into the blood to keep the glucose concentration from falling too low. AIIMS Raipur

22. The mechanism by which insulin causes glucose uptake and storage in the liver ( during well fed state ) includes several almost simultaneous steps: Insulin inactivates liver phosphorylase , the principal enzyme that causes liver glycogen to split into glucose. This inactivation prevents breakdown of the glycogen that has been stored in liver cells. Insulin enhances the enzyme glucokinase, that causes the initial phosphorylation of glucose after it diffuses into the liver cells. AIIMS Raipur

23. 3 . Once phosphorylated ,glucose cannot diffuse back through the cell membrane. 4 . Insulin increases the activities of enzymes that promote glycogen synthesis, including especially glycogen synthase . The net effect of all these actions is to increase the amount of glycogen in the liver. AIIMS Raipur

24. Glucose is released from the liver between meals ,into the circulating blood. The decreasing blood glucose causes the pancreas to decrease its insulin secretion. The lack of insulin then reverses all the effects listed earlier for glycogen storage The lack of insulin activates the enzyme phosphorylase , which causes the splitting of glycogen into glucose phosphate. During fasting AIIMS Raipur

25. The enzyme glucose phosphatase, now becomes activated by the lack of insulin and causes the phosphate radical to split away from the glucose, allowing the free glucose to diffuse back into the blood. Thus, the liver removes glucose from the blood when it is present in excess after a meal and returns it to the blood when the blood glucose concentration falls between meals. Ordinarily, about 60% of the glucose in the meal is stored in this way in the liver and then returned later.  AIIMS Raipur

26. Insulin Promotes Conversion of Excess Glucose Into Fatty Acids and Inhibits Gluconeogenesis in the Liver Excess glucose entering the liver cells is converted into fatty acids. These fatty acids are subsequently packaged as triglycerides in very low density lipoproteins( VLDL ) which are transported in the blood to adipose tissue, and deposited as fat . AIIMS Raipur

27. Lack of Effect of Insulin on Glucose Uptake and Usage by the Brain Insulin has little effect on uptake or use of glucose by brain. Most of the brain cells are permeable to glucose and can use glucose without the insulin. The brain cells normally use only glucose for energy. When the blood glucose level falls too low, into the range of 20 to 50 mg/dl, symptoms of hypoglycemic shock develop, characterized by progressive nervous irritability that leads to fainting, seizures, and even coma.  AIIMS Raipur

28. Effect of Insulin on Fat Metabolism The long- term insulin deficiency causes atherosclerosis, often leading to heart attacks, cerebral strokes, and other vascular accidents . Insulin promotes fat synthesis and storage. Insulin increases glucose utilization by most of the body’s tissues, which automatically decreases fat utilization, thus functioning as a fat sparer . AIIMS Raipur

29. The following factors lead to increased fatty acid synthesis in the liver : Insulin increases glucose transport into the liver cells. After the liver glycogen concentration reaches 5% to 6%, further glycogen synthesis is inhibited. All the additional glucose entering the liver cells then becomes available to form fat. The glucose is first split to pyruvate and the pyruvate subsequently is converted to acetyl coenzyme A (acetyl- CoA), the substrate from which fatty acids are synthesized. AIIMS Raipur

30. , Most of the fatty acids are then synthesized within the liver and used to form triglycerides , the usual form of storage fat. They are released from the liver cells to the blood in the lipoproteins . Insulin activates lipoprotein lipase in the capillary walls of the adipose tissue, which splits the triglycerides again into fatty acids, a requirement for them to be absorbed into adipose cells, where they are again converted to triglycerides and stored. AIIMS Raipur

31. Role of Insulin in Storage of Fat in the Adipose Cells Insulin has two essential effects: Insulin inhibits the action of hormone- sensitive lipase . Therefore, release of fatty acids from adipose tissue into the circulating blood is inhibited . 2. Insulin promotes glucose transport through cell membranes into fat cells in the same way that it promotes glucose transport into muscle cells. AIIMS Raipur

32. Some of this glucose, also forms α- glycerol phosphate . This substance combines with fatty acids to form triglycerides , the storage form of fat in adipose cells. Therefore, when insulin is not available, even storage of the large amounts of fatty acids transported from the liver in lipoproteins is almost blocked.  All aspects of fat breakdown and its use for providing energy are greatly enhanced in the absence of insulin. AIIMS Raipur

33. Lipolysis of Stored Fat and Release of Free Fatty Acids In the absence of insulin, all the effects of insulin noted earlier that cause storage of fat are reversed. The enzyme hormone-sensitive lipase in the fat cells gets activated. Hydrolysis of triglycerides, releasing fatty acids and glycerol into the circulating blood. These free fatty acids then become the main energy substrate to all tissues of the body except the brain. AIIMS Raipur

34. Effect on Plasma Cholesterol and Phospholipid Concentrations Excess of fatty acids are converted into phospholipids and cholesterol, two of the major products of fat metabolism. These two substances, are then discharged into the blood in the lipoproteins . This high lipid concentration—especially the high concentration of cholesterol—promotes development of atherosclerosis in people with severe diabetes.  AIIMS Raipur

35. Ketosis Insulin deficiency also causes excessive amounts of acetoacetic acid to be formed in liver cells. In the mitochondria, beta oxidation of the fatty acids proceeds rapidly, releasing extreme amounts of acetyl- CoA. This excess acetyl- CoA is then condensed to form acetoacetic acid, which is then released into the circulating blood. At the same time, the absence of insulin also depresses utilization of acetoacetic acid in peripheral tissues . AIIMS Raipur

36. Effect of Insulin on Protein Metabolism and Growth Insulin Promotes Protein Synthesis and Storage . It stimulates transport of many of the amino acids into the cells. It “turns on” the ribosomal machinery . It inhibits catabolism of proteins,  thus decreasing the rate of amino acid release from the cells, especially from muscle cells. It promotes formation of protein and prevents degradation of proteins. AIIMS Raipur

37. Administration of either growth hormone or insulin one at a time causes almost no growth. However, a combination of these hormones causes dramatic growth . AIIMS Raipur

38. Feedback Relation Between Blood Glucose Concentration and the Insulin Secretion Rate As blood glucose concentration rises above 100 mg/dl of blood, secretion of insulin rises rapidly, reaching a peak some 10 to 25 times the basal level at blood glucose concentrations between 400 and 600 mg/100 ml. Furthermore, the turnoff of insulin secretion is almost equally as rapid, occurring within 3 to 5 minutes after a reduction in blood glucose concentration back to the fasting level. AIIMS Raipur

39. Role of Insulin in switching between carbohydrate and lipid metabolism The signal that controls this switching mechanism is principally the blood glucose concentration. When glucose concentration is low, insulin secretion is suppressed, and fat is used almost exclusively for energy everywhere except in the brain. When the glucose concentration is high, insulin secretion is stimulated, and carbohydrate is used instead of fat. AIIMS Raipur

40. Growth hormone and cortisol are secreted in response to hypoglycemia, and both inhibit cellular utilization of glucose while promoting fat utilization. Epinephrine -increases plasma glucose concentration during periods of stress when the sympathetic nervous system is excited. Epinephrine -increases plasma fatty acid concentration at the same time. AIIMS Raipur

41. Effects of Anesthesia on insulin secretion and action - Surgical stress with inhalation anesthesia is associated with increased circulating catecholamines, hyperglycemia, and impaired insulin secretion. Inhalation anesthesia - suppress basal insulin levels and the insulin response to intravenous glucose . AIIMS Raipur

42. In postoperative period , suppressed insulin secretion was found to be correlated with elevated plasma epinephrine concentrations mediated by adrenergic mechanisms . I mpaired insulin secretion have two etiologies - the type of anesthesia used adrenomedullary stimulation due to pain. AIIMS Raipur

43. Summary Insulin is a polypeptide linked by disulphide bonds secreted by Beta cells of Pancreas in the form of pre -pro insulin which is cleaved to pro insulin releasing c -peptide which is useful in diagnostic tests. Glucose induces insulin secretion from pancreas wherein blockage of K+ channels induce opening of voltage gated Ca+2 channels. GLP1 and GIP are incretin hormones involved in insulin production during fasting. AIIMS Raipur

44. Insulin has an enzyme linked receptor, by autophosphorylation of beta subunits forms Insulin Receptor Substrate ( IRS ) phosphorylation and further cellular effects. Insulin – increase s permeability of cell to glucose, - glucose uptake and storage in liver, - promotes conversion of excess glucose into fatty acid, - promotes protein synthesis and storage. Deficiency of insulin increases plasma cholesterol and phospholipid concentration causing atherosclerosis,  may cause acidosis and ketosis due to excess use of fat. Type of anesthesia and surgical stress affect the secretion of Insulin which is to be managed accordingly. AIIMS Raipur

45. References - Guyton’s And Hall textbook of Medical Physiology - 2 nd – South Asia Edition Harrison’s Principles of Internal Medicine - 20 th edition Ganong’s review of Medical Physiology – 26 th edition Research publications from https://www.ncbi.nlm.nih.gov.in AIIMS Raipur

46. AIIMS Raipur