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Metabolic effect of pancreatic hormones,insulin glucagon and PPP(PANCREATIC POLY PEPTIDE)

  1. Metabolic effects of pancreatic hormones By Yerukneh Solomon 7/18/2017 1
  2. Outlines  Introduction  Pancreatic hormones synthesis and secretion  Pancreatic hormones effects on metabolism  Summary 7/18/2017 2
  3. Introduction Pancreas  Pancreas contains exocrine & endocrine cells  Roughly 99% of the cells of the pancreas are arranged in clusters called acini. The acini produce digestive enzymes, which flow into the GIT.  Endocrine cells are called Islets of Langerhans, 1-2% of pancreatic tissue. 7/18/2017 3
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  5. Introduc…  There are 4-types of endocrine cells 1. α-cells: secret glucagon (25%) 2. β-Cells: secret insulin (65%) 3. δ-Cells: secret somatostatin (8%) 4. F-Cells: secret pancreatic polypeptides (2%) 7/18/2017 5
  6. Insulin Chemistry and Synthesis Insulin is a small protein; human insulin has a molecular weight of 5808. It is composed of two amino acid chains connected to each other by disulfide linkages Beta cells - beginning with translation of the insulin RNA by ribosomes attached to the ER to form an insulin preprohormone (11500) - cleaved in the ER to form a proinsulin (9000) - further cleaved in the Golgi apparatus to form insulin - secretory granules unbound form; it has a plasma half-life that averages only about 6 minutes - degraded by the enzyme insulinase mainly in the liver, to a lesser extent in the7/18/2017 6
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  11. Cellular effect of insulin 7/18/2017 11
  12. Carbohydrate Metabolism • Immediately after a high-carbohydrate meal, rapid secretion of insulin occur • The normal resting muscle membrane is only slightly permeable to glucose, except when the muscle • fiber is stimulated by insulin • Moderate or heavy exercise • Few hours after a meal because of insulin – Glucose stored as muscle GLYCOGEN – used during anaerobic exercise 7/18/2017 12
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  14. Carbohydrate Metabolism • Glucose absorbed after a meal to be stored almost immediately in the liver in the form of glycogen  Insulin promotes storage by:  Increasing the activity of the Glucokinase,  inactivating liver phosphorylase  Increasing the activities of glycogen synthase 7/18/2017 14
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  16. Carbohydrate Metabolism Glucose Is Released from the Liver Between Meals 1. The decreasing blood glucose causes the pancreas to decrease its insulin secretion. 2. Stopping further synthesis of glycogen in the liver and preventing further uptake of glucose by the liver from the blood. 3. The lack of insulin along with increase of glucagon, activates the enzyme phosphorylase, 4. The enzyme glucose phosphatase, becomes activated 7/18/2017 16
  17. Carbohydrate Metabolism • When the quantity of glucose entering the liver cells is more than can be stored as glycogen, Conversion of excess glucose into fatty acids • Insulin also inhibits gluconeogenesis by:  Decreasing the quantities and activities of the liver enzymes required for gluconeogenesis  Decreases the release of amino acids from muscle and other extrahepatic tissues • Brain cells use only glucose for energy 7/18/2017 17
  18. Fat Metabolism Insulin acts as fat sparer. Promotes fatty acid synthesis in liver from excess glucose 1. Insulin increases the transport of glucose into the liver cells 2. Energy from glucose via citric acid cycle - excess of citrate and isocitrate ions - activates acetyl CoA carboxylase – acetyl CoA to form malonyl CoA Fat storage in adipose tissue  Fatty acids (triglycerides) are then transported from the liver by way of the blood lipoproteins to the adipose cells. 7/18/2017 18
  19. Fat Metabolism  Insulin promotes glucose transport into the fat cells  Insulin inhibits the action of hormone-sensitive lipase  insulin deficiency - free fatty acid  FFA become main energy substrate The excess of fatty acids in the plasma promotes liver conversion of some of the fatty acids into phospholipids and cholesterol 7/18/2017 19
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  21. Protein Metabolism and Growth 1. Insulin stimulates transport of many of the amino acids into the cells 2. Insulin increases the rate of transcription of selected DNA genetic sequences 3. Insulin increases the translation of mRNA 4. Insulin inhibits the catabolism of proteins 5. In the liver, insulin depresses the rate of gluconeogenesis - conserves the amino acids in the protein stores of the body 7/18/2017 21
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  23. fasting level of blood glucose of 80 to 90 mg/100 ml, the rate of insulin secretion is minimal — 25 ng/min/kg of body weight 7/18/2017 23
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  25. Glucagon and Its Functions Glucagon, a hormone secreted by the alpha cells of the islets of Langerhans when the blood glucose concentration falls Glucagon - large polypeptide - molecular weight of 3485 – chain of 29 amino acids 1 µg/kg of glucagon can elevate the blood glucose concentration about 20 mg/100 ml of blood (25 per cent increase) in about 20 minutes (1) breakdown of liver glycogen (glycogenolysis) (2) increased gluconeogenesis in the liver 7/18/2017 25
  26. Glucagon  Synthesis, Secretion and metabolism ◦ Synthesized from the preprohormone precursor called preproglucagon in the α- cells of islets. ◦ Preproglucagon is converted into proglucagon, which gives rise to glucagon. ◦ Secreted from α-cells in the islets of Langerhans of pancreas. ◦ It is also secreted from A cells of stomach and L cells of intestine. 7/18/2017 26
  27.  Chemistry And Half-life ◦ Polypeptide with a molecular weight of 3,485. ◦ It contains 29 amino acids. ◦ Half-life of glucagon is 3 to 6 minutes. 7/18/2017 27
  28.  Metabolism ◦ About 30% of glucagon is degraded in liver and 20% in kidney. ◦ The cleaved glucagon fragments are excreted through urine. ◦ 50% of the circulating glucagon is degraded in blood itself by enzymes such as serine and cysteine proteases 7/18/2017 28
  29.  Actions Of Glucagon ◦ Actions of glucagon are antagonistic to those of insulin ◦ It increases:  Blood glucose level,  Peripheral utilization of lipids  Conversion of proteins into glucose 7/18/2017 29
  30. On Carbohydrate Metabolism Glucagon increases the blood glucose level by:  Increasing glycogenolysis in liver.  Increasing gluconeogenesis in liver  Decreasing glycolysis  Decreasing glycogenolysis 7/18/2017 30
  31. Cellular effect of glucagon  Glucagon causes glycogenolysis in the liver, which in turn increases the blood glucose concentration within minutes. 7/18/2017 31
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  33. glycogenolysis 1. Glucagon activates adenylyl cyclase in the hepatic cell membrane - cAMP - protein kinase, 2. Which activates phosphorylase b kinase, 3. Which converts phosphorylase b into phosphorylase a, 4. Which promotes the degradation of glycogen into glucose-1-phosphate, 5. Which then is dephosphorylated; and the glucose is released from the liver cells.7/18/2017 33
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  36. Gluconeogenesis ◦ by:  Activating the enzymes, which convert pyruvate into phosphoenol pyruvate  Increasing the transport of amino acids into the liver cells.  The amino acids are utilized for glucose formation 7/18/2017 36
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  38. Gluconeogenesis increase the rate of amino acid uptake by the liver cells and then the conversion of many of the amino acids to glucose activation of the enzyme system for converting pyruvate to phosphoenolpyruvate, a rate-limiting step in gluconeogenesis glucagon activates adipose cell lipase, making increased quantities of fatty acids available to the energy systems of the body Glucagon also inhibits the storage of triglycerides in the liver, which prevents the liver from removing fatty acids from the blood 7/18/2017 38
  39. On Fat Metabolism ◦ Glucagon shows lipolytic and ketogenic actions. ◦ It increases lipolysis by increasing the release of free fatty acids from adipose tissue and making them available for peripheral utilization. ◦ The lipolytic activity of glucagon, in turn promotes ketogenesis (formation of ketone bodies) in liver 7/18/2017 39
  40. ◦ In the adipocyte, glucagon activates hormone- sensitive lipase,  the enzyme that breaks down triglycerides (stored fat) into diacylglycerol and free fatty acids, releasing them into the circulation. ◦ Glycerol released into the circulation can be utilized in the liver for gluconeogenesis ◦ Free fatty acids are used as fuel by most tissues, 7/18/2017 40
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  43. Somatostatin  Somatostatin is secreted from: Hypothalamus D cells (δ-cells) in islets of Langerhans of pancreas D cells in stomach and upper part of small intestine.  Somatostatin brings out its actions through cAMP 7/18/2017 43
  44. Chemistry ,Half-life & metabolism  Somatostatin is a polypeptide.  It is synthesized in two forms, namely somatostatin-14 and somatostatin-28  Both the forms have similar actions.  Half-life of somatostatin is 2 to 4 minutes.  Somatostatin is degraded in liver and kidney. 7/18/2017 44
  45.  Actions Of Somatostatin 1. Somatostatin acts within pancreas, inhibits β and α cells, 2. It decreases the motility of stomach, duodenum and gallbladder 3. It reduces the secretion of gastrin, CCK, GIP and VIP 4. Hypothalamic somatostatin inhibits the secretion of GH and TSH 7/18/2017 45
  46. Regulation Of Secretion Of Somatostatin  Pancreatic Somatostatin  Secretion of pancreatic somatostatin is stimulated by glucose, amino acids and CCK.  The tumor of D cells of islets of Langerhans causes hypersecretion of somatostatin.  It leads to hyperglycemia and other symptoms of diabetes mellitus. 7/18/2017 46
  47. Pancreatic Polypeptide  Source Of Secretion ◦ Pancreatic polypeptide is secreted by F cells or PP cells in the islets of Langerhans of pancreas.  Chemistry And Half-life ◦ Pancreatic polypeptide is a polypeptide with 36 amino acids. ◦ Its half-life is 5 minutes. 7/18/2017 47
  48. Synthesis and metabolism  Pancreatic polypeptide is synthesized from preprohormone precursor called prepropancreatic polypeptide in the PP cells of islets  Pancreatic polypeptide is degraded and removed from circulation mainly in kidney. 7/18/2017 48
  49. Actions Of Pancreatic Polypeptide ◦ Exact physiological action of pancreatic polypeptide is not known. ◦ It is believed to increase the secretion of glucagon from α-cells in islets of Langerhans.  Pancreatic polypeptide brings out its actions through cAMP. 7/18/2017 49
  50.  Regulation Of Secretion ◦ Secretion of pancreatic polypeptide is stimulated by the presence of chyme containing more proteins in the small intestine. 7/18/2017 50
  51. Clinical correlations 7/18/2017 51
  52. Hypoglycemia  Hypoglycemia is common in insulin-treated diabetic patients and also occurs occasionally in patients treated with the oral hypoglycemic sulfonylurea agents.  Hypoglycemia may range from very mild lowering of glycemia (60-70 mg/dl) with minimal or no symptoms, to severe hypoglycemia with very low levels of glucose (<40 mg/dl) and neurologic impairment. 7/18/2017 52
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  54. Clinical correlation 7/18/2017 54
  55. References  Guyton & Hall:2011, Textbook of Medical Physiology, 12th ed. Insulin, glucagon and DM chapter XIV,  Williams textbook of endocrinology, 13th edition.  Berney, and Levy, physiology, 6th edition.  L. Sherwood, human physiology, 7th edition.  Vander's, human physiology,11th edition. 7/18/2017 55
  56. Thank You… 7/18/2017 56