1. PANCREATIC HORMONES Dr. Amel Eassawi 1

2. OBJECTIVES The student should be able to:  Know the cell types associated with the endocrine pancreas.  Discuss the biosynthesis and secretion of insulin by the pancreatic beta cells.  Describe the regulation of insulin secretion from the pancreatic beta cells.  Describe the regulatory effects of insulin on the metabolism of carbohydrates, fats and proteins.  Discuss the regulation of glucagon synthesis and release from the pancreatic alpha cells.  Know the actions of glucagon at the target tissue.  Describe the dynamic relationship between insulin and glucagon in terms of fuel storage, fuel mobilization and overall carbohydrate homeostasis.  Describe glucose counter regulatory mechanisms.  Discuss type 1 and type 2 diabetes mellitus with respect to etiology, symptoms, and treatment. 2

3. METABOLIC FUEL IN THE BODY 3

4. 4 PATHWAYS OF FUEL METABOLISM

5. METABOLIC FUEL IN THE BODY Food intake is intermittent – nutrients must be stored for use between meals – Excess circulating glucose Stored in liver and muscle as glycogen Once liver and muscle stores are “filled up”, additional glucose is transformed into fatty acids and glycerol and stored in adipose tissue – Excess circulating fatty acids Become incorporated into triglycerides – Excess circulating amino acids Converted to glucose and fatty acids. 5

6. 6 ENERGY METABOLISM

7. METABOLIC FUEL IN THE BODY Absorptive State – Fed state – Glucose is plentiful and serves as major energy source Postabsorptive State – Fasting state – Endogenous energy stores are mobilized to provide energy 7

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9. METABOLIC FUEL IN THE BODY Roles of Key Tissues in Metabolic States: Liver – Primary role in maintaining normal blood glucose levels – Principal site for metabolic interconversions such as gluconeogenesis Adipose tissue – Primary energy storage site – Important in regulating fatty acid levels in the blood Muscle – Primary site of amino acid storage – Major energy user Brain – Normally can only use glucose as an energy source – Does not store glycogen Mandatory blood glucose levels be maintained 9

10. 10 Pancreas

11. PANCREAS Beta (B cells) – 60-70% of islet cells – Insulin Alpha (A cells) – 20 -25% of islet cells – Glucagon Delta (D cells) – 10% of islet cells – Somatostatin F (PP) cells – Approx 1% of islet cells – Pancreatic polypeptide 11

12. 12 Factors Affecting Blood Glucose Levels

13. INSULIN Insulin – Anabolic hormone – Promotes cellular uptake of glucose, fatty acids, and amino acids and enhances their conversion into glycogen, triglycerides, and proteins, respectively Lowers blood concentration of these small organic molecules – Secretion is increased during absorptive state Primary stimulus for secretion is increase in blood glucose concentration 13

14. INSULIN Insulin Receptor: Membrane glycoproteins composed of 2 subunits  sub unit has Tyrosine kinase activity Sequence of events: Binding of insulin to  site unit trigger the autophosphorylation of tyrosine kinase of  sub unit. Thus insulin exerts its biological action. 14

15. 15 STIMULATION OF INSULIN SECRETION

16. INSULIN Glucose Transporters Recruitment: Insulin increases glucose uptake in most of the cells by GLUT4 ( glucose transporters) GLUT4 operates only after binding with insuline. In insuline dependent cells GLUT4 are retrieved from plasma membrane when insulin secretion decreases 16

17. INSULIN Carbohydrate Metabolism: Liver : Promotes glucose uptake & storage:  Promote glycogenesis( synthesis of glycogen from glucose)  Increases activity of Glycogen Synthetase  Inhibits Glycogenolysis( breakdown of glycogen into glucose)  Inactivates liver Phosphorylase thus in liver.  Inhibits Gluconeogenesis by( Conversion of amino acids into glucose)  decreasing the activity of liver enzymes necessary for gluconeogenesis.  Increases activity of Glucokinase.  This causes initial phosphorylation of glucose after it diffuses into the cells. Therefore net effect is  To increase glycogen synthesis in liver.  To decrease glucose in blood 17

18. INSULIN – Muscle – It increases glucose entry by increasing GLUT4. – Increases storage of glycogen – Adipose tissue Promotes glucose entry [GLUT4.] which is then used to form  glycerol phosphate. This provides the glycerol which combines with fatty acids to form triglycerides thus promoting deposition of fat. 18

19. 19 ATP PRODUCTION

20. 20 PRODUCTION OF KETONE BODIES

21. INSULIN Tissue that do not depend on insulin for glucose uptake Brain Working Muscles (Exercising Muscles) Liver 21

22. INSULIN 22 Brain: Under physiologic conditions, glucose is a necessary fuel Does not synthesize glucose Cannot store more than a few minutes’ supply of glucose as glycogen Facilitated diffusion of glucose from the blood to the brain is a direct function of the arterial plasma glucose concentration

23. INSULIN Protein Metabolism: Insulin decreases blood amino acid level & stimulate protein synthesis.  Promotes active transport of amino acids in muscles and other tissues  Stimulates protein synthesis in cell  Inhibits protein breakdown 23

24. INSULIN Fat Metabolism: Decrease blood fatty acid level & promotes Triglyceride storage – Promotes entry of fatty acids into adipose tissue cells – Promotes entry of glucose into adipose tissue cells- precursors for fatty acids and glycerol, raw material for synthesis of triglycerides – Promotes synthesis of triglycerides from fatty acids and glycerol – Inhibits lipolysis hence release of fatty acids from adipose tissue 24

25. INSULIN Fasting State Decline in glucose utilization by muscle and adipose tissue Increase in lipolysis and ketogenesis Ketones become major fuel source for the brain Fed State Suppression of endogenous glucose production Increase in glucose utilization by liver, muscle and adipose tissue 25 Glucose Metabolism

26. INSULIN Other Effects of insuline 1.Helps in general growth along with other hormones. 2. On electrolytes causes increased entry of K+ into cells thereby decreasing plasma K+ levels. 26

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28. 28 Factors Controlling Insulin Secretion

29. GLUCAGON Glucagon – Mobilizes energy-rich molecules from storage sites during post absorptive state – Secreted in response to a direct effect of a fall in blood glucose on pancreatic α cells – Generally opposes actions of insulin – Glucagon is the hormone of "starvation." – It produces hyperglycemia 29

30. 30 Blood Glucose and the Pancreatic Hormones

31. 31 GLUCAGON ACTIVITY

32. GLUCAGON CARBOHYDRATE: -Stimulates hepatic glycogenolysis. -Increases gluconeogenesis. FAT: -Promotes fat breakdown and inhibits triglyceride synthesis - Increase fatty acids and glycerol in blood -used for gluconeogenesis - Oxidation for energy (Ketogenesis) PROTEIN: -Inhibits protein synthesis (proteolytic Effects) -Glycogenolytic, Gluconeogenic, Lipolytic, Ketogenic Hormone. 32

33. 33 Interaction of Glucagon and Insulin

34. 34 Counteracting action of insulin & glucagon during absorption of high protein

35. 35 Importance of Maintaining Blood Glucose Within the Normal Range

36. SOMATOSTATIN Released from pancreatic D cells in direct response to increase in blood sugar and blood amino acids during absorption of a meal Inhibitory effect on both insulin and glucagon Decreases motility of stomach, duodenum and gallbladder Decreases secretion and absorption in the gastrointestinal tract. Therefore somatostatin: 1.Inhibits digetion and absorption of nutrients 2.Decreased utilization of absorbed nutrients by tissues 3.Extends the availability of nutrients for longer periods of time 36

37. 37 REGULATION OF INSULIN AND GLUCAGON BY SOMATOSTATIN Somatostatin inhibits the release of both insulin and glucagon Its release, in turn, is stimulated by glucagon and inhibited by insulin

38. DIABETES MELLITUS Most common of all endocrine disorders Prominent feature is elevated blood glucose levels – Urine acquires sweetness from excess blood glucose that spills into urine Two major types – Type I diabetes Characterized by lack of insulin secretion – Type II diabetes Characterized by normal or even increased insulin secretion but reduced sensitivity of insulin’s target cells

39. TYPE I DIABETES MELLITUS JUVENILE ONSET (IDDM) 10 % of D.M Cases No insulin Autoimmune process- selective destruction of β-cells Precise cause unknown Genetic susceptibility Environmental triggers Treatment : Insulin Dietary control Exercise

40. Type II Diabetes Mellitus Maturity onset (NIDDM) 90 % of cases Normal or increase insulin secretion Decrease sensitivity of target cells to insulin i.e. insulin resistance Cause : – Ultimate cause unknown – Various Genetic & lifestyle factors – Obesity is biggest risk factor ( 90% are obese)

41. TYPE II DIABETES MELLITUS – Link between obesity and insulin resistance Adipokines secreted by adipose tissue modulate response of target tissue o insulin – Resistine( promotes resistance ), increases in obesity – adiponektin (increase insulin sensitivity), decreases in obesity Increase FA can indirectly triggers the apoptosis ofβ- cells Treatment : Dietary control Exercise Oral hypoglycemic agents

43. 43 Acute Effects of Diabetes Mellitus

44. 44 Both insulin-dependent and insulin-independent glucose uptake is reduced in insulin resistant tissues Obesity aggravates the tissue resistance

45. REFERENCES Human physiology by Lauralee Sherwood, seventh edition Text book physiology by Guyton &Hall,11 th edition Text book of physiology by Linda.s contanzo,third edition 45