1. Endocrine function of Pancreas Insulin-secretion, action and regulation

2. Learning Outcomes At the end of the lecture, students should be able to: List the hormones produced by each of the cell types in the islets of the pancreas and explain why the pancreas is both an endocrine and exocrine gland. Describe insulin receptors and its mechanism of action of insulin. List the hormones that affect the plasma glucose concentration and briefly describe the action of each of the hormone. List the major factors that affect the secretion of insulin. Explain the nutrient, neural, and hormonal mechanisms that regulate pancreatic hormone release

3. Normal Pancreatic Function Exocrine pancreas aids digestion Bicarbonate Lipase Amylase Proteases Endocrine pancreas (islets of Langerhans) Beta cells secrete insulin Alpha cells secrete glucagon Other hormones such as Amyelin, somatostatin and Pancreatic Polypeptide.

4. Pancreas – Endocrine/Exocrine Mixed gland performed exocrine and endocrine function Plays a central role in digestion and in metabolism, utilization, and storage of energy substrates. Endocrine function through the release of insulin and glucagon to regulate events to maintaining glucose homeostasis. Exocrine function through secretions of acini cells, connected to the pancreatic duct and into the duodenum. Product of the pancreatic exocrine cells (alkaline fluid rich with digestive enzymes) secreted into the small intestine to aid in the digestive process.

5. exocrine pancreas is a highly lobulated gland consisting of clusters of secretory cells forming acini and a complex branched ductal system. The pancreatic acini consist of pyramidal shaped cells with their apexes projecting towards the lumen of a minute duct. The acinar cells are typical protein secreting cells. Pancreas – Endocrine/Exocrine

6. Endocrine Cells : Islets of Langerhans o Small clusters of endocrine cells, richly vascularised, Embedded within the acini. o localization of these cell types has a particular pattern. o β-cells located centrally, surrounded by α and δ cells. This arrangement plays a role in the cell-to- cell paracrine regulation of hormone release. o represent only 1–2% of the mass of the pancreas, they receive about 10–15% of the pancreatic blood flow

7. o β-cells constitute about 73–75% ~ principal secretory product is insulin. o α cells account for about 18–20% responsible for glucagon secretion. o δ cells about 4–6% secrete somatostatin, o Smaller number of cells PP Cells (1%) secrete pancreatic polypeptide. Islets of Langerhans-

8. Types of Cells and secretions α Cells 25% 25% β Cells 25% 25% δ Cells 10% 10% PP Cells InsulinInsulinGlucagonGlucagon AmyelinAmyelinSomatostatinSomatostatin PPPP

9. Insulin: Anabolic hormone Best and Banting Discovered by Best and Banting in 1922 Increase Main function~ Increase storage of glucose, fatty acids and amino acids. Excesshypoglycemia Excess causes hypoglycemia leading to convulsions and unconsciousness. Deficiency diabetes Deficiency results in complex and debilitating disease~ diabetes

10. Insulin receptor combination of four subunits held together by disulfide linkages: two alpha subunits that lie entirely outside the cell membrane two beta subunits that penetrate through the membrane, protruding into the cell cytoplasm.

11. The insulin receptor. Insulin binding to the  -chains transmits a signal through the transmembrane domain of the  -chains to activate the tyrosine kinase activity CYTOPLASM EXTRACELLULAR NH 3 + S S S S Insulin - OOC -S-S- + 3 HN COO -  -subunits  -subunits Transmembrane domain Tyrosine kinase domain + 3 HN NH 3 + - OOC COO - Plasma membrane S S S S

12. Mechanism of Action The receptor tyrosine kinase activity begins a cascade of cell phosphorylation that increases or decreases the activity of enzymes, including activation of (IRS) insulin receptor substrates, that mediate the effects of glucose on glucose, fat, and protein metabolism. For example, glucose transporters are moved to the cell membrane to facilitate glucose entry into the cell.

13. Effects of activated IRS Increase glucose uptake Increase glucose uptake especially in by muscle and adipose tissue. Increase permeability Increase permeability of cell membrane for amino acids, K+ and phosphate ions. activity of many more intracellular enzymes Change in activity of many more intracellular enzymes. remodeling the cellular enzymatic machinery. Rate of translation of mRNAs at ribosomes to form new protein as well as transcription of DNA to achieve metabolic goals by remodeling the cellular enzymatic machinery.

14. Hormones and Plasma Glucose concentration The hormones which decrease blood glucose level 1. Insulin 2. Somatostatin The hormones which increases blood glucose level 1. Glucagon 2. Growth hormone, 3. ACTH 4. Cortisol, 5. Thyroxine 6. Epinephrine 7. Amyelin, 8. Pancreatic Polypeptide

15. Insulin Stimulates Cellular Glucose Uptake Liver Skeletal Muscle Adipocytes Pancreas Insulin

16. Physiological Action of Insulin

17. Actions of Insulin

18. Effects of Insulin Rapid (seconds): Increased transport of glucose, amino acids, and K+ into insulin sensitive cells. Intermediate (minutes): Stimulation of protein synthesis Inhibition of protein degradation Activation of glycogen synthase and increased glycogenesis Inhibition of phosphorylase and gluconeogenic enzymes (decreased gluconeogenesis) Delayed actions (hours): Increase in mRNAs for lipogenic and other enzymes (increased lipogenesis)

19. On carbohydrate metabolism.. Reduces rate of release of glucose from the liver by inhibiting glycogenolysis stimulating glycogen synthesis stimulating glucose uptake stimulating glycolysis inhibiting gluconeogenesis Increases rate of uptake of glucose into all insulin sensitive tissues, notably muscle and adipose tissue.

20. On protein metabolism Stimulates transport of free amino acids across the plasma membrane in liver and muscle. Stimulates protein synthesis and reduces release of amino acids from muscle.

21. On lipid metabolism… Decreases rate of release of free fatty acids from adipose tissue. Stimulates synthesis of fatty acids and also conversion of fatty acids to triglycerides in liver.

22. Effects on Adipose Tissue Insulin -sensitive reactions, including 1. Transport of glucose into adipose cell; 2. Conversion of excess glucose to glycogen; 3. Decarboxylation of pyruvate 4. Initiation of fatty acid synthesis 5. Uptake of fatty acids from circulating lipoproteins. Storage of fat in adipose tissue.

23. Effects on Muscle 1.Transport of glucose into muscle cells 2.Phosphorylation of glucose by hexokinase 3.Storage of glucose as glycogen 4.Addition of the second phosphate by phosphofructokinase 5.Inhibition of fatty acid entry into mitochondria by malonyl CoA

24. Effects of Insulin on protein turnover in muscle. 1.Increase uptake of amino acids from blood by stimulating their transport across the plasma membrane. 2.Increase protein synthesis by promoting phosphorylation of the initiation factors 3.Enhanced attachment of mRNA to ribosomes. 4.Decrease protein degradation (decreasing activity of the proteasomal protein degrading apparatus and by modulating the protease activity). 1 2 3 4

25. Effects on Liver Promote glycogen synthesis Prevents breakdown of the stored glycogen in the liver cells. Insulin causes enhanced uptake of glucose from the blood by the liver cells. insulin promotes the conversion of all this excess glucose into fatty acids.

26. Effect on Lipogenesis in liver 1. Increases the activity of acetyl CoA activating acetyl-CoA carboxylase, the enzyme required to carboxylate acetyl-CoA to form malonyl-CoA, the first stage of fatty acid synthesis. 2. Most of the fatty acids are then synthesized within the liver itself and used to form triglycerides. 3. Activates lipoprotein lipase 3. Activates lipoprotein lipase splits the triglycerides again into fatty acids, absorbed into the adipose cells, where they are again converted to triglycerides and stored

27. Action of Glucagon Increases the blood glucose level by Enhancing release of glucose from glycogen; Increased synthesis of glucose from amino acids or fatty acids. Action of Growth Hormone Increases the blood glucose level by Decreased glucose uptake in muscle and adipose tissue cells Increased glucose production by liver cells Antagonize the action of insulin

28. Action of Thyroxine Increases the blood glucose level by Increases glycolysis, gluconeogenesis, Increases absorption of sugars from intestine Action of ACTH Increases the blood glucose level by Enhances release of cortisol Enhances release of fatty acids from adipose tissue.

29. Action of Epinephrine Enhances release of glucose from glycogen; Enhances release of fatty acids from adipose tissue.

31. Receptors: Mechanism of secretion functions Pancreatic β -cell functions as a fuel sensor. Glucose is the principal stimulus for insulin release from the pancreatic -cells, In addition, other modulators of insulin secretion such as; Nutrients (amino acids), Hormones (cortisol, growth hormone, glucagon-like peptide-1 (GLP-1), Somatostatin, and epinephrine), Neurotransmitters (norepinephrine and acetylcholine).

32. Mechanism of secretion

33. Release of insulin Pulsatile and rhythmic Pulsatile and rhythmic in nature Acute and delayed rise Important for achieving maximal physiologic effects. suppression of liver glucose production insulin-mediated glucose disposal by adipose tissue critical in the suppression of liver glucose production and in insulin-mediated glucose disposal by adipose tissue. Insulin release rises after a meal in response to the increases in plasma levels of glucose and amino acids.

34. Synchronized increase in insulin release is thought to be the result of recruitment of -cells to release insulin. Proposed mechanisms include allowing the passage of ions and small molecules; membrane depolarization, aiding the propagation of the synchronization between the cells; glucose-induced changes in the extracellular potassium concentration and in nitric oxide. Intra -pancreatic neural, hormonal, and substrate factors – play role in the pulsatile pattern of insulin release. Release of insulin

35. Increased blood Glucose level causes increase secretion of insulin biphasic Secretion is biphasic~ first phase -- acute about 10 fold (within 3-5 min) Second phase- rise after first phase (after 20-30 min) Insulin Secretion- Phasic

36. Insulin Secretion- Acute Phase immediate dumping 1.First phase rise ~ due to immediate dumping of available preformed insulin stored in vesicles of Beta Cells. 2.Gradually decline to half way of normal level.

37. Gradual rise after 30 min or so. Reaches higher peak than first rise. Reaches plateau within 2-3 hours as long as BSL remain elevated. Due to Activation of enzyme system responsible for synthesis of insulin in beta cells. Additional release of preformed insulin remain available. Insulin Secretion- Delayed Phase

38. Control of Insulin Secretion

39. Regulation of Insulin secretion Earlier belief Earlier belief ~ Secretion is regulated almost entirely Blood Glucose level; not true. Metabolic factorsamino acidshormonal & neural Metabolic factors such as blood amino acids as well as other hormonal & neural factors ~ controlling insulin secretion.

40. Regulation: Feedback Mechanism  Principal Mechanism  Based on negative feedback  Blood Glucose level above normal promote secretion of insulin  Below normal circulating blood glucose level inhibit secretion of insulin

41. Regulation of Insulin ; Amino Acids Potentiate the glucose stimulus for insulin secretion Increase Amino acids cause small increase in insulin secretion. But in condition with increased blood glucose concentration secretion of insulin ~ doubled most potent AA are arginine and lysine. Stimulation of insulin secretion by amino acids ;- proper utilization of excess amino acids in the same way that it is important for the utilization of carbohydrates. promotes transport of amino acids into the tissue cells as well as intracellular formation of protein.

42. Growth hormone and Cortisol enhance secretory activity of beta cells Growth hormone and cortisol enhance secretory activity of beta cells in response to hypoglycemia. Conversely, insulin secretion is reduced when either is deficient. Excessive growth hormone or cortisol decreases tissue sensitivity to insulin and can produce diabetes

43. Regulation: role of catecholamine Epinephrine or nor epinephrine virtually shut off Insulin secretion by either the circulation or sympathetic neurons. Effect is seen not only as a response to low blood glucose as well as high blood glucose level. It is mediated through α 2 adrenergic receptors on the surface of beta cells. Physiologic significance ~ remove the major restraint on mobilization of metabolic fuels needed to cope with an emergency.

44. Gastrointestinal Hormones Some of the GI Hormones causes a moderate increase in insulin secretion such as Gastrin, Secretin Cholecystokinin Gastric inhibitory peptide (GIP). Released in the gastrointestinal tract after meal as preparation for the glucose and amino acids to be absorbed from the meal. Mechanism is same as amino acids Increase the sensitivity of insulin

45. Other Hormones Directly increase insulin secretion or potentiate the glucose stimulus for insulin secretion Glucagon Growth hormone, Cortisol, Progesterone Estrogen. Prolonged secretion of any one of them in large quantities can occasionally lead to exhaustion of the beta cells, thereby increase risk for developing diabetes mellitus. Prolonged high pharmacological doses of such hormones often results in Diabetes Diabetes is particularly common in giants or acromegalic, people with growth hormone-secreting tumors, or in people whose adrenal glands secrete excess glucocorticoids.