1. Endocrine function of Pancreas-II Glucagon; glycogenolytic, gluconeogenic, lipolytic and ketogenic

2. Learning Outcomes At the end of the lecture, students should be able to: Describe the physiological actions of glucagon. Describe the physiological effects of somatostatin and other pancreatic hormones. List the consequences of insulin deficiency & insulin resistance and explain physiological basis of these abnormalities.

3. Glucagon alpha cells Polypeptide hormone secreted from alpha cells of islets of Langerhans Promotes release of energy ( Promotes release of energy (catabolic in nature) Promotes glucose sparing Promotes glucose sparing for nervous system by diverting body cells to utilizing other sources of energy

4. Glucagon Composed of 29 amino acids in a single chain Molecular weight of 3500 Synthesized from pre-proglucagon precursor by alpha cells of islets Actual synthesized as proglucagon and undergo sequential degradation and form glucagon Stored in dense granules and released in response to Ca++ in alpha cell by process of exocytosis

5. Mechanism of Action o Binds with specific receptor and activate cAMP as second messenger– causes modification in enzymatic activities by phosphorylation. o Act competitively at similar points as insulin, on liver and adipose tissue o Receptors are mainly present on liver and adipose tissues

6. Actions of Glucagon

7. Action on Carbohydrate metabolism o Increased Glycogenolysis- breakdown of glycogen in to Glucose 1- phosphate which in-turn converted in to glucose. o Glucose 1- phosphate is product of phosphorylation process, can not be converted back in to glycogen. o Net effect is increased blood glucose level promptly.

8. Action on Carbohydrate metabolism o Increased Gluconeogenesis- formation of glucose from lactate, pyruvate, glycerol and amino acids. o Begins soon after the exhaustion of glycogen present in the liver o Gluconeogenesis responsible for slow but sustained maintenance of blood glucose level. o The effect mediated by activation of enzyme system converting pyruvate to phosphopyruvate. o Also increase amino acids transport from blood to liver.

9. Action on Lipid metabolism Powerful lipolytic hormone Act via cAMP system and activate lipase enzyme present in Adipose tissue and cause release of free fatty acids and glycerol in circulation FFA in liver oxidised and results in to production of energy Prevent synthesis of triglycerides from free fatty acids by inhibiting acetyl Co A carboxylase enzyme. FFA, spared, undergo Beta oxidation and results in production of ketoacids.

10. Effect on Protein Metabolism Increases uptake of amino acids by liver cells Increased rate of gluconeogenesis Consequently decrease plasma level of amino acids

11. Calorigenic effects of Glucagon Related to increased deamination of amino acid in the liver. Requires the presence of glucocorticoids and thyroid.

12. Other actions of Glucagon Inhibition of renal tubular absorptions leading to natriuresis Modest increase in force of contraction of heart probably due to activation of Adenylyl cyclase. Known to stimulate secretion of growth hormone, insulin and pancreatic somatostatin Has role in regulation of appetite as it may act locally in CNS with feeding center.

13. Glucagon Regulation Via Glucose Adipose tissue Glucagon secretion Glucose spared Plasma fatty acids Lipolysis Alpha cells in pancreas Plasma glucose Negative feedback Glycogenolysis Liver Gluconeogenesis

14. Role of Plasma Amino Acids in secretion Protein rich diet mainly arginine and alanine, increases glucagon secretion. Converts the Amino acids in to glucose. Increased blood glucose level inhibit secretion of glucagon This is due to feedback relationship between blood amino acid and glucagon secretion.

15. amino acids (after a protein meal) secretion of glucagon conversion of the amino acids to glucose Secretion of Insulin Increase uptake of blood glucose Hypoglycemic featuresHyperglycemic Features Glucagon Regulation Via Amino Acids Counter balance the effect of Insulin after meal

16. Nervous regulation of Glucagon Secretion Sympathetic stimulation increases Glucagon secretion Mediated by beta adrenergic receptor stimulation Vagal stimulation and Ach acutely increases glucagon secretion

17. Insulin and Glucagon Release

18. Regulation of blood glucose levels by insulin and glucagon.

19. Synthesizes by delta cells of the islets Polypeptide containing 14 amino acids, Extremely short half-life of only 3 minutes in the circulation Acts along with insulin and glucagon and co- ordinate the nutrients input with substrate disposal. Somatostatin; Source

20. Secretion somatostatin increased blood glucose increased amino acids increased fatty acids increased concentrations of some of GI hormones Somatostatin; Regulation of Secretion

21. Principal role~  decreases the utilization of the absorbed nutrients by the tissues,  preventing rapid exhaustion of the food and therefore making it available over a longer period of time Physiologic Actions

22. secretion of both insulin and glucagonActs locally on islets of Langerhans & inhibit secretion of both insulin and glucagon. Increases the motility of the stomach, duodenum, and gallbladder. Decreases secretion of HCl, Pepsin, gastrin, secretin, intestinal and pancreatic juices Inhibit absorption of glucose, Xylose, and triglycerides across the mucosal membrane.

23. Amylin 37–amino acid peptide hormone stored in β-granules, and released along with insulin Commonly found in the majority of patients with type 2 diabetes mellitus,Commonly found in the majority of patients with type 2 diabetes mellitus, thought to contribute to destruction of the pancreatic -cell.thought to contribute to destruction of the pancreatic -cell.

24. Amylin Its plasma conc. increase after a meal or glucose infusion. Decrease postprandial secretion of glucagon and slowing gastric emptying. In muscle, opposes glycogen synthesis and activates glycogenolysis and glycolysis, thereby increasing lactate production.

25. Pancreatic Polypeptide Synthesis;- Synthesized by PP cells of islet Has 36 amino acids Actions;- Best known action is inhibition of exocrine pancreatic secretion Serve as markers for pancreatic tumors Secretion;- Food ingestion trigger the secretion via GIT cholinergic stimulation. Hypoglycemia increases the secretion while glucose ingestion decreases the secretion

26. Consequences of Insulin deficiency & Insulin resistance

27. Syndrome of impaired carbohydrate, fat, and protein metabolism Consequences of Insulin deficiency & Insulin resistance Diabetes mellitus (IDDM)~ T1 caused by lack of insulin secretion Diabetes mellitus (NIDDM) ~ T2 caused by insulin resistance (decreased sensitivity of target tissues to action of insulin)

28. Consequences of insulin deficiency & insulin resistance: Features Hyperglycemia- increased blood sugar level Glycosuria- excretion of glucose into the urine Polydipsia- patient displays excessive thirst Polyuria- excessive or abnormally large production or passage of urine Polyphagia- excessive hunger or increased appetite Ketosis, acidosis, coma and eventually death if left untreated

29. Type 1 Diabetes Immune mediated, absolute insulin deficiency due to autoimmune destruction of β cells in the pancreatic islets Genetic Susceptibility Environmental Factors / Viral infection Islet Auto Antibodies attack Beta cells β cell destruction Insulin deficiency ++ Type 1 Diabetes

30. Type 2 Diabetes Individuals with insulin resistance or insensitivity of tissues to insulin. Maybe due to deficiency of GLUT 4 in insulin sensitive tissues, or genetic defects in the insulin receptor or insulin molecule itself. Secretory defect Insulin Resistance in Target cells Beta cell Relative Insulin Deficiency Type 2 Diabetes (T2D) β cell exhaustion Beta cell defect Genetic Low Birth weight Excess food Obesity TV Sedentary lifestyle Motorization

31. Fundamental Defects are…… Reduced entry of glucose into various peripheral tissues Increased liberation of glucose into circulation from liver. Therefore there is an extracellular glucose excess and in many cells an intracellular glucose deficiency – “starvation in the midst of plenty”. Various signs and symptoms in diabetes are due to disturbances in carbohydrate, protein and lipid metabolism.

32. Glycosuria Polyuria, Polydipsia and Polyphagia The renal threshold for glucose is 180 mg% i.e. if the plasma glucose value is raised above 180 mg%, glucose will start appearing in urine (glycosuria). As glucose is lost in the urine, it takes along with it water (osmotic diuresis) leading to increased urination (polyuria ). o consequences of disturbed Carbohydrate metabolism

33. Since lot of water is lost in the urine, it leads to dehydration and increased thirst (polydipsia). Electrolytes are also lost in the urine Glycosuria Polyuria, Polydipsia and Polyphagia o consequences of disturbed Carbohydrate metabolism

34. The quantity of glucose lost in urine is enormous and thus to maintain energy balance the patient takes in large quantities of food. Also because of decreased intracellular glucose, there is reduced glucose utilization by the ventromedial nucleus of hypothalamus (satiety center) and is probably the cause for the hyperphagia. Consequences of disturbed Carbohydrate metabolism

35. The principal abnormalities are acceleration of lipid catabolism with increasing formation of ketone bodies and decreased synthesis of fatty acids and triglycerides. Acidosis and ketosis is due to overproduction of ketone bodies (acetoacetate, acetone and β-hydroxybutyrate). Most of the hydrogen ions liberated from acetoacetate and β-hydroxybutyrate are buffered, but still severe metabolic acidosis still develops. The low pH (metabolic acidosis) stimulates the respiratory center and produces the rapid, deep, regular kussmaul breathing. Liver Low Insulin Accelerated lipid catabolism ↑ Ketone Bodies Metabolic Acidosis Ketonuria Fruity odour Coma / death Kussmaul breathing

36.  The acidosis and dehydration can lead to coma and even death. Triglycerides Free fatty acids (FFA) + glycerol lipase plasma level of FFA increases to doubles  Insulin inhibits the hormone sensitive lipase in adipose tissue and in the absence of insulin, the plasma level of FFA increases to doubles. acetyl Co A converted to ketone bodies  In liver and other tissues, the FFA are catabolized to acetyl Co A, and the excess acetyl Co A is converted to ketone bodies. Hormone-sensitive lipase

37. ↑↑ protein breakdown  muscle wasting ↓ protein synthesis ↑ plasma amino acids and nitrogen loss in urine leading to negative nitrogen balance and protein depletion. Protein depletion is associated with poor resistance to infections.

38. Micro vascular complications like retinopathy, nephropathy and neuropathy involving the peripheral nerves and autonomic nervous system. Macro vascular complications like stroke, peripheral vascular disease and myocardial infarction due to increased atherosclerosis caused by increased amounts of LDL.

39. Some Causes of Insulin Resistance Obesity/overweight (especially excess visceral adiposity) Excess glucocorticoids (Cushing’s syndrome or steroid therapy) Excess growth hormone (acromegaly) Pregnancy, gestational diabetes Polycystic ovary disease Lipodystrophy (acquired or genetic; associated with lipid accumulation in liver) Auto antibodies to the insulin receptor Mutations of insulin receptor Mutations of the peroxisome proliferators’ activator receptor g(PPARg) Mutations that cause genetic obesity (e.g., melanocortin receptor mutations) Hemochromatosis (a hereditary disease that causes tissue iron accumulation)