Insulin, Glucagon, and Diabetes Mellitus

1. Insulin, Glucagon, and Diabetes Mellitus Prof. dr. ZoranValić Department of Physiology University of Split School of Medicine

2. digestive functions • two important hormones: insulin and glucagon (crucial for normal regulation of glucose, lipid, and protein metabolism) • other hormones: amylin, somatostatin, and pancreatic polypeptide

3. acini (secrete digestive juices) • islets of Langerhans (secrete insulin and glucagon directly into the blood) • 1-2 million islets of Langerhans (0.3 mm in diameter) • three major types of cells: alpha, beta, and delta cells

5. beta cells – 60%, lie mainly in the middle of each islet, secrete insulin and amylin • alpha cells – 25%, secrete glucagon • delta cells – 10%, secrete somatostatin • PP cells – present in small numbers, secretepancreatic polypeptide? • insulin inhibits glucagon secretion, amylin inhibits insulin secretion, and somatostatin inhibits secretion of insulin and glucagon

7. Insulin and Its Metabolic Effects • Bantingand Best (1922) – isolated inzulin • insulin has always been associated with "blood sugar“, but it has profound effect on metabolism of fat (acidosis, arteriosclerosis) and proteins • insulin secretion is associated with energy abundance

8. excess amounts of carbohydrates cause increase in insulin secretion • insulin stores the excess carbohydrates as glycogen (liver and muscles) • inzulin storesadipose tissue • inzulin promotes amino acid uptake by cells and conversion of amino acids into protein • inzulin inhibits the breakdown of proteins

9. Insulin Chemistry and Synthesis • small protein (5808) • it is composed of two amino acid chains connected by disulfide linkages • spliting of the chains – loss of activity • translation of the insulin RNAby ribosomes preproinsulin (11500)  in the ERproinsulin (9000)  in Golgi apparatus insulinand the C chain peptide

12. circulates almost entirely in an unbound form • plasma half-life averages only about 6 min • cleared from circulation within 10 to 15 min • degraded by the enzyme insulinase mainly in the liver, to a lesser extent in the kidneys and muscles

13. Activation of Target Cell Receptors and Resulting Effects • activation of membrane receptor protein • autophosphorylation of beta subunits activation of tyrosine kinase phosphorylation of multiple other intracellular enzymes including a group called insulin-receptor substrates (IRS)

15. after few seconds 80% of cells increase their uptake of glucose (muscle and adipose cells) • cells become more permeable for many amino acids, potassium and phosphate ions • within 10-15 min change in activity of many intracellular metabolic enzymes • within few hours or days – rates of translation and transcription

16. Inzulin  Muscle Glucose Uptake and Metabolism • muscle tissue depends on fatty acids, resting muscle membrane is only slightly permeable to glucose • moderate or heavy exercise – fibers more permeable in absence of insulin • few hours after a meal (BGC is high and pancreas is secreting large quantities of insulin)

17. if the muscles are not exercising after a meal, glucose is stored in the form of muscle glycogen (2-3%) • spurts of anaerobic energy • insulin facilitates glucose transport through the muscle cell membrane

20. Insulin  Liver Uptake, Storage, and Use of Glucose • storing most of glucose in the form of glycogen after a meal and its release between two meals • inactivates liver phosphorylase (glikogen) • increasing the activity of glucokinase(initial phosphorylation of glucose) • increase activity of glycogen synthase • about 5-6% of the liver mass (100g)

21. Glucose Release Between Meals • pancreas decrease its insulin secretion • stopping synthesis of glycogen and preventing uptake of glucose in the liver • lack of insulin & increase of glucagon activates phosphorylase(splitting of glycogen into glucose phosphate) • activation ofglucose phosphatase (spliting of phosphate radical, diffusion of glucose)

22. insulin promotes conversion of excess glucose into fatty acids (lipoproteins – fat) • inzulin inhibits gluconeogenesis (decreasing the quantities and activities of the liver enzymesand availability of precursors required for gluconeogenesis)

23. Lack of effect of insulin on glucose uptake and usage by brain • most of the brain cells are permeable to glucose and can use glucose without the intermediation of insulin • only glucose for energy • when the BGC falls too low (1-3 mmol/L) – hypoglycemic shock (nervous irritability, fainting, seizures, and even coma)

24. Effect of Insulin on Fat Metabolism • not quite as visible, but equally important • long-term effect of insulin lack – extreme atherosclerosis (MI, cerebral strokes) • insulin promotes fat synthesis and storage • increases the utilization of glucose (fat sparer) • promotes fatty acid synthesis (in liver):

25. insulin increases transport of glucose into liver cells (glucose pyruvate  acetyl-CoA  fatty acids) • excess of citrate and isocitrate ions formed by citric acid cycle when excess amounts of glucose are being used for energy activation of acetyl-CoAcarboxylase • formation of triglyceridesand release from liver cells in form of lipoproteins; insulin activates lipoprotein lipase in adipose tissue

26. Storage of Fat in Adipose Cells • insulin inhibits the action of hormone-sensitive lipase (hydrolysis of the triglycerides in fat cells) • insulin promotes glucose transport through the cell membrane into the fat cells; forms large quantities of α-glycerol phosphate (base for glycerol)

27. Insulin Deficiency Increases Use of Fat for Energy • hormone-sensitive lipase in the fat cells becomes strongly activated (release of fatty acids and glycerol into circulating blood) • increases plasma cholesterol and phospholipid concentrations (3x increase inplasma lipoproteins) • ketosis and acidosis (acetoacetic acid – acidosis, β-hydroxybutyric acid & acetone)

30. Effect of Insulin on Protein Metabolism and on Growth • insulin stimulates transport of many amino acids into the cells (valine, leucine, isoleucine, tyrosine, and phenylalanine) • increases translation of mRNA ("turns on" the ribosomal machinery) • increases transcription of DNA (enzymes) • inhibits catabolism of proteins (lysosomes) • depresses gluconeogenesis (enzymes)

31. insulin and growth hormone interact synergistically to promote growth • insulin is essential for growth • two hormones function synergistically to promote growth • each promotes cellular uptake of a different selection of amino acids, all of which are required for growth

33. Mechanisms of Insulin Secretion • response to increased BGC • glucose transporters (GLUT 2) in beta cells • glucose is phosphorylated to glucose-6-phosphate by glucokinase • “rate limiting step” • ATP is formed – inhibits KATPchannels (sulfonylurea) – openingCachannels – exocytosis of inzulina

35. Control of Insulin Secretion • formerly, it was believed that insulin secretion was controlled almost entirely by BCG

37. increased BGC stimulates insulin secretion • at BGC 4,5-5,0 mmol/L (80-90 mg/100 ml) – lučenje 25 ng/min/kg • increase in BGCinsulin secretion increases markedly in two stages

40. feedback relation between BGC and insulin secretion rate • BGC of 20-30 mmol/L (400-600 mg/100 ml)insulin secretion is reaching a peak (10-25x basal level)

43. Other Factors That Stimulate Insulin Secretion • amino acids (arginine & lysine; little alone, but combined with BGC x2; important) • gastrointestinal hormones (gastrin, secretin, cholecystokinin, GIP; amplify the action of glucose; anticipatory effect) • other hormones and autonomic nervous system (glucagon, hGH, cortisol, progesterone and estrogen; prolonged secretion – exhaustion of beta cells)

44. Switching Between Carbohydrate and Lipid Metabolism • insulin promotes use of carbohydrates for energy, depresses the utilization of fats • control – BGC • hGH, cortisol – are secreted in response to hypoglycemia, inhibit cellular utilization of glucose while promoting fat utilization • epinephrine – increasing both (BGC and fatty acids)

45. Glucagon and Its Functions • alpha cells of the islets of Langerhans • increaseBGC • large polypeptide (3485); composed of a chain of 29 amino acids • hyperglycemic effect/hyperglycemic hormone

46. Effects on Glucose Metabolism • breakdown of liver glycogen (glycogenolysis; adenylylcyclase cAMP protein kinase  phosphorylase b phosphorylase a  degradation of glycogen into glucose-1-phosphate  dephosphorylation  BGC; amplifying mechanism)

47. Effects on Glucose Metabolism • increased gluconeogenesis in the liver (increase in the rate of amino acid uptake by the liver cells and then the conversion of many of the amino acids to glucose by gluconeogenesis(pyruvate phosphoenolpyruvate))

48. Other Effects of Glucagon • activation of adipose cell lipase • inhibition of storage of triglycerides in liver • in high concentrations : • enhances the strength of the heart, increases blood flow in some tissues, especially the kidneys, enhances bile secretion, inhibits gastric acid secretion

49. Regulation of Glucagon Secretion • increased BGC inhibits glucagon secretion (exactly opposite from effect of insulin) • increased blood amino acids stimulate glucagon secretion (same as insulin; alanine and arginine) • exercise stimulates glucagon secretion (4-5x, prevents a decrease in BGC)