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18. Pancreatic function and metabolism

18. Pancreatic function and metabolism. V BS 122 2012 Luis A. Bate. Objectives. To understand the role of the pancreas in the regulation of carbohydrate metabolism To learn in depth about insulin and glucagon actions

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18. Pancreatic function and metabolism

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  1. 18. Pancreatic function and metabolism V BS 122 2012 Luis A.Bate

  2. Objectives • To understand the role of the pancreas in the regulation of carbohydrate metabolism • To learn in depth about insulin and glucagon actions • To identify tha main pathophysiologies associated with these systems (Diabetes)

  3. Reading Chapter 78 Guyton

  4. Pancreatic structures ISLETS OF LANGERHANS DUCTULES DUCTS PANCREATIC ACINI F18-1

  5. Pancreatic islets F18-2

  6. Pancreatic secretions • In addition to the digestive enzymes the pancreas serves an important endocrine role • Produces • Insulin • Glucagon • Pancreatic polypeptide • Somatostatin • Amylin F18-3

  7. Pancreatic islets α cells (Glucagon) β cells (Insulin, Amylin) D cells (Somatostatin) F cells (Pancreatic Polypeptide) F18-4

  8. INSULIN • Traditionally associated with carbohydrate metabolism • It also affects fat and protein metabolism, specially under disease conditions • Circulates in an unbound form • Half-life of 6 minutes • Circulating for 10 minutes after release F18-5

  9. PROINSULIN INSULIN α chain β chain C peptide

  10. Insulin secretion β cell Ca++ F18-6

  11. α α β β TK TK Enzyme phosphorylation Growth and gene expression Glucose transport Fat synthesis Glucose synthesis Protein synthesis EFFECT F18-7

  12. GLYCOGEN PHOSPHORYLASE GLUCOSE-6 PHOSPHATASE GLYCOGEN SYNTHASE GLUCOSE GLUCOSE-6-PHOSPHATE GLUCOKINASE 6-PHOSPHOFRUCTOKINASE FRUCTOSE-1-,6-BIPHOSPHATE ALDOLASE TRIOSE PHOSPHATE PHOSPHOENOLPYRUVATE PYRUVATE KINASE PYRUVATE DEHYDROGENASE PYRUVATE ACETYL-CoA ACETYL-CoA CARBOXYLASE MALONYL-CoA FATTY ACID SYNTHASE F18-8 FFA

  13. Use of glucose • Brain tissue can only use glucose as a fuel • Brain can uptake glucose from circulation independently of insulin • Only few types of cells permit free transport of glucose onto themselves • Brain • Liver • Erythrocytes F18-9

  14. Metabolic pathways of glucose in muscle • Once inside a cell, glucose is phosphorilated by the enzyme glucokinase • Once phosphorilated glucose cannot cross the cell membrane (leave the cell) • Unlike the liver, muscle tissues lacks glucose-6-phosphatase • Cannot release glucose into circulation • Can only use it for its own metabolism • Storage • Energy F18-10

  15. GLYCOGEN GLUCOSE-6-PHOSPHATE GLYCOGEN GLUCOSE GLUCOSE-6-PHOSPHATE TCA GLUCOSE GLUCOSE GLUCOSE FFA GLUCOSE TCA (ENERGY) FFA F18-11

  16. Sequence of events following insulin elevation • After seconds of attachment • Increased glucose uptake by cells • Muscle and adipose cells not on neurons • Glucose is phosphorylated • Enters metabolic pathway • Permeability to aa increases • After 10-15 minutes • Increases internal enzymes • After hours or days • Increases translation of mRNA F18-12

  17. Role of insulin • Lowers the circulatory concentrations of glucose, fatty acids and amino acids • Enhances storage of these in large molecules • Glycogen • Triglycerides • Proteins F18-13

  18. Effect of insulin on carbohydrates • Muscle absorption of glucose • Conversion of glucose to glycogen for storage • Liver uptake of glucose • Conversion of glucose to glycogen for short storage • Inhibition of gluconeogenesis in the liver F18-14

  19. Effect of insulin on fat metabolism • After the deposit of glycogen is full (6% liver weight) it promotes the synthesis of fat in the liver • Exported to circulation as VLDL • Uptake by adipose tissue • Stored as fat • Inhibit hormone-sensitive lipase (no FFA release from adipocytes) • Promotes glucose uptake in adipocytes • Synthesis of glycerol and FFA F18-15

  20. Effect of insulin on protein metabolism • Promotes protein synthesis and storage • Increases uptake of amino acids • Increases translation of mRNA • Turns on ribosomal assembly • Inhibits catabolism • In liver reduces gluconeogenesis (amino acid sparing) F18-16

  21. Effect of the lack of insulin on protein metabolism • Protein storage stops • Increases plasma amino acids concentration • Used for gluconeogenesis • Convertion to urea and excreted • Overall protein wastage • Causes weakness • Organ malfunction F18-17

  22. Insulin catabolism • Takes place in the liver and kidney • Enzyme insulinase • Disulfide bonds are reduced • Peptide enzymes chop chains into small peptides and amino acids F18-18

  23. Glucagon • 29 amino acid protein • Produced by alpha cells • Released when circulatory glucose is low • Contributes to elevation of circulatory glucose F18-19

  24. Effect of glucagon on glucose metabolism • Promotes glycogenolysis • Through a complex enzymatic cascade • Increases gluconeogenesis in the liver • Promotes amino acid uptake • Convert them to glucose F18-20

  25. Regulation of circulatory glucose HYPOGLYCEMIA HYPERGLYCEMIA α β α β INSULIN GLUCAGON NORMOGLYCEMIA F18-21

  26. Regulation of glucagon secretion • High circulatory glucose inhibits secretion • Low concentration enhances secretion • Increased circulating amino acids increase secretion • Permits conversion to glucose • Exercise increases glucagon secretion F18-22

  27. Other effects of glucagon • Activates adipose cell lipase • Makes available fatty acids for energy • Inhibits storage of triglycerides in the liver • Enhances heart strength • Increases irrigation of kidney • Enhances bile secretion • Inhibits gastric secretion F18-23

  28. Somatostatin inhibits both glucagon and insulin • Acts locally in islets • SS decreases stomach, duodenum and gallbladder motility • SS inhibits secretion and absorption by the GIT • Amylin is a protein produced by the pancreas which selectively inhibits insulin stimulated glucose utilization and glycogen deposition in muscle • Amylin does not affect adipocyte glucose metabolism F18-24

  29. Pancreatic cell interaction β INSULIN α D GLUCAGON SOMATOSTATIN F18-25

  30. Pathophysiology • Diabetes Mellitus • Type I diabetes (Insulin-dependent) • Due to lack of insulin production • Juvenile diabetes mellitus • Type II diabetes (non insulin-dependent) • Due to decrease sensitivity of tissue to insulin (insulin resistance) • Adult-onset diabetes F18-26

  31. Type I diabetes • Damage of B cells • Viral infection, autoimmune disorder, genetic predisposition • Appears at a young age • Very rapidly • High glucose concentration • Loss of glucose in urine • Osmotic diuresis (dehydration) • Polyurea F18-27

  32. Cont . . . • Structural changes in tissue • Malfunction of blood vessels • Risk of heart attack, stroke, kidney disease, retinopathy and blindness, ischemia and gangrene of limbs • Also neurological problems • Switch to use of fats • Causes metabolic acidosis • Diabetic coma... Death F18-27

  33. Type II diabetes • Accounts for 80-90% of cases • Manifest at mature age (adult onset diabetes) • Increased plasma insulin • Many metabolic abnormalities • Except ketosis • Patients usually obese • Can be managed through diet F18-28

  34. Summary • Reviewed the role of the pancreas in the regulation of carbohydrate metabolism • Identified the functions of insulin and glucagon • Pointed out the most common pathophysiologies associated with these systems (Diabetes)

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