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  1. 1. Regulation of Carbohydrate Metabolism
  2. 2.  Gland with both exocrine and endocrine functions  15-25 cm long  60-100 g  Location: retro-peritoneum, 2nd lumbar vertebral level  Extends in an oblique, transverse position  Parts of pancreas: head, neck, body and tail
  3. 3. Production of Pancreatic Hormones Alpha cells produce glucagon. Beta cells produce insulin. Delta cells produce somatostatin. PP cells produce pancreatic polypeptide.
  4. 4.  Three cell types are present, A (glucagon secretion), B (Insulin secretion) and D (Somatostatin secretion)  A and D cells are located around the perimeter while B cells are located in the interior  Venous return containing insulin flows by the A cells on its way out of the islets
  5. 5.  Insulin is a polypeptide hormone, composed of two chains (A and B)  Both chains are derived from proinsulin, a prohormone.  The two chains are joined by disulfide bonds.
  6. 6. Roles of Insulin Acts on tissues (especially liver, skeletal muscle, adipose) to increase uptake of glucose and amino acids. - without insulin, most tissues do not take in glucose and amino acids well (except brain). Increases glycogen production (glucose storage) in the liver and muscle. Stimulates lipid synthesis from free fatty acids and triglycerides in adipose tissue. Also stimulates potassium uptake by cells (role in potassium homeostasis).
  7. 7.  The insulin receptor is composed of two subunits, and has intrinsic tyrosine kinase activity.  Activation of the receptor results in a cascade of phosphorylation events.
  8. 8. Activation of glycogen synthetase. Converts glucose to glycogen. Inhibition of phosphoenolpyruvate carboxykinase. Inhibits gluconeogenesis. Increased activity of glucose transporters. Moves glucose into cells.
  9. 9. Activation of acetyl CoA carboxylase. Stimulates production of free fatty acids from acetyl CoA. Activation of lipoprotein lipase (increases breakdown of triacylglycerol in the circulation). Fatty acids are then taken up by adipocytes, and triacylglycerol is made and stored in the cell. lipoprotein lipase
  10. 10.  Major stimulus: increased blood glucose levels - after a meal, blood glucose increases - insulin causes uptake of glucose into tissues, so blood glucose levels decrease. - insulin levels decline as blood glucose declines
  11. 11.  ↑ glucose uptake in most cells  ↑ glucose use and storage  ↑ protein synthesis  ↑ fat synthesis
  12. 12.  Amino acids stimulate insulin release (increased uptake into cells, increased protein synthesis).  Keto acids stimulate insulin release (increased glucose uptake to prevent lipid and protein utilization).  Insulin release is inhibited by stress-induced increase in adrenal epinephrine - epinephrine binds to alpha adrenergic receptors on beta cells - maintains blood glucose levels  Glucagon stimulates insulin secretion (glucagon has opposite actions).
  13. 13.  Chemically – high levels of glucose and amino acids in the blood  Hormonally – beta cells are sensitive to several hormones that may inhibit or cause insulin secretion  Neurally – stimulation of the parasympathetic nervous system causes insulin to be secreted. 16
  14. 14. 17 • Decreased blood glucose concentration. • Increased blood insulin concentration. • Sympathetic stimulation.
  15. 15. Structure and Actions of Glucagon Peptide hormone, 29 amino acids Acts on the liver to cause breakdown of glycogen (glycogenolysis), releasing glucose into the bloodstream. Inhibits glycolysis Increases production of glucose from amino acids (gluconeogenesis). Also increases lipolysis, to free fatty acids for metabolism. Result: maintenance of blood glucose levels during fasting.
  16. 16.  Main target tissues: liver, muscle, and adipose tissue  Binds to a Gs-coupled receptor, resulting in increased cyclic AMP and increased PKA activity.  Also activates IP3 pathway (increasing Ca++ )
  17. 17.  Glucagon prevents hypoglycemia by ↑ cell production of glucose.  Liver is primary target to maintain blood glucose levels
  18. 18.  Activates a phosphorylase, which cleaves off a glucose 1-phosphate molecule off of glycogen.  Inactivates glycogen synthase by phosphorylation (less glycogen synthesis).  Increases phosphoenolpyruvate carboxykinase, stimulating gluconeogenesis.  Activates lipases, breaking down triglycerides.  Inhibits acetyl CoA carboxylase, decreasing free fatty acid formation from acetyl CoA.  Result: more production of glucose and substrates for metabolism
  19. 19.  Increased blood glucose levels inhibit glucagon release.  Amino acids stimulate glucagon release (high protein, low carbohydrate meal).  Stress: epinephrine acts on beta-adrenergic receptors on alpha cells, increasing glucagon release (increases availability of glucose for energy).  Insulin inhibits glucagon secretion.
  20. 20.  Glucocorticoids (cortisol): stimulate gluconeogenesis and lipolysis, and increase breakdown of proteins.  Epinephrine/norepinephrine: stimulates glycogenolysis and lipolysis.  Growth hormone: stimulates glycogenolysis and lipolysis.  Note that these factors would complement the effects of glucagon, increasing blood glucose levels.
  21. 21. Hormonal Regulation of Nutrients Right after a meal (resting): - blood glucose elevated - low glucagon, cortisol, GH, epinephrine - insulin increases (due to increased glucose) - Cells uptake glucose, amino acids. - Glucose converted to glycogen, amino acids into protein, lipids stored as triacylglycerol. - Blood glucose maintained at moderate levels.
  22. 22. A few hours after a meal (active): - blood glucose levels decrease - insulin secretion decreases - increased secretion of glucagon, cortisol, GH, epinephrine - glucose is released from glycogen stores (glycogenolysis) - increased lipolysis (beta oxidation) - glucose production from amino acids increases (oxidative deamination; gluconeogenesis) - decreased uptake of glucose by tissues - blood glucose levels maintained Hormonal Regulation of Nutrients
  23. 23.  Rate at which a molecule is broken down and resynthesized.  Average daily turnover for carbohydrates is 250 g/day.  Some glucose is reused to form glycogen. ▪ Only need about 150 g/day.  Average daily turnover for protein is 150 g/day.  Some protein may be reused for protein synthesis. ▪ Only need 35 g/day. ▪ 9 essential amino acids.  Average daily turnover for fats is 100 g/day.  Little is actually required in the diet. ▪ Fat can be produced from excess carbohydrates. ▪ Essential fatty acids:  Linoleic and linolenic acids.
  24. 24.  Mainly regulated by blood [glucose].  Lesser effect: blood [amino acid].  Regulated by negative feedback.  Glucose enters the brain by facilitated diffusion.  Normal fasting [glucose] is 70-110 mg/dl.
  25. 25.  When blood [glucose] increases:  Glucose binds to GLUT2 receptor protein in β cells, stimulating the production and release of insulin.  Insulin:  Stimulates skeletal muscle cells and adipocytes to incorporate GLUT4 (glucose facilitated diffusion carrier) into plasma membranes. ▪ Promotes anabolism.
  26. 26.  Glucose homeostasis – Putting it all together Figure 26.8 Insulin Beta cells of pancreas stimulated to release insulin into the blood Body cells take up more glucose Blood glucose level declines to a set point; stimulus for insulin release diminishes Liver takes up glucose and stores it as glycogen High blood glucose level STIMULUS: Rising blood glucose level (e.g., after eating a carbohydrate-rich meal) Homeostasis: Normal blood glucose level (about 70-110 mg/100 mL) STIMULUS: Declining blood glucose level (e.g., after skipping a meal) Alpha cells of pancreas stimulated to release glucagon into the blood Glucagon Liver breaks down glycogen and releases glucose to the blood Blood glucose level rises to set point; stimulus for glucagon release diminishes
  27. 27.  Absorptive state:  Absorption of energy.  4 hour period after eating.  Increase in insulin secretion.  Postabsorptive state:  Fasting state.  At least 4 hours after the meal.  Increase in glucagon secretion.
  28. 28.  Insulin is the major hormone that promotes anabolism in the body.  When blood [insulin] increases:  Promotes cellular uptake of glucose.  Stimulates glycogen storage in the liver and muscles.  Stimulates triglyceride storage in adipose cells.  Promotes cellular uptake of amino acids and synthesis of proteins.
  29. 29.  Maintains blood glucose concentration.  When blood [glucagon] increased:  Stimulates glycogenolysis in the liver (glucose- 6-phosphatase).  Stimulates gluconeogenesis.  Skeletal muscle, heart, liver, and kidneys use fatty acids as major source of fuel (hormone- sensitive lipase).  Stimulates lipolysis and ketogenesis.
  30. 30. Insert fig. 19.10
  31. 31. Figure 22-8: Metabolism is controlled by insulin and glucagon
  32. 32.  Chronic high blood [glucose].  2 forms of diabetes mellitus:  Type I: insulin dependent diabetes (IDDM).  Type II: non-insulin dependent diabetes (NIDDM).
  33. 33. Insert table 19.6
  34. 34.  β cells of the islets of Langerhans are destroyed by autoimmune attack which may be provoked by environmental agent.  Killer T cells target glutamate decarboxylase in the β cells.  Glucose cannot enter the adipose cells.  Rate of fat synthesis lags behind the rate of lipolysis. ▪ Fatty acids converted to ketone bodies, producing ketoacidosis.  Increased blood [glucagon].  Stimulates glycogenolysis in liver.
  35. 35. Insert fig. 19.11
  36. 36.  Slow to develop.  Genetic factors are significant.  Occurs most often in people who are overweight.  Decreased sensitivity to insulin or an insulin resistance.  Obesity.  Do not usually develop ketoacidosis.  May have high blood [insulin] or normal [insulin]. Insert fig. 19.12
  37. 37.  Change in lifestyle:  Increase exercise: ▪ Increases the amount of membrane GLUT-4 carriers in the skeletal muscle cells.  Weight reduction.  Increased fiber in diet.  Reduce saturated fat.
  38. 38.  Over secretion of insulin.  Reactive hypoglycemia:  Caused by an exaggerated response to a rise in blood glucose.  Occurs in people who are genetically predisposed to type II diabetes. Insert fig. 19.13
  39. 39.  Anabolic effects of insulin are antagonized by the hormones of the adrenals, thyroid, and anterior pituitary.  Insulin, T3, and GH can act synergistically to stimulate protein synthesis.
  40. 40.  Measurement of the ability of β cells to secrete insulin.  Ability of insulin to lower blood glucose.  Normal person’s rise in blood [glucose] after drinking solution is reversed to normal in 2 hrs. Insert fig. 19.8