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PHYSIOLOGY OF PANCREAS

PHYSIOLOGY OF PANCREAS. S. Sh. Sadr MD Professor of Tehran University Department of Physiology. General Informations. W : 50 – 75 gr Langerhans Islet : 0.5 – 1.5 million Histology : α : 20 – 30 % ; Glucagon (around of islet) β : 60 – 80 % ; Insulin (center of islet)

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PHYSIOLOGY OF PANCREAS

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  1. PHYSIOLOGY OF PANCREAS S. Sh. Sadr MD Professor of Tehran University Department of Physiology

  2. General Informations • W : 50 – 75 gr • Langerhans Islet : 0.5 – 1.5 million • Histology : • α : 20 – 30 % ; Glucagon (around of islet) • β : 60 – 80 % ; Insulin (center of islet) • δ : 8 % ; Sumatostatin & Gastrin (between α, β) • PP or F : variable ; pancreatic polypeptide)

  3. Insulin • W : 6000 d • 51 aa (A chain = 21, B chain = 30) • Pro-insulin : 9000 d, 84 aa (= 51+33) • C-peptide : 33 aa • Store : 4 u/kg (in adult = 200 u) • Gene on short arm of Chr. 11

  4. Secretion of Insulin • 1- Basal secretion : • Continuous, 1 u/h • 2- Stimulated secretion : • IV Glu. : peak : after 3 – 5 min = 8 – 10 x BS • Oral Glu. : peak : after 0.5 – 1 h = 6 – 8 x BS • Insulin response to Glu. Infusion shows a rapid first phase of release followed by a fall and a later slower second phase

  5. Metabolism of Insulin • Half life : 6 min • When insulin is secreted into the blood, it circulates almost entirely in an unbound form • Each hepatic passage : 40 – 50 % inactivation

  6. Mechanism of Action • Receptor : • W = 300,000 d • 2α (extracellular) + 2β(intracellular) • Insulin + α subunit → autophosphorilation of β subunit → tyrosine kinase activity • ↓ cAMP • ↑ Glycogenesis, lipogenesis and Pr. Synthesis • ↓ Glycogelolysis, lipolysis, proteolysis, gluconeogenesis and ketogenesis

  7. Effects of Insulin • Metabolism of Carbohydrates : • ↑ Glu. Uptake from plasma • Facilitates Glu. entrance into cells • ↓ rate of release of Glu. From liver by : • By Inhibiting glycogenolysis • By Stimulating glycogen synthesis • By Stimulating Glu. Uptake • By Stimulating glycolysis • By indirectly inhibiting glycogenesis via inhibition of fatty acid mobilization from adipose tissue • Insulin is necessary for entrance of Glu. Into the most of cells (Except of CNS, intestine epithelium, pancreas cells and renal tubul epithelium)

  8. Effects of Insulin • Metabolism of Carbohydrates : • Effect on Liver: • Glu. Uptake from plasma • ↑ glycogenesis • ↓ glycogenolysis • ↓ glyconeogenesis • Glu. Converting to fatty acids • Effect on Muscles: • Most of day time: fatty acid • At rest: glu. resistant • during sport: needs glu. for providing energy • After meal: rapid glu. Transport into muscle cells

  9. Effects of Insulin • Metabolism of Proteins: • ↑ transport of aa into hepatic and muscle cells (unrelated to glu. transport but may be related to Na/K pump activity) • Val • Leu • Ile • Tyr • Phe • ↑ synthesis of protein • ↓ proteolysis

  10. Effect of Insulin on Protein Metabolism and on Growth Insulin Promotes Protein Synthesis and Storage. 1 . Insulin stimulates transport of many of the amino acids into the cells 2. Insulin increases the translation of messenger RNA 3. Insulin also increases the rate of transcription of selected DNA genetic sequences in the cell nuclei

  11. 4. Insulin inhibits the catabolism of proteins 5. In the liver, insulin depresses the rate of gluconeogenesis • Insulin Deficiency Causes Protein Depletion and Increased Plasma Amino Acid • Insulin and Growth Hormone Interact Synergistically to Promote Growth

  12. Effects of Insulin • Metabolism of Lipids: • ↓ lipolysis • ↑ synthesis of fatty acids in liver As a result:Insulin is an Anabolic Hormone • Effect on growth: • In embryonic life, Insulin is the most important hormone for embryonic growth. • Effect on Glucagon: • Insulin refuses glucagon secretion

  13. The end effects of Insulin • 1. Within seconds after insulin binds with its membrane receptors, the membranes of about 80 percent of the body’s cells markedly increase their uptake of glucose. • 2. The cell membrane becomes more permeable to many of the amino acids, potassium ions, and phosphate ions,causing increased transport of these substances into the cell • 3. Slower effects occur during the next 10 to 15 minutes to change the activity levels of many more intracellular metabolic enzymes.

  14. 3. Slower effects occur during the next 10 to 15 minutes to change the activity levels of many more intracellular metabolic enzymes • 4. Much slower effects continue to occur for hours and even several days. They result from changed rates of translation of messenger RNAs at the ribosomes to form new proteins and still slower effects from changed rates of transcription of DNA in the cell nucleus

  15. Insulin Secretion

  16. Glucagon • Single chain polypeptide 29 aa • 3485 d • α cells • Entro-glucagon: • Larger molecule • Half life = 6 min • Hepatic and renal metabolizing • Glomerule infiltration

  17. Effects of Glucagon (Completely against Insulin effects) • Metabolism of Carbohydrates : • ↑ glycogenolysis in liver • ↑ glyconeogenesis (slow process) • Inhibition of glycogen synthesis in liver • Metabolism of Lipids : • ↑ lipolysis • Other effects: • β cell stimulation • Catecholamine secretion stimulation • ↑ heart muscle contractility • ↑ bile and calcitonin secreton

  18. Glucagon Causes Glycogenolysis and Increased Blood Glucose

  19. Factors Influencing Glucagon Release

  20. Pancreas Islets Control • Effective agents: • Metabolites • Hormones • Neural factors

  21. Pancreas Islets Control • Metabolites: • Glucose:↑ insulin, ↓ glucagon and hypothalamic effects • Amino acids: Arg, lys and Leu aa. amplifies glu. effect on insulin secretion • Lipids: Fatty acids and Ketons: inhibitory effects on α cells and stimulatory effect on β cells.

  22. Pancreas Islets Control • Hormones: • GI hormones: • oral glu. increases insulin more than IV glu. • Gastrin • Secretin • CCK • GIP • Entroglucagon • Gastrin, CCK and GIP, ↑ glucagon secretion. • glucagon • Other hormones: GH, Thyroxin, Glucocorticoids, SS

  23. Pancreas Islets Control • Neural factors: • α2 adrenergic: ↓ insulin • β adrenergic: ↑ insulin • Parasympathetic, dopamine, serotonin and PG : ?

  24. Somatostatin • δ cells • Polypeptide with 14 aa • Half life = 2 min • All of the factors related to digestion and absorption stimulates SS. secretion: • ↑ glu. • ↑ aa • ↑ fatty acids • ↑ GI hormones

  25. Effects of Somatostatin • Insulin and glucagon secretion inhibition (local effect) • ↓ gastric, duodenal and biliary bladder motility • ↓ GI secretions and absorption • GH inhibitor

  26. Blood Sugar Control • Normal FBS = 70 – 100 mgr/100cc • 1 hour after eating = 120 – 140 mgr/100cc • Control Mechanism: • Liver • Insulin and glucagon • Hypoglycemia • Early • Late

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