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GI hormone

GI hormone. Maneerat Chayanupatkul, MD.CU. Department of Physiology. Regulation of GI function. Endocrine regulation : EEC secretes regulatory peptide or hormones that travel via blood stream to remote target organ. Ex gastrin, secretin

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GI hormone

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  1. GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology

  2. Regulation of GI function • Endocrine regulation : EEC secretes regulatory peptide or hormones that travel via blood stream to remote target organ. Ex gastrin, secretin • Paracrine regulation : regulatory peptide secreted by EEC acts on a nearby target cell by diffusion through interstitial space. Ex histamine, 5-HT

  3. Regulation of GI function • Autocrine : regulatory peptide secreted by the cells acting on themselvesex. TGF-α, β potentiate differentiation of crypt cell to villi cell • Juxtacrine : 1 regulatory peptide acts on many target cells • Neurocrine : through nerves and neurotransmitters

  4. neuronal paracrine endocrine

  5. Hormone/peptide neurocrine endocrine paracrine • VIP + • Substance P + • Neuropeptide + • Somotostatin + + + • Cholecystokinin + + • Gastrin + • Secretin + • GIP + • Motilin + + • Neurotensin ? + + • Guanylin + +

  6. Enteroendocrine cell (EEC) • Hormone-secreting cells in the mucosa of stomach, small intestine, colon • May produce 1 hormone : G cell, S cell • Produce 5-HT & hormones : enterochromaffin cell • Produce amine or polypeptide : neuroendocrine cell (APUD: Amine Precursor Uptake and Decarboxylase)

  7. Enteroendocrine cell (EEC) • Have 2 types • Open-type : apical membrane contact with GI lumen (receptor), secretion occurs in basolateral membrane ex. G cell • Closed-type : No contact with luminal surface ex. Enterochromaffin-like cell (ECL) which secretes histamine

  8. GI hormones • Classified by similarity in structure and function • Gastrin family : gastrin, CCK • Secretin family : secretin, glucagon, glicentin, VIP, GIP • Others (not fit in either family) : motilin, substance P, GRP, guanylin

  9. Gastrin • Produced by G cell in the mucosal gland of gastric antrum and duodenum • Can be found in fetal pancreatic islet, hypothalamus, medulla oblongata, vagus n. (unidentified function)

  10. Structure of gastrin • Polypeptide hormone with multiple forms • Macroheterogenity : diff in length of peptide chain • Microheterogenity : diff on derivatization of amino acid residues ex. Sulfation of tyrosine (6th aa residue from C-terminal), amidation of the C-terminal phynylalanine

  11. Structure of gastrin • Preprogastrin (101 aa) is processed into 3 fragments • G34 : 34 aa secreted mainly by duodenal G cell • G17 : 17 aa secreted mainly by antral G cell • G14 : 14 aa All forms have the same C-terminal configuration

  12. Structure of gastrin

  13. Gastrin • Different forms, different activity, different tissues that are found • G17 : principal form of gastric acid secretion (more active and more amount than G34) • t1/2 : G14, G17 2-3 min in blood. G34 15 min • Inactivated in kidney, small bowel

  14. Action of gastrin • Stimulation of gastric acid and pepsin secretion • Stimulation of mucosal growth in stomach, SB, colon (trophic action) • Stimulation of gastric motility • Release of histamine from ECL cell • Stimulate insulin secretion after protein meal (not CHO) • +/- constriction of LES

  15. ↑ gastrin secretion Luminal : peptide, aa (Phy, Tryp), gastric distention Neural : vagal stimulation via GRP (can’t be blocked by atropine) Blood : Ca, epinephrine ↓ gastrin secretion Luminal : acid, somatostatin Blood : secretin, GIP, VIP, glucagon, calcitonin Regulation of gastrin secretion

  16. Feedback inhibition of gastrin • Acid in antrum inhibit gastrin secretion by 2 ways • Direct action on G cell • Stimulate release of somatostatin by D cell • In condition which parietal cells are damaged, pernicious anemia, gastrin level is elevated.

  17. Cholecystokinin-Pancreozymin (CCK) • Also shows macro- and microheterogenity Prepro-CCK is processed into several fragments • CCK58, CCK39, CCK33, CCK22 ,CCK12, CCK8 • Every forms has the same 5 aa at C-terminal as gastrin • Every forms has amidation of C-terminal, sulfation of 7thtyrosine from C-terminal

  18. CCK • Secreted by I cell in duodenum and jejunum • Also found in nerves in distal ileum and colon, neurons in brain (regulation of food intake) • CCK8, CCK22, CCK33 : principal circulating forms secreted in response to meal • Enteric & pancreatic nerve : CCK4 • Brain : CCK8, CCK58

  19. Action of CCK • Gall bladder contraction, sphincter of Oddi relaxation • ↑ pancreatic enzyme secretion • Augment effect of secretin in producing alkaline pancreatic juice • ↓ gastric emptying • Trophic effect on pancrease

  20. Action of CCK • ↑ secretion of enterokinase • ↑ motility of small intestine and colon • Augment contraction of pyloric sphincter (↓ duodenal reflux) • ↑ glucagon secretion (work with gastrin) • Induced satiety by acting through hypothalamus

  21. Mechanism of action • Through CCK receptor (2 type) • CCK-A : locates in periphery, brain • CCK-B : locates in brain • CCK bind to receptor activate phospholipase C → IP3, DAG → ↑ intracellular Ca → activate protein kinase → release of granule (pancreatic enzyme)

  22. Mechanism of action • CCK also stimulate vagus nerve to pancrease (via CCK-A receptor) → release of Ach, GRP, VIP → fusion of granule with membrane and release of pancreatic enzyme • Gastrin receptor is very similar to CCK-B receptor.

  23. Mechanism of action

  24. Control of CCK secretion • Most potent stimulator of CCK release is lipid • Peptones, amino acid also increase CCK release but CHO has little effect. • Also secreted in response to CCK-releasing factor • Positive feedback : CCK → enzyme release → more digestive products → more CCK (stop when digestive products move to next part)

  25. CCK-releasing peptide& monitor peptide • CCK-RP is secreted from duodenal mucosa, and monitor peptide by pancreatic acinar cell • Secreted in response to fat, protein digestive products, and also to neural input (cephalic phase) • Match the release of CCK, pancreatic enzyme and the need for enzyme to digest foods • These peptides are degraded by pancreatic trypsin (if there are proteins in duodenum, these peptides won’t be degraded and CCK will be released )

  26. Secretin • 27 amino-acid polypeptide • Secreted by S cell located deeply in the mucosal gland of duodenum and jejunum • Similar structure with glucagon, VIP, GIP • Only 1 form has been isolated • t1/2 : 5 min • Stored in an inactive form (prosecretin)

  27. Action of secretin • Most potent humoral stimulator of fluid and HCO3 secretion by pancrease • Acts in concert with CCK, Ach to stimulate HCO3 secretion • ↑ HCO3 secretion by duct cells of pancrease and biliary tract→ ↑secretion of a watery, alkaline pancreatic juice • Acting through cAMP

  28. Action of secretin • ↑ pancreatic enzyme secretion (augment CCK) • ↓ gastric acid secretion • Pyloric sphincter contraction • Stimulate growth of exocrine pancrease (work with CCK)

  29. Mechanism of action

  30. Action of secretin & CCK in pancrease

  31. Effect of secretin on bile secretion • Produce a watery bile rich in HCO3 • Activate via cAMP → stimulate CFTR (Chloride channel) and Cl– HCO3 exchanger • Work in concert with glucagon, VIP

  32. Action of secretin in bile secretion

  33. Effect of secretin and CCK in bile secretion

  34. Control of secretin secretion • Secretin is secreted in response to protein digestive products, bile acid, fatty food and increased acidity in duodenal content (pH< 4.5-5) • Inhibited by somatostatin and Met-enkephalin • Secretin release may be mediated by secretin-releasing peptide

  35. Gastric inhibitory peptide (GIP) • 42 amino-acid polypeptide • Produced by K cell in duodenal and jejunal mucosa • Stimulated by glucose and fat in duodenum, acid in stomach • Inactivated by dipeptidyl-peptidase IV (DPP-IV) in many tissues and in portal circulation

  36. Action of GIP • Mild effect in decreasing gastric motility • Inhibit gastric acid secretion by directly inhibit parietal cells or indirectly inhibit gastrin release from antral G cells (via somatostatin) • Stimulate insulin release from pancreatic islet in response to duodenal glucose and fatty acid Oral glucose can stimulate larger amount of insulin release than IV glucose

  37. Enteric factors increasing insulin release • CCK, GIP, GLP-1, Glucagon • GIP is also called glucose-dependent insulinotropic polypeptide by this action • GLP-1 is morepotent than GIP (limited study) • GIP, GLP-1 act via protein kinase A pathway (increased cAMP and cytosolic calcium)

  38. Glucagon-Like Peptide 1 (GLP-1) • 30 amino-acid polypeptide • Incretin hormone : intestinal hormone secreted in response to nutrient ingestion which potentiate glucose-induced insulin release • Produced by L cell in ileum and colon, pancreatic alpha cell, neurons in hypothalamus, pituitary gland • 2 bioactive forms : GLP-1[7-36] amide , GLP-1[7-37] both forms are equipotent, same t1/2

  39. GLP-1 • Derivative of glucagon

  40. Action of GLP-1

  41. Glucagon • Produced by alpha cell of pancreatic islet • Action : • Increase glycogenolysis • Increase gluconeogenesis hyperglycemia

  42. Glicentin • 69 amino-acid polypeptidederived from proglucagon • Secreted from L cell along with GLP-1 and GLP-2 • Action : stimulation of insulin secretion, inhibit gastric acid secretion, regulation of gut motility, stimulation of intestinal growth

  43. Vasoactive intestinal peptide (VIP) • 28 amino-acid polypeptide • Found in ENS neurons (both myenteric and submucosal plexus), brain, autonomic nerves • Released in response to esophageal and gastric distention, vagal stimulation, fatty acid and ethanol in duodenum • Amino acid and glucose don’t affect VIP release • Half life 2 min in circulation

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