gi hormone maneerat chayanupatkul, md.cu. department of physiology
TRANSCRIPT
![Page 1: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/1.jpg)
GI hormoneGI hormone
Maneerat Chayanupatkul, MD.CU.
Department of Physiology
![Page 2: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/2.jpg)
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
![Page 3: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/3.jpg)
Regulation of GI function• Autocrine : regulatory peptide
secreted by the cells acting on themselves ex. 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
![Page 4: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/4.jpg)
endocrine
paracrine
neuronal
![Page 5: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/5.jpg)
Hormone/peptide neurocrine endocrine paracrine
VIP +Substance P +Neuropeptide +Somotostatin + + +Cholecystokinin + +Gastrin +Secretin +GIP +Motilin + +Neurotensin ? + +Guanylin + +
![Page 6: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/6.jpg)
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)
![Page 7: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/7.jpg)
• 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
Enteroendocrine cell (EEC)
![Page 8: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/8.jpg)
GI hormones• Classified by similarity in structure
and function
1. Gastrin family : gastrin, CCK
2. Secretin family : secretin, glucagon, glicentin, VIP, GIP
3. Others (not fit in either family) : motilin, substance P, GRP, guanylin
![Page 9: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/9.jpg)
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)
![Page 10: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/10.jpg)
Structure of gastrin• Polypeptide hormone with multiple
forms
1. Macroheterogenity : diff in length of peptide chain
2. Microheterogenity : diff on derivatization of amino acid residues
ex. Sulfation of tyrosine (6th aa residue from C-terminal), amidation of the C-terminal phynylalanine
![Page 11: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/11.jpg)
Structure of gastrin• Preprogastrin (101 aa) is processed
into 3 fragments
1. G34 : 34 aa secreted mainly by duodenal G cell
2. G17 : 17 aa secreted mainly by antral G cell
3. G14 : 14 aa
All forms have the same C-terminal configuration
![Page 12: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/12.jpg)
Structure of gastrin
![Page 13: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/13.jpg)
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
![Page 14: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/14.jpg)
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
![Page 15: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/15.jpg)
![Page 16: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/16.jpg)
Regulation of gastrin secretion• ↑ 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
![Page 17: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/17.jpg)
![Page 18: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/18.jpg)
Feedback inhibition of gastrin• Acid in antrum inhibit gastrin
secretion by 2 ways
1. Direct action on G cell
2. Stimulate release of somatostatin by D cell
• In condition which parietal cells are damaged, pernicious anemia, gastrin level is elevated.
![Page 19: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/19.jpg)
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
![Page 20: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/20.jpg)
![Page 21: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/21.jpg)
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
![Page 22: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/22.jpg)
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
![Page 23: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/23.jpg)
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
![Page 24: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/24.jpg)
Mechanism of action• Through CCK receptor (2 type)
1. CCK-A : locates in periphery, brain
2. CCK-B : locates in brain
• CCK bind to receptor activate phospholipase C → IP3, DAG → ↑ intracellular Ca → activate protein kinase → release of granule (pancreatic enzyme)
![Page 25: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/25.jpg)
• 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.
Mechanism of action
![Page 26: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/26.jpg)
Mechanism of action
![Page 27: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/27.jpg)
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)
![Page 28: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/28.jpg)
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 )
![Page 29: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/29.jpg)
![Page 30: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/30.jpg)
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)
![Page 31: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/31.jpg)
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
![Page 32: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/32.jpg)
• ↑ pancreatic enzyme secretion (augment CCK)
• ↓ gastric acid secretion
• Pyloric sphincter contraction
• Stimulate growth of exocrine pancrease (work with CCK)
Action of secretin
![Page 33: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/33.jpg)
Mechanism of action
![Page 34: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/34.jpg)
Action of secretin & CCK in pancrease
![Page 35: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/35.jpg)
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
![Page 36: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/36.jpg)
Action of secretin in bile secretion
![Page 37: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/37.jpg)
Effect of secretin and CCK in bile secretion
![Page 38: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/38.jpg)
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
![Page 39: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/39.jpg)
![Page 40: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/40.jpg)
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
![Page 41: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/41.jpg)
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
![Page 42: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/42.jpg)
Enteric factors increasing insulin release
• CCK, GIP, GLP-1, Glucagon
• GIP is also called glucose-dependent insulinotropic polypeptide by this action
• GLP-1 is more potent than GIP (limited study)
• GIP, GLP-1 act via protein kinase A pathway (increased cAMP and cytosolic calcium)
![Page 43: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/43.jpg)
![Page 44: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/44.jpg)
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
![Page 45: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/45.jpg)
GLP-1• Derivative of glucagon
![Page 46: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/46.jpg)
Action of GLP-1
![Page 47: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/47.jpg)
![Page 48: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/48.jpg)
Glucagon • Produced by alpha cell of pancreatic
islet
• Action :
• Increase glycogenolysis
• Increase gluconeogenesis
hyperglycemia
![Page 49: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/49.jpg)
Glicentin • 69 amino-acid polypeptide derived
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
![Page 50: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/50.jpg)
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
![Page 51: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/51.jpg)
Action of VIP• ↑ secretion of E’lyte and water from small
bowel
• Intestinal circular smooth ms relaxation
• Longitudinal smooth muscle contraction
• ↑ pancreatic secretion
• Inhibit gastric acid secretion and motility
• Potentiate axn of Ach in salivary gland
• VIPoma : presented with profused diarrhea
![Page 52: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/52.jpg)
Motilin • 22 amino-acid polypeptide
• Secreted by enterochromaffin cell and M cell in duodenum, jejunum
• Acts on G-protein coupled receptor on enteric neurons in stomach, duodenum → GI tract smooth muscle contraction
• Its circulating level increased at interval of 90-100 mins in the interdigestive state
![Page 53: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/53.jpg)
Motilin • Major regulator of MMCs (Migrating
Motor Complex) that move through the stomach and small intestine every 90 mins in fasted person
• Motilin secretion is inhibited after ingestion
• Vagal nerve may play some role in motilin secretion
• Erythromycin bind to motilin receptor → ↑ GI motility in constipated person
![Page 54: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/54.jpg)
Somatostatin • Growth hormone inhibitory hormone
(GH-IH)
• First found in hypothalamus
• Secreted by D cell in stomach, duodenum, pancreatic islet
• Secreted in larger amount into gastric lumen > circulation
• Released in response to acid in stomach
![Page 55: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/55.jpg)
somatostatin• Presented in 2 forms
1. Somatostatin 14 : prominent in hypothalamus
2. Somatostatin 28 : prominent in GI tract
• Acts through G-protein couple receptor (inhibit adenylate cyclase)
![Page 56: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/56.jpg)
Action of somatostatin• Inhibit secretion of gastrin, VIP, GIP, secretin,
motilin, GH, insulin, glucagon
• ↑ fluid absorption and ↓ secretion from intestine
• ↓ endocrine and exocrine pancreatic secretion
• ↓ bile flow and gall bladder contraction
• ↓ gastric acid secretion and motility
• ↓ absorption of glucose, amino acid, triglyceride
![Page 57: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/57.jpg)
Other GI hormones
![Page 58: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/58.jpg)
![Page 59: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/59.jpg)
Neurotensin • 13 amino-acid polypeptide
• Produced by neuron and endocrine cell in ileal mucosa
• Released in response to fatty food
• Action : inhibit GI motility, ↑ intestinal blood flow, ↓ gastric acid secretion
![Page 60: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/60.jpg)
Substance P• 11 amino-acid polypeptide
• Found in myenteric and submucosal plexus and endocrine cell in GI tract
• Stimulated by distention of GI tract
• ↑ GI motility (potent spasmogenic effect on GI smm by direct action on smm or indirect via Ach- releasing myenteric neurons)
• ↓ HCO3 secretion
• ↑ intestinal blood flow (vasodilatation)
![Page 61: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/61.jpg)
Gastrin releasing peptide (GRP)• 27 amino-acid polypeptide
• Released by vagal nerve endings
• Stimulate gastrin release from G cell
![Page 62: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/62.jpg)
Bombesin • Presented in vagal nerve endings
• Stimulate gastrin release from G cell
![Page 63: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/63.jpg)
Guanylin • 15 amino-acid polypeptide
• Secreted by paneth cells in the crypts of Lieberkuhn of small bowel and colon
• Acts via C-type guanylyl cyclase → ↑ cGMP → ↑CFTR → ↑ Cl secretion through Cl channel into small intestine
• Mostly act in paracrine fashion
![Page 64: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/64.jpg)
Guanylin • Heat stable enterotoxin of E.coli has
very similar structure to guanylin → activates guanylin receptor in small bowel → diarrhea
• Guanylin receptor also found in kidney, liver, female reproductive tract → regulate fluid movement in these tissues
![Page 65: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/65.jpg)
Enkephalin • 5 amino-acid oligopeptide
• Secreted from myenteric plexus
• 2 forms : Met-enkephalin, Leu-enkephalin
• Stimulated by GI distention
• Action : control GI peristalsis, ↓ intestinal fuild secretion, inhibit release of Ach, substance P (anti-diarrhea effect)
![Page 66: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/66.jpg)
Pancreatic polypeptide• Secreted by PP cell in pancreatic
islet
• Released in response to vagal stimulation, gastric distention, fat/amino acid/glucose in SB
• Action : decrease pancreatic enzyme and HCO3 secretion
![Page 67: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/67.jpg)
Peptide YY (PYY)• Produced by L cell in ileum, colon
• Secreted in response to fatty acid, glucose, hydrolyzed protein
• Action : ↓ vagally mediated gastric acid secretion, gastric emptying
↓ pancreatic enzyme and fluid secretion by inhibiting neural pathway to pancrease and ↓ pancreatic blood flow
↓ intestinal motility, food intake
![Page 68: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/68.jpg)
Neuropeptide Y• 36 amino-acid polypeptide (PP family)
• Found in CNS, postganglionic SANS, myenteric plexus
• Action : - vasoconstriction (↓blood flow)
- inhibit fluid/E’lyte secretion from SB
- inhibit pancreatic secretion
- ↓ GI motility
- stimulate feeding
![Page 69: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/69.jpg)
Effect of GI hormones on feeding• Suppression of feeding (anorexigenic effect)
• CCK : released in response to fat in duodenum causing activatiob of melanocortin in hypothalamus → ↓ food intake
• PYY : secreted by cells in ileum and colon in response to calories and composition of food intake (esp. fat meal) → ↓ food intake by unknown mechanism
• GLP-1 : enhance insulin secretion → ↓ appetite
![Page 70: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/70.jpg)
• Increased feeding (orexigenic effect)
• Ghrelin
• Neuropeptide Y
Effect of GI hormones on feeding
![Page 71: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/71.jpg)
![Page 72: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/72.jpg)
![Page 73: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/73.jpg)
Ghrelin • 28 amino-acid polypeptide
• Secreted by oxyntic cell in gastric fundus
• Can be found in pancrease, intestine, hypothalamus, pituitary gland
• Is first produced as preproghrelin (117 amino acids)
![Page 74: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/74.jpg)
Structure of ghrelin• 28 amino acids
• n-octanoyl contacts to third serine from N-terminal (important for hormone activity)
• Bind to GH-secretgogue-receptor 1a (GHS-R1a)
• G-protein coupled receptor
![Page 75: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/75.jpg)
Ghrelin structure
![Page 76: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/76.jpg)
Factors influencing ghrelin secretion• Food intake
• Most important
• Ghrelin level increases 1-2 hr prior to meal, max just before eating and decreases dramatically within 1 hr after meal
• Degree of ghrelin level decrease is in proportion with calories and composition of food (CHO can decrease ghrelin > fat)
![Page 77: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/77.jpg)
• Glucose, lipid, amino acid
• Ghrelin ↓ in postprandial hypoglycemia or after administration of IV glucose/fat diet
• High protein diet, essential amino acid →↑ ghrelin →↑ GH (controversial)
Factors influencing ghrelin secretion
![Page 78: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/78.jpg)
Factors influencing ghrelin secretion• ↑ ghrelin
• leptin
• Fasting
• GHRH, thyroid hormone
• Testosterone
• Sleep
• Lean people/ low BMI
• Anorexia nervosa
• ↓ ghrelin
• Food intake
• Glucose/lipid
• Insulin
• Somatostatin
• PYY/PP
• Obese people/high BMI
![Page 79: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/79.jpg)
Physiological roles of ghrelin• Hormonal effect
• Stimulation of GH secretion
• Synergistic of GHRH
• ↓ somatostatin secretion from hypothalamus
• ↑ ACTH, PRL, cortisol
![Page 80: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/80.jpg)
• Appetite
• Acting at arcuate nucleus by stimulation of NPY/AGRP neurons (neuropeptide Y/ Agouti-related peptide) →↑ appetite (orexigenic effect)
Physiological roles of ghrelin
![Page 81: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/81.jpg)
![Page 82: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/82.jpg)
• Gastric effects
• ↑ gastric acid secretion and motility (acting through vagus nerve which also has GHS-R1a receptor)
Physiological roles of ghrelin
![Page 83: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/83.jpg)
Other effects of ghrelin• Inhibit proinflammatory cytokin (IL-
1, IL-6, TNF)
• Increase bone mineral density
• Decrease MAP by decreasing peripheral vascular resistance
![Page 84: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/84.jpg)
![Page 85: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/85.jpg)
Possible clinical application of ghrelin
![Page 86: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/86.jpg)
Orexins/hypocretins• Neuropeptides synthesized by neurons
in posterolateral hypothalamus
• Derived from prepro-orexin (131 aa)
• Orexin A : 33 aa, N-terminal pyroglutamyl residue, 2 intrachain disulfide bonds
• Orexin B : linear 28 aa
• Only orexin A can pass BBB
![Page 87: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/87.jpg)
Orexin receptor• Mediated via G protein couple
receptor
• OxR1 (selective for orexin A) amd OxR2 (bind to both orexin A, B)
• Distributed in hypothalamus, thalamus, brainstem (locus ceruleus), spinal cord, GI tract, pancrease, genital tissues
![Page 88: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/88.jpg)
Role of orexin in feeding• Orexin neurons in lateral
hypothalamus connect and stimulate NPY-, AGRP- neurons in arcuate nucleus stimulate food intake
• Orexin neurons are stimulated by starvation and hypoglycemia, and inhibited by feeding (via vagal sensory pathway and NTS)
• Also plays an important role in regulation of metabolic rate
![Page 89: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/89.jpg)
Tumors of EEC• 50% gastrinoma (presented with
Zollinger-Ellison syndrome)
• 25% glucagonoma
• Others : VIPoma, neurotensinoma
![Page 90: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/90.jpg)
Zollinger-Ellison syndrome• Triad of gastrinoma,
hypergastrinemia, severe peptic ulcer disease
• Gastrinoma can occur in duodenal wall (more common), pancrease
• S&S : PU refractory to treatment, multiple ulcers, ulcers in distal part duodenum, jejumun, GERD, diarrhea, steatorrhea, weight loss, vitamin B12 malabsorption
![Page 91: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/91.jpg)
Glucagonoma • Pancreatic tumor (benign/malignant)
• S&S : 4D syndrome Diabetes(hyperglycemia), Dermatitis (necrolytic migratory erythema ), DVT (Factor X from tumor cells), Depression, diarrhea, weight loss
![Page 92: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/92.jpg)
Summation of GI hormone
![Page 93: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/93.jpg)
Hormone Source Target ActionCholecystokinin
I cell in duo, jeju, neurons in ileum, colon
Pancrease
gallbladder
↑enz secretion
↑contraction
GIP K cell in duo, jeuju
pancrease ↓fluid absorp
↑insulin release
Gastrin G cell in antrum, duo
Parietal cell ↑acid secretion
↑motility
GRP Vagus nerve G cell Gastrin release
![Page 94: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/94.jpg)
Hormone Source Target ActionGlucagon Alpha cell in
pancreatic islet
liver ↑glycogenolysis
↑gluconeogenesis
Guanylin Ileum, colon Small and large intestine
↑fluid secretion
Motilin EC cell, Mo cell in upper GI tract
Eso sphincter
Stomach, duo
Smooth muscle contraction
Neurotensin Neurons, ECC in ileum
Intestinal smooth muscle
↓ GI motility
↑ blood flow
![Page 95: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/95.jpg)
Hormone Source Target ActionPeptide YY L cell in
ileum, colonStomach
Pancrease
↓ vagal mediated acid secretion
↓ enz and fluid secretion
Secretin S cell in small intestine
Pancrease
Stomach
↑HCO3 and fluid secretion by pancreatic ducts
↓ gastric a secretion
somatostatin D cell in stomach , duodenum, pancreatic islet
Stomach
Intestine
Pancrease
Liver
↓ gastrin release
↑fluid absorption
↑smm contraction
↓endo/exocrine secretion
↓bile flow
![Page 96: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/96.jpg)
Hormone Source Target Action
Substance P Enteric neurons
Intestine
Pancrease
↑GI motility
↓HCO3 secretion
VIP ENS neurons Small intestine
Pancrease
smm contraction
↑SB secretion
↑pancreatic secretion
![Page 97: GI hormone Maneerat Chayanupatkul, MD.CU. Department of Physiology](https://reader036.vdocuments.us/reader036/viewer/2022081511/56649de35503460f94ada2a6/html5/thumbnails/97.jpg)
Thank you for your attention