gi hormone
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GI hormoneGI 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
• Paracrine regulation : regulatory peptide secreted by EEC acts on a nearby target cell by diffusion through interstitial space. Ex histamine, 5-HT
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
endocrine
paracrine
neuronal
Hormone/peptide neurocrine endocrine paracrine
VIP +Substance P +Neuropeptide +Somotostatin + + +Cholecystokinin + +Gastrin +Secretin +GIP +Motilin + +Neurotensin ? + +Guanylin + +
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)
• 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)
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
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)
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
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
Structure of gastrin
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
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
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
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.
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
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
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
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
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)
• 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
Mechanism of action
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)
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 )
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)
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
• ↑ pancreatic enzyme secretion (augment CCK)
• ↓ gastric acid secretion
• Pyloric sphincter contraction
• Stimulate growth of exocrine pancrease (work with CCK)
Action of secretin
Mechanism of action
Action of secretin & CCK in pancrease
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
Action of secretin in bile secretion
Effect of secretin and CCK in bile secretion
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
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
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
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)
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
GLP-1• Derivative of glucagon
Action of GLP-1
Glucagon • Produced by alpha cell of pancreatic
islet
• Action :
• Increase glycogenolysis
• Increase gluconeogenesis
hyperglycemia
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
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
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
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
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
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
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)
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
Other GI hormones
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
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)
Gastrin releasing peptide (GRP)• 27 amino-acid polypeptide
• Released by vagal nerve endings
• Stimulate gastrin release from G cell
Bombesin • Presented in vagal nerve endings
• Stimulate gastrin release from G cell
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
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
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)
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
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
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
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
• Increased feeding (orexigenic effect)
• Ghrelin
• Neuropeptide Y
Effect of GI hormones on feeding
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)
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
Ghrelin structure
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)
• 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
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
Physiological roles of ghrelin• Hormonal effect
• Stimulation of GH secretion
• Synergistic of GHRH
• ↓ somatostatin secretion from hypothalamus
• ↑ ACTH, PRL, cortisol
• Appetite
• Acting at arcuate nucleus by stimulation of NPY/AGRP neurons (neuropeptide Y/ Agouti-related peptide) →↑ appetite (orexigenic effect)
Physiological roles of ghrelin
• Gastric effects
• ↑ gastric acid secretion and motility (acting through vagus nerve which also has GHS-R1a receptor)
Physiological roles of ghrelin
Other effects of ghrelin• Inhibit proinflammatory cytokin (IL-
1, IL-6, TNF)
• Increase bone mineral density
• Decrease MAP by decreasing peripheral vascular resistance
Possible clinical application of ghrelin
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
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
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
Tumors of EEC• 50% gastrinoma (presented with
Zollinger-Ellison syndrome)
• 25% glucagonoma
• Others : VIPoma, neurotensinoma
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
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
Summation of GI hormone
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
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
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
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
Thank you for your attention
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