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