GIT Hormones

MUHAMMAD RAMZAN UL REHMAN 1

GI GI hormonhormonee

BY MUHAMMAD RAMZAN UL REHMAN


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


Regulation of GI function Autocrine : regulatory peptide secreted by the cells acting on themselves.

Juxtacrine : 1 regulatory peptide acts on many target cells.

Neurocrine : through nerves and neurotransmitters.


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

produce by : G cell, S cell

Produce 5-HT & hormones : enterochromaffin cell

Produce amine or polypeptide : neuroendocrine cell (APUD: Amine Precursor Uptake and Decarboxylase)


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


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)

Half Life (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)


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.


Mechanism of action

MUHAMMAD RAMZAN UL REHMAN

25

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


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


Mechanism of action



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



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


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


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 BY MUHAMMAD RAMZAN UL REHMAN


Education

GIT Hormones