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

1. GI hormone

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 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

4. endocrine
paracrine
neuronal

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. • 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)

8. 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

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
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

11. 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

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

16. 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

18. 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.

19. 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

21. 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

22. 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

23. 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

24. 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)

25. • 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

26. Mechanism of action

27. 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)

28. 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 )

30. 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)

31. 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

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

33. Mechanism of action

34. Action of secretin & CCK in pancrease

35. 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

36. Action of secretin in bile secretion

37. Effect of secretin and CCK in bile secretion

38. 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

40. 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

41. 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

42. 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)

44. 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

45. GLP-1
• Derivative of glucagon

46. Action of GLP-1

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

49. 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

50. 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

51. 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

52. 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

53. 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

54. 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

55. 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)

56. 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

57. Other GI hormones

59. 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

60. 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)

61. Gastrin releasing peptide (GRP)
• 27 amino-acid polypeptide
• Released by vagal nerve endings
• Stimulate gastrin release from G cell

62. Bombesin
• Presented in vagal nerve endings
• Stimulate gastrin release from G cell

63. 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

64. 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

65. 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)

66. 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

67. 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

68. 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

69. 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

70. • Increased feeding (orexigenic effect)
• Ghrelin
• Neuropeptide Y
Effect of GI hormones on feeding

73. 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)

74. 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

75. Ghrelin structure

76. 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)

77. • 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

78. 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

79. Physiological roles of ghrelin
• Hormonal effect
• Stimulation of GH secretion
• Synergistic of GHRH
• ↓ somatostatin secretion from hypothalamus
• ↑ ACTH, PRL, cortisol

80. • Appetite
• Acting at arcuate nucleus by stimulation of
NPY/AGRP neurons (neuropeptide Y/ Agouti-
related peptide) →↑ appetite (orexigenic effect)
Physiological roles of ghrelin

82. • Gastric effects
• ↑ gastric acid secretion and motility (acting
through vagus nerve which also has GHS-R1a
receptor)
Physiological roles of ghrelin

83. Other effects of ghrelin
• Inhibit proinflammatory cytokin (IL-1, IL-6,
TNF)
• Increase bone mineral density
• Decrease MAP by decreasing peripheral vascular
resistance

85. Possible clinical application of ghrelin

86. 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

87. 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

88. 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

89. Tumors of EEC
• 50% gastrinoma (presented with Zollinger-
Ellison syndrome)
• 25% glucagonoma
• Others : VIPoma, neurotensinoma

90. 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

91. 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

92. Summation of GI hormone

93. Hormone Source Target Action
Cholecystokinin 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

94. Hormone Source Target Action
Glucagon 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

95. Hormone Source Target Action
Peptide YY L cell in ileum,
colon
Stomach
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

96. 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

97. Thank you for your attention