Transcript Gastrointestinal Hormones

Gastrointestinal Hormones
Overview of the GI Tract
Digestion and Absorption
Regulation of Digestive Functions
GI Hormones and Paracrine Factors
Integration of Neural and Endocrine Signals
Signaling Mechanisms
Functions of the GI Tract
 Ingestion: Taking in food
 Digestion: Chemical and Mechanical
 Absorption: moving nutrients from the lumen of
the GI tract into the cells of the body
 Excretion: getting rid of undigested and
unabsorbed material
 Movement: movement of ingested food
throughout the GI tract
Organs of the Digestive System
 Accessory Digestive Organs:
Salivary glands
Liver, gall bladder
Pancreas
 Digestive Tract:
Oral Cavity
Pharynx
Esophagus
Stomach
Small Intestine
Large Intestine
The Oral Cavity
 Boundaries are:
- lips (anteriorly)
- cheeks (laterally)
- palate (superiorly)
 The oral cavity is important in:
- mastication (chewing): mechanical
digestion
- secretion of saliva for digestion
(amylase; digests starch), coating food
(mucus)
- no significant absorption of nutrients
occurs in the oral cavity
The Pharynx
 The pharynx is the passageway from the nose
and mouth to the esophagus and respiratory
tract
 Boundaries: uvula to epiglottis
 During swallowing, food is directed from pharynx
to esophagus (away from respiratory tract).
Esophagus
 The esophagus is a passageway from the
pharynx to stomach
 Contains two sphincters: upper and lower
esophageal sphincters (controls flow)
 Upper sphincter is skeletal (voluntary), lower
sphincter is smooth muscle (involuntary)
 Peristaltic waves move food from pharynx to
stomach.
The Stomach
 The stomach stores food, and mixes and
mechanically and chemically digests it
 The stomach also secretes digestive juices
pepsin: digests protein
hydrochloric acid (acidic pH, required for
pepsin activity, and to kill ingested
bacteria)
Mucus: protects the stomach wall
 Partially digested food: chyme
 Little absorption occurs in the stomach
(exceptions: alcohol, aspirin…)
Histology of the Stomach
 Cell types:
Chief cells: produce pepsinogen (inactive
precursor to pepsin)
Parietal cells: produce HCl and intrinsic factor
(absorption of vitamin B12; important in RBC
maturation)
“Endocrine” cells:
G cells: gastrin
D cells: somatostatin (paracrine)
Enterochromaffin-like cells: histamine (paracrine)
Small Intestine
 Connects the stomach with the large intestine
 It is the major site of digestion
 It is also the major site of absorption
 Specialized structures (villi, microvilli) increase
the surface area of the small intestine, aiding
absorption.
 The small intestine has three parts (duodenum,
jejunum, and ileum)
 The bile duct (from liver) and pancreatic duct
(digestive juices) empty into the duodenum.
Histology of the Small Intestine
 Absorptive cells
 Goblet cells (mucus)
 Enteroendocrine cells:
secretin
cholecystokinin
Digestion & Absorption: Carbohydrates
Carbohydrates: small amount of digestion begins in
oral cavity (amylase). Most digestion in small
intestine:
Enzyme
Digests
pancreatic amylase
polysaccharides to
disaccharides
disaccharidases
disaccharides into
(small intestine)
monosaccharides
What’s absorbed: monosaccharides
Digestion & Absorption: Proteins
Proteins: Digestion begins in stomach (pepsin),
continues in small intestine:
Enzyme
Digests
trypsin, chymotrypsin,
polypeptides into
carboxypeptidase
small peptides
(from pancreas)
aminopeptidase
dipeptidases
small peptides
into smaller
peptides
What’s absorbed: mono-, di-, and tri-peptides
Digestion & Absorption : Lipids
Lipids: Digestion begins in the small intestine (minor
amount in oral cavity)
Note: Lipids are not soluble in water. Thus, it is hard
for enzymes to act on them.
 The first step in lipid digestion is emulsification of
lipids with bile (secreted from the liver).
 Emulsification: transformation of large lipid
droplets into small lipid droplets.
 This increases the surface area of lipid that can
be acted on by the digestive enzyme, pancreatic
lipase.
Emulsification of Lipids by Bile
 Bile acts on lipids in a way similar to
detergent acting on greasy water:
large lipid droplet
bile
lipase
Absorption of Lipids
 Bile also helps absorption of products of lipid
digestion, forming micelles (free fatty acids,
glycerol, cholesterol).
 Absorption of lipids is required for absorption of
fat-soluble vitamins (vitamins A, D, E, K)
Digestion and Absorption: Nucleic Acids
 Food also contains RNA and DNA (also from
shed cells of the GI tract).
 The pancreas releases nucleases into the small
intestine.
 Nucleases digest RNA and DNA into
components.
 Digestion and absorption of dietary nucleic acids
probably not important for DNA/RNA synthesis.
Absorption in the Small Intestine: Water
 About 9 liters of water enters the digestive tract
each day.
 About 8 liters of this is absorbed by the small
intestine (by osmosis, following movement of
ions).
Large Intestine
 Last portion of the digestive tract.
 No digestion occurs in the large intestine.
 In the large intestine, there is absorption of
water (about 1 liter/day) and salts from feces
(undigested, unabsorbed food).
 Bacteria produce vitamin K, B vitamins.
 Secretion of mucus (lubrication of feces)
 Contractions move feces along large intestine
and rectum, to be expelled out of the anal
canal.
Accessory Digestive Organs
 Pancreas: exocrine portion produces digestive
enzymes, bicarbonate
 Liver: Produces bile, stores glycogen,
interconverts nutrients (gluconeogenesis),
detoxifies toxic substances (alcohol, drugs,
ammonia…), makes blood proteins (albumin,
fibrinogen, clotting factors)
 Gallbladder: concentrates and stores bile
Regulation of Digestion
 Allow communication between different parts of
the digestive tract
 Ensure the presence of sufficient secretions
when food present
 Help avoid overabundance of secretions in
absence of food
 Two types of mechanisms: neural and endocrine
Neural Control of Digestion
 Neural control of digestion is controlled largely by the
parasympathetic nervous system, and local (enteric) reflexes.
 Activation of the parasympathetic system results in secretion
of digestive juices, increased motility of the stomach, and
slowing down movement of food from the stomach to small
intestine.
 Stimuli: Thought, sight, taste of smell of food; distension of GI
tract; chemoreceptors detecting nutrients, pH.
 Example: Thought, chewing, or taste of food activates
parasympathetic system, resulting in increased release of
mucus, HCl, and pepsin in the stomach.
The goal of this is to prepare the stomach for oncoming food.
Intestinal Phase of Gastric Secretion
(~ 10% of total)
(due to some G cells extending from
antrum into the duodenum)
Important aspect of intestinal phase is feedback
regulation and inhibition
Involves interactions between duodenal contents
and duodenal hormones, including their actions
on pancreas, liver, gall bladder, and stomach
B. Functional Phases of Gastric Secretion
2. Gastric Phase of
1. Cephalic Phase of
Gastric Secretion (approx.
30% of total)
Gastric Secretion
(approx 60% of total)
(initiated by brain)
(initiated by gastric events)
vagus
nerve
vagus
nerve
FOOD
HCl
HCl
Distension
Peptides
circulation
G
circulation
G
gastrin
gastrin
C. G.I. HORMONES
+
+
+
+
+
H+
psnogn
motil.
LES
growth
+
+
+
-
Gastrin (17 AA)
HCO3 output
psnogn
synrg w/ CCK
gastr emptying
H+
Cholecystokinin (CCK (33 AA))
+
+
+
-
Structure of Secretin (27 AA)
(comparison with other GI hormones)
panc enz
G.B.
growth
Oddi
gastr emptying
synrg w/ Secretin
Endocrine Control of Digestion
 Gastrin:
- produced from the stomach (G cells)
- release increased by stomach
distension, peptides, amino acids, alcohol,
caffeine, parasympathetic innervation
- release inhibited by highly acidic pH
(< 2.0)
- functions: increases gastric (stomach)
secretions (primarily HCl); increases
histamine release; increases gastric motility;
opens pyloric sphincter (between stomach
and small intestine), relaxes ileocecal
sphincter, stimulates growth of gastric
mucosa.
Endocrine Control of Digestion
 Histamine:
Produced by enterochromaffin-like cells (ECL
cells) of the stomach.
Release is stimulated by gastrin.
Action: increase HCl secretion from parietal
cells (major factor in HCl secretion).
HOW IT WORKS AT THE RECEPTOR LEVEL
Combined neurocrine, endocrine and paracrine
events in the activation of gastric HCl secretion
Acetylcholine
neural input
neurocrine
ACh
receptor
PARIETAL cell
histamine
receptor
H/K
P
ECL cell
transductionactivation events
histaminesecreting cell
HCl
secretion
H/K
P
gastrin
receptor
Gastrin
hormonal input
endocrine
paracrine
release of
histamine
ECL cell =
enterochromaffin-like cell
G cell =
gastrin-secreting cell
G cell
HOW IT WORKS AT THE RECEPTOR LEVEL
Combined neurocrine, endocrine and paracrine
events in the activation of gastric HCl secretion
Acetylcholine
neural input
neurocrine
ACh
receptor
PARIETAL cell
histamine
receptor
H/K
P
ECL cell
HCl
transductionactivation events
histaminesecreting cell
secretion
H/K
P
gastrin
receptor
Gastrin
hormonal input
endocrine
paracrine
release of
histamine
G cell
H-2 receptor blockers
Tagamet
ECL cell =
Zantac
enterochromaffin-like
cell
Pepcid
H/K ATPase
pump
G cell
= inhibitors
gastrin-secreting
cell
Prilosec
Nexium
Aciphex
Turning the G-cell On
and Off
vagus
nerve
ACh
gastric
mucosa
ACh
ACh
-
GRP
cell
(Gastrin)
SS
+
H+
+
G
D
(Somatostatin)
Gastric Lumen
GRP
neuron
cholinergic
neuron
cell
+
digested
protein
Gastric Lumen
Circulating
Gastrin
Turning the G-cell On
and Off
vagus
nerve
ACh
gastric
mucosa
ACh
GRP
neuron
cholinergic
neuron
GRP
ACh
D
(Somatostatin)
cell
SS
+
H+
Circulating
Gastrin
+
G
(Gastrin)
cell
+
digested
protein
Gastric Lumen
SS = somatostatin
Endocrine Control of Digestion
 Somatostatin
Produced by D cells of the stomach
Secretion is stimulated by activation of the
sympathetic nervous system and by acidic pH, and is
inhibited by activation of the parasympathetic nervous
system, continuously released, overridden by gastrin
and nerves.
Actions: inhibit gastrin and histamine secretion
(decreased acid release and gastric motility); also
directly inhibits acid release from parietal cells.
Endocrine Control of Digestion
 Secretin:
- Produced by duodenum (enteroendocrine cells
of the small intestine); crypts of Lieberkühn
- stimulated by arrival of acidic chyme in
duodenum.
- functions: stimulates bicarbonate secretion
from pancreas; inhibits gastric secretion
(decreases HCl production by inhibiting gastrin
release); decreases gastric motility (slowing
rate of gastric digestion and delivery to the
small intestine), increases hepatic bile
production, increases CCK, promotes growth
and maintenance of the pancreas.
Endocrine Control of Digestion
 Cholecystokinin (CCK):
- produced by enteroendocrine cells of the
duodenum
- release stimulated by fatty acids in
duodenum (also amino acids, acidic chyme)
- functions: causes gallbladder contraction
(bile to small intestine); stimulates release of
pancreatic enzymes; decreases gastric
motility and secretion (increases somatostatin
release).
Endocrine Control of Digestion
Gastric Inhibitory Peptide (GIP):
Secretion: Enteroendocrine cells in the small
intestine mucosa Crypts of Lieberkuhn
Stimulus: Chyme rich in triglycerides, fatty acids,
and glucose enter the small intestine.
Actions:




Stimulates release of insulin by beta cells
Inhibits gastric secretion and motility
Stimulates lipogenesis by adipose tissue
Stimulates glucose use by skeletal muscle cells
Endocrine Control of Digestion
Vasoactive Intestinal Peptide (VIP):
Secretion: Enteroendocrine cells in the small
intestine mucosa Crypts of Lieberkuhn
Stimulus: Chyme entering the small intestine.
Actions:
 Stimulates buffer secretion
 Inhibits gastric secretion
 Dilates intestinal capillaries
Control of Gastric Acid Secretion
 How does a parietal cell secrete hydrochloric
acid?
H+
Cl-
CO2 + H20
H2CO3
H+ + HCO3-
HCO3- Cl-
Control of Gastric Acid Secretion
D Cell
CCK
SECRETIN
somatostatin (-)
G Cell
Gastrin
ECL
histamine
HCl
parietal
cell
Integration of Neural and Endocrine
Functions: Central Effects
 CNS: Thoughts, taste, smell of food; chewing –
activates parasympathetic nervous system
(neurotransmitter: acetylcholine).
 ACh acts directly on parietal cells to increase
acid secretion.
 Ach increases gastrin release, inhibits
somatostatin release (increased gastric
secretion and motility).
 Sympathetic input (activity, stress): increased
somatostatin release (inhibiting gastrin secretion
– decreased gastric secretion and motility)
Integration of Neural and Endocrine
Functions
Vagus N.
ACh
(-)
D Cell
CCK
SECRETIN
somatostatin (-)
G Cell
Gastrin
(+)
Digested protein
ECL
histamine
(+)
(+)
HCl
parietal
cell
Integration of Neural and Endocrine
Functions: Local Reflexes
 Mechanoreceptors in the walls of the GI tract detect
movement of food into an organ
Example: In the stomach distension causes
activation of the parasympathetic system,
increasing gastrin secretion and acid release, and
decreasing somatostatin secretion.
 Chemoreceptors detect nutrients and pH.
Example: Presence of amino acids, alcohol, or
caffeine in the stomach increases gastrin release.
Presence of fatty acids in the duodenum causes
release of CCK.
Signaling Mechanisms
 Histamine: Receptor coupled to Gs – increases
cyclic AMP production and acts via PKA.
Results in phosphorylation and increased
transport of proton pumps to cell membrane.
 Gastrin: Receptor coupled to Go/IP3/DAG;
increased intracellular calcium, and activation of
PKC (PKC also phosphorylates proton pumps).
 Somatostatin: Receptor coupled to Gi – inhibits
cyclic AMP production, decreasing PKA
signaling.
Signaling Mechanisms
 CCK: Receptor coupled to Go (increased
calcium causes somatostatin release)
 Secretin: Receptor couple to Gs (increased
cyclic AMP, causes increased secretion of
bicarbonate from the pancreas)
Integration of Gastric Secretion
+
+
+
+
+
+
Integration of Gastric Secretion
-
+
+
-
-
+
+
+
+
+
+
D. Duodenal Integration & Control:
1. Response to Acidity
Regulation by Secretin
liver
+
HCO3
+
gall
bladder
-
HCl
motility
NaCl
+ H2O
HCl
+ HCl
HCl + NaHCO3
NaCl + CO2 + H2O
2. Duodenal Response to Food
Regulation by CCK (Cholecystokinin)
liver
 Bile
gall
+
+
bladder
fat &
protein
digestion
- HCl
bile &
enzymes
fats &
peptides
FOOD