Gastrointestinal Hormones
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Transcript of 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 foodDigestion: Chemical and MechanicalAbsorption: moving nutrients from the lumen of
the GI tract into the cells of the bodyExcretion: getting rid of undigested and
unabsorbed materialMovement: movement of ingested food
throughout the GI tract
Organs of the Digestive System
Accessory Digestive Organs:Salivary glandsLiver, gall bladderPancreas
Digestive Tract:Oral CavityPharynxEsophagusStomachSmall IntestineLarge 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 epiglottisDuring 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 proteinhydrochloric acid (acidic pH, required for
pepsin activity, and to kill ingested bacteria)
Mucus: protects the stomach wallPartially digested food: chymeLittle 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: gastrinD cells: somatostatin (paracrine)Enterochromaffin-like cells: histamine (paracrine)
Small Intestine
Connects the stomach with the large intestineIt is the major site of digestion It is also the major site of absorptionSpecialized 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 cellsGoblet cells (mucus)Enteroendocrine cells:
secretincholecystokinin
Digestion & Absorption: Carbohydrates
Carbohydrates: small amount of digestion begins in oral cavity (amylase). Most digestion in small intestine:Enzyme Digestspancreatic amylase polysaccharides to
disaccharidesdisaccharidases disaccharides into (small intestine) monosaccharides
What’s absorbed: monosaccharides
Proteins: Digestion begins in stomach (pepsin), continues in small intestine:
Enzyme Digeststrypsin, chymotrypsin, polypeptides intocarboxypeptidase small peptides(from pancreas)aminopeptidase dipeptidases small peptides
into smaller peptides
What’s absorbed: mono-, di-, and tri-peptides
Digestion & Absorption: Proteins
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.
Digestion & Absorption : Lipids
Emulsification of Lipids by Bile
Bile acts on lipids in a way similar to detergent acting on greasy water:
bile
large lipid droplet
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 DigestionNeural 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
G
gastrin
circulation
HCl
vagus nerve
FOODFOOD
DistensionPeptides
2. Gastric Phase of Gastric Secretion (approx 60% of total)
(initiated by gastric events)
G
gastrin
circulation
HCl
vagus nerve
1. Cephalic Phase of Gastric Secretion (approx.
30% of total)
(initiated by brain)
B. Functional Phases of Gastric Secretion
C. G.I. HORMONESC. G.I. HORMONES
Structure of Structure of SecretinSecretin (27 AA) (27 AA) (comparison with other GI hormones)(comparison with other GI hormones)
Gastrin (17 AA)Gastrin (17 AA)
Cholecystokinin (CCK (33 AA))Cholecystokinin (CCK (33 AA))
+ + HH++
++ psnognpsnogn++ motil.motil.++ LESLES++ growthgrowth
+ + panc enz panc enz ++ G.B.G.B.++ growthgrowth- OddiOddi- gastr emptying gastr emptying - synrg w/ Secretinsynrg w/ Secretin
+ + HCO3 outputHCO3 output++ psnogn psnogn++ synrg w/ CCK synrg w/ CCK- gastr emptyinggastr emptying-- HH++
Endocrine Control of DigestionGastrin:
- 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).
H/KP
H/KP
histamine-secreting cell
Acetylcholine neural input neurocrineneurocrine
Gastrin hormonal input
endocrineendocrine
PARIETAL cell
paracrineparacrine release of histamine
histamine receptor
ACh receptor
gastrin receptor
transduction-activation events
HCl
secretion
Combined neurocrine, endocrine and paracrine events in the activation of gastric HCl secretion
ECL cell
G cellG cellcirculationcirculation
ECL cell = enterochromaffin-like cell
G cell = G cell = gastrin-secreting cellgastrin-secreting cell
HOW IT WORKS AT THE RECEPTOR LEVEL
neural inputneural input
chemical inputchemical input
H/KP
H/KP
histamine-secreting cell
Acetylcholine neural input neurocrineneurocrine
Gastrin hormonal input
endocrineendocrine
PARIETAL cell
paracrineparacrine release of histamine
histamine receptor
ACh receptor
gastrin receptor
transduction-activation events
HCl
secretion
Combined neurocrine, endocrine and paracrine events in the activation of gastric HCl secretion
ECL cell
G cellG cellcirculationcirculation
ECL cell = enterochromaffin-like cell
G cell = G cell = gastrin-secreting cellgastrin-secreting cell
HOW IT WORKS AT THE RECEPTOR LEVEL
H-2 receptor blockers
H/K ATPase pump inhibitors
Tagamet ZantacPepcid
Prilosec Nexium Aciphex
neural inputneural input
chemical inputchemical input
Turning the G-cell On and Off
ACh ACh
ACh GRP
(Somatostatin)cell
(Gastrin)cellSS
GRPneuron
digestedprotein
H+
vagusnerve
CirculatingGastrin
GD
+-
++
cholinergic neurongastric
mucosa
Gastric LumenGastric Lumen
Turning the G-cell On and Off
ACh ACh
ACh GRP
(Somatostatin)cell
(Gastrin)cellSS
GRPneuron
digestedproteinH+
vagusnerve
CirculatingGastrin
GD
+
++
cholinergic neurongastric
mucosa
Gastric Lumen
SS = somatostatin
-
Endocrine Control of Digestion
SomatostatinProduced by D cells of the stomachSecretion 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.
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
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?
CO2 + H20 H2CO3 H+ + HCO3-
Cl-
Cl-H+
HCO3-
Control of Gastric Acid Secretion
ECLparietal
cellG Cell
HCl
Gastrin
histamine
D Cell
somatostatin (-)SECRETIN
CCK
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
ECLparietal
cellG Cell
HCl
Gastrin
histamine
D Cell
somatostatin (-)SECRETIN
CCK
ACh(-)
(+) (+)
Vagus N.
Digested protein
(+)
Integration of Neural and Endocrine Functions: Local Reflexes
Mechanoreceptors in the walls of the GI tract detect movement of food into an organExample: 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 SecretionIntegration of Gastric Secretion
++
++
++++
++
++
Integration of Gastric SecretionIntegration of Gastric Secretion
++ ++
++
--
-- --
++
++++
++
++
D. Duodenal Integration & Control: 1. Response to Acidity
Regulation by Secretin
HCl + NaHCOHCl + NaHCO33 NaCl + CO NaCl + CO22 + H + H22OO
+
+
-
+
gallbladder
liver
HCl
HClmotility
NaCl+ H2O
HCO3HCO3
HCl
NaHCO 3
NaHCO3
Secretin
Secretin
Regulation by CCK (Cholecystokinin)
CCKCCKCCKCCK
gall
bladder
Bile
FOOD
+
-
liver
+
fats & peptides
bile & enzymes
fat & protein digestion
- HCl
2. Duodenal Response to Food