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denum to promote growth of the duodenal mucosa. The
trophic action of gastrin is independent of its secretory
effect. Gastrin is also trophic to the colonic mucosa, and
the colonic cancer cells may elaborate gastrin that may act
on them in autocrine fashion.
3. Motor effects. Gastrin causes contraction of the
lower esophageal sphincter, but higher doses are required
than those that stimulate its secretory action. It also stimulates antral motility. In vitro, gastrin stimulates smooth
muscle contraction. In pharmacologic doses, as seen in
Zollinger-Ellison syndrome (ZES), gastrin stimulates
small intestinal peristalsis and shortens intestinal transit
time.
4. Stimulation of pancreatic enzyme secretion. Gastrin
stimulates the secretion of pancreatic enzyme, an action
that is far less marked in humans than in dogs.
5. Stimulation of somatostatin release. Gastrin stimulates release of somatostatin from fundic endocrine cells
but is less potent in this action than CCK.
CHOLECYSTOKININ
One of the longest known gastrointestinal peptides, cholecystokinin (CCK) was first described in 1928 by Ivy and
Oldberg, who demonstrated that perfusion of fat into the
intestine stimulated contraction of the gallbladder.
1943, Harper and Raper showed that intestinal perfusion
of proteins and injection of small intestinal mucosal
extracts into rats stimulated pancreatic enzyme secretion;
they called the active substance pancreozymin.
Mutt and Jorpes purified CCK from intestinal extracts and
demonstrated that it is identical to pancreozymin.
historical reasons, the name CCK has been adopted.
Distribution
CCK is released by I cells, which are endocrine cells located
mostly in the mucosa of the duodenum and upper
5
In 1966,
4
In
6
For
jejunum. CCK is present in high concentrations in the
cerebral cortex, especially in layers II and III. It is colocalized with dopamine. In the peripheral nervous
system, CCK is found in pancreatic neurons and in the
nerves of the colon and ileum. CCK is also abundant
in the celiac plexus and in the vagus. Human CCK has
also been found in some pituitary and adrenal medullary
cells.
Structure and Synthesis
CCK exists in multiple molecular forms (CCK58, CCK39,
CCK33, CCK25, CCK22, CCK18, CCK8, CCK7, and
CCK5). The major biological form of large CCK is CCK58.
Cleavage at mono and dibasic residues of CCK58 releases
smaller forms. In the brain, CCK exists primarily as CCK8
and CCK58. In humans, the gene for CCK is located on
chromosome 3 (Figure 5.9). The third exon on chromosome 3 encodes the biologically active region of the
peptide, including CCK58. CCK mRNA is about 750 bases,
of which 345 encode protein. All the smaller forms of CCK
are subsequently derived from CCK58. All molecular
forms of CCK must be sulfated at the seventh amino acid
from the carboxyl terminal in order to have biological
function.
Release of CCK
CCK is released from the I cells of the duodenum and
jejunum in response to luminal fat, peptides, amino acids
and acid. Proteins must undergo partial digestion, and
triglycerides must be hydrolyzed to become effective
releasers of CCK. CCK is also released by GRP
(bombesin). Monitor peptide, a CCK-releasing peptide,
has been isolated from rat pancreatic juice and can release
CCK in vitro from duodenal mucosal cells. Its role in vivo
is uncertain. Trypsin in the duodenum inhibits CCK release, presumably by inactivating a CCK-releasing peptide
FIGURE 5.9. The gene for human CCK, located on chromosome 3, is 7 kilobases in length, containing
three exons and two introns.
C lassification of Gastrointestinal P eptides ...................................................................................... 139
FIGURE 5.10. Intracellular processing of CCK. Post-translational processing releases multiple molecular
forms of CCK (CCK58, CCK39, CCK33, and CCK8).
in the duodenal mucosa. Trypsin inhibitors release CCK
by preventing inactivation of CCK-releasing peptide.
Recent evidence in rats suggests that vagal electrical stimulation releases CCK from intrapancreatic neurons and
that the so-released CCK acts as a neurotransmitter in
vagal stimulation of enzyme secretion.
Receptors and Postreceptor Signaling
The action of CCK is mediated by two types of receptors, the CCK-A and CCK-B receptors, both from the 7transmembrane, G-protein-linked receptor family. CCK-A
receptor has a high affinity for sulfated CCK analogues and
is the principal receptor that mediates pancreatic enzyme
secretion and gallbladder contraction. CCK-B receptor has
high affinity for both gastrin and CCK. Both receptors are
coupled to phospholipase C, and activation produces diacylglycerol (DAG) and inositol triphosphate (IP
). The
3
subsequent intracellular processes are similar to those
described for gastrin (Figure 5.10). Receptors for CCK are
present on acinar cells; on gallbladder, ileum, and colon
muscle; on lower esophageal sphincter; and on delta cells.
Specific antagonists to both receptors have been developed and have proven useful for studying physiology. It is
likely that these antagonists have a therapeutic role in the
future.
Biological Actions of CCK
The following are the major biological actions of CCK:
1. Stimulation of pancreatic enzyme secretion. CCK is
the principal mediator of food-stimulated pancreatic
secretion. The action is complex and involves intrapancreatic cholinergic mechanisms. Intrapancreatic CCK is
also involved in the mediation of vagal stimulation of pancreatic secretion.
2. Gallbladder contraction. CCK is the primary stimulant of gallbladder contraction and acts partly by releasing
acetylcholine from cholinergic neurons within the wall of
the gallbladder.
3. Delay of gastric emptying. Regulation of gastric
emptying is a physiological action of CCK, probably indi-
rect, resulting from activation of afferent sensory
neurons.
4. Peristaltic reflex. CCK is a cotransmitter, in con-
junction with acetylcholine, of the peristaltic reflex.
5. Colonic motility. CCK is an inhibitor of colonic
motility.
6. Gastric acid. CCK inhibits gastric acid secretion,
probably through the release of somatostatin.
7. Insulin and pancreatic polypeptide. CCK initiates
the release of insulin and pancreatic polypeptide.
8. Satiety. CCK initiates the sensation of satiety.
SECRETIN
Secretin was the first peptide hormone to be identified.
Its discovery inaugurated the beginning of modern
endocrinology as we know it. In 1902, Bayliss and Starling
showed that perfusion of the small intestine with acid
released a circulating substance that stimulated pancreatic
juice flow.
humoral substance dealt a severe blow to the tenet of
nervism upheld by Pavlov and his students.
secretin was purified and subsequently sequenced.
Distribution
Secretin is secreted by S cells located predominantly in the
duodenum and proximal jejunum. As far as is known,
secretin is found only in these cells and has not been
shown to be present in neural tissue. In this sense, it is a
classical hormone.
Structure and Synthesis
Secretin is a linear peptide containing 27 amino acid
residues. It is structurally similar to glucagon, VIP, GIP,
growth hormone-releasing factor (GHRF), PHI, pituitary
cyclase-activating polypeptide (PCAP), and calcitonin
gene-related peptide (CGRP). The secretin gene is composed of four exons spanning 813 base pairs, and the entire
secretin sequence is encoded in a single exon. A precursor
secretin consisting of the secretin molecule plus a 41amino acid C-terminal extension is first produced, from
7
This first demonstration of a circulating
8
In 1968,
9
140 ............................................. Gastrointestinal P eptides and Peptide-Secreting T umors (Apudomas)
C lassification of Gastrointestinal Peptides ...................................................................................... 141
which the secretin is cleaved. While the S-17 C-terminal
fragment retains activity, the full 27-amino acid sequence
is required for full potency.
Release of Secretin
Secretin is released by acid in the duodenum. The pH
threshold for secretin release is 4.5. Fat is another potent
releaser of secretin. Oleate releases secretin but triglycerides do not. Bile in the duodenum releases secretin,while
pancreatic juice inhibits its release. Vagal stimulation does
not release secretin, while somatostatin and metenkephalin inhibit its release.
Receptors and Postreceptor Signaling
The secretin receptor has been cloned and is similar to the
receptors of VIP, calcitonin, and parathyroid hormone
(PTH). They are all G protein-coupled, 7-transmembrane
receptors. Secretin binding to its receptor activates adenylate cyclase, and cAMP serves as the second messenger.
Biological Actions of Secretin
Secretin has several major biological actions:
1. Pancreatic bicarbonate secretion. The most important action of secretin is stimulation of ductal cells to
secrete water and bicarbonate. Small doses of secretin also
potentiate the action of CCK to stimulate pancreatic
enzyme release.
2. Biliary secretion. Secretin stimulates bile acidindependent bile flow.
3. Pancreatic growth. Secretin has only minimal
trophic action on pancreatic growth but potentiates the
trophic effects of CCK.
4. Gastric acid secretion. Secretin is an inhibitor of
gastric acid secretion.
5. Gastric pepsin secretion. Secretin stimulates the
secretion of gastric pepsin.
6. Chloride, sodium, and bicarbonate secretion.
Secretin stimulates chloride secretion and inhibits sodium
and bicarbonate secretion in the intestine.
7. Inhibition of gastrin release. Secretin is a weak
inhibitor of food-stimulated gastrin release. In patients
with ZES, it has the paradoxical effect of significantly
increasing the release of gastrin, a phenomenon that
is the basis for the secretin test in the diagnosis of
gastrinoma.
8. Gastric emptying of solids. Secretin inhibits gastric
emptying of solids.
VASOACTIVE INTESTINAL POLYPEPTIDE
Vasoactive intestinal polypeptide (VIP) was discovered in
1970 by Said and Mutt, while they were screening extracts
of gut and lung for vasodilator activities.
6
VIP belongs to
the secretin family of peptides.
Distribution
VIP is found in neurons throughout the GI tract. The
same neurons also contain PHI. In pancreatic and
salivary neurons, VIP is colocalized with acetylcholine.
VIP-containing neurons are abundant in the enteric
nervous system and its ganglia. In the anal sphincter,
it is colocalized with NO synthase. VIP neurons project
to the circular smooth muscle of the gut and are
particularly numerous in the sphincters of the GI
tract.
Structure and Synthesis
VIP is a 28-residue basic peptide. The gene for VIP was
cloned from human neuroblastoma and contains seven
exons, of which five contain coding sequences separately
for VIP, PHI and signal sequence.
Release of VIP
Because VIP is a locally acting neuropeptide, plasma
concentrations are low unless excessive VIP is being
secreted by a vipoma. However, elevated levels of VIP are
present in the venous outflow of the gut in response to
luminal fat and HCl, electric stimulation of extrinsic
nerves, and in response to distension or stroking of the
mucosa.
Receptors and Postreceptor Signaling
The VIP receptor has been cloned and has a molecular
weight of 48.8 kDa. The VIP receptor binds VIP and
PACAP with equal affinity but binds secretin with lower
affinity. PHI acts via the VIP receptor. The VIP receptor is
also a G-protein-coupled, 7-transmembrane receptor. Like
the secretin receptor, it is adenylate cyclase linked, with
cAMP acting as the second intracellular messenger.
Biological Actions of VIP
The major biological actions of VIP include:
1. Secretory action. VIP stimulates intestinal secretion
and pancreatic water and bicarbonate secretion.
2. Somatostatin release. Both VIP and PHI release
somatostatin from delta cells in the stomach. This mechanism probably explains its inhibitory effect on gastric
acid secretion.
3. Motility effects.VIP is a powerful relaxant of smooth
muscle and is responsible for the descending inhibition of
the peristaltic reflex; the receptive relaxation of the
stomach; and the relaxation of the lower esophageal,
pyloric, ileocecal and anal sphincters. Its musclerelaxing effect appears to take place in cooperation with
NO.
4. Mucosal blood flow. VIP increases mucosal blood
flow.
142 ............................................. Gastrointestinal P eptides and Peptide-S ecreting T umors (Apudomas)
GLUCAGON FAMILY OF PEPTIDES
The glucagon family of peptides consists of pancreatic
glucagon and enteroglucagons. The latter are a group of
peptides produced in the intestine by differential processing
of the same glucagon gene as the one present in pancreatic
alpha cells. The enteroglucagons include glicentin, oxyntomodulin, glucagon-like peptide (GLP-1) and GLP-2.
Distribution
Pancreatic glucagon is secreted by the alpha cells of the
pancreatic islets. Enteroglucagons are released by the L
cells, endocrine cells in the small intestinal mucosa.
Structure and Synthesis
The structure of the preproglucagon gene consists of six
exons and five introns. Separate exons encode the signal
peptide and each of the glucagon sequences. Proglucagon
is formed first and in the pancreas is processed to form
glucagon. In the small intestine, post-translational processing is accomplished by enzymes to produce glicentin,
GLP-1, GLP-2, and oxyntomodulin. Pancreatic glucagon
is a 29-amino acid peptide. Glicentin is the largest
molecule, consisting of 69 amino acid residues. Oxyntomodulin, also known as enteroglucagon, is a 37-amino
acid peptide, consisting of the glucagon molecule with
an 8-amino acid extension at the C terminus. GLP-1
corresponds to proglucagon 78–107 amide. GLP-2 is
proglucagon 126–158 and does not appear to have much
biological action.
Release of Glucagon and GLP
Glucagon is released from the A cells of the pancreas
in response to hypoglycemia and catchelomines.
Enteroglucagons are released from the intestine by an
ordinary mixed meal, digestible fat and carbohydrates.
Enteroglucagon, also released by GRP, GIP, and substance
P, is inhibited by somatostatin.
Receptors and Postreceptor Signaling
Two important receptors have been identified and cloned.
One is the glucagon receptor, which binds not only
glucagon but also oxyntomodulin. The second is the
GLP-1 receptor, which does not bind glucagon. Both
are G protein-coupled, adenylate cyclase-activating, 7transmembrane receptors with cAMP serving as the
second messenger.
Biological Actions of the Glucagon
Family of Peptides
The different peptides of the glucagon family have different biological actions, as follows:
1. Pancreatic glucagon. Glucagon has general biological and metabolic actions that include glycogenolysis,
lipolysis, gluconeogenesis, and ketogenesis. Other actions
include the inhibition of: intestinal motility and absorption, pancreatic exocrine secretion, gastric acid secretion,
and pentagastrin-stimulated lower esophageal sphincter
pressure. Relaxation of the sphincter of Oddi and stimulation of hepatic bile flow are additional actions.
2. GLP-1. The most biologically active glucagon gene
product made in the intestine, GLP-1 stimulates insulin
release and inhibits pancreatic glucagon release. It is thus
an important incretin. GLP-1 inhibits pentagastrinstimulated gastric acid secretion and is a strong inhibitor
of gastric emptying. It also inhibits pancreatic exocrine
secretion. It stimulates the release of somatostatin. GLP-1
is an important enterogastrone and inhibitor of pancreatic
secretion.
3. Oxyntomodulin and glicentin. Oxyntomodulin is a
weak stimulator of insulin release, but glicentin has no
such action. Glicentin is a weak inhibitor of gastric acid
and pancreatic secretion, while oxyntomodulin is equipotent to GLP-1. Enteroglucagon has trophic action on small
intestinal mucosa and may be responsible for the adaptive
intestinal hypertrophy seen after massive small bowel
resection. Tumors that produce enteroglucagon cause
giant small intestinal villi.
GASTRIN-RELEASING PEPTIDE
OR BOMBESIN
The amphibian analogue of the mammalian gastrinreleasing peptide (GRP), bombesin, was isolated from frog
skin by Erspamer and colleagues.
10
It is a general stimu-
lant of gastrointestinal peptide release, analogues to
Distribution
GRP is found in neurons of the enteric nervous system in
the stomach, intestines, and pancreas but not in endocrine
cells.
Structure and Synthesis
GRP is a 27-amino acid peptide. The human GRP gene
contains three exons and two introns.
Release of GRP
Vagal stimulation releases GRP into the gastric venous
outflow, and vagal release of gastrin is mediated through
GRP. GRP is also released by gastric distention and luminal
nutrients, suggesting that it may play a role in the release
of gastrin by these stimuli.
C lassification of Gastrointestinal Peptides ...................................................................................... 143
Receptors and Postreceptor Signaling
Three bombesin receptors have been cloned, one of which
has high affinity for GRP. The receptor belongs to the G
protein superfamily. Activation of GRP receptors increases
inositol triphosphate and intracellular calcium.
Biological Actions of GRP
The major biological actions of GRP include the following:
1. Release of gastrin and other GI peptides. GRP is an
important mediator of vagal stimulation of gastrin and
inhibition of somatostatin, as well as of gastrin release in
response to luminal stimulants. GRP also stimulates
release of CCK and several other GI peptides.
2. Stimulation of the pancreas. GRP stimulates pancreatic exocrine and endocrine secretion.
3. Mitogenic effects. GRP and bombesin stimulate division of various cell lines and may stimulate growth of
small-cell lung cancer. Chronic exogenous administration
of GRP in the rat increases antral G cell proliferation.
4. Motility. GRP has an excitatory effect on GI smooth
muscle. The motor response of the gastric antrum to vagal
stimulation is mediated by GRP.
SOMATOSTATIN
Guillemin and Schally isolated somatostatin from sheep
hypothalamus in 1973, and, in 1977, they were awarded
the Nobel Prize for their discovery.
11
Distribution
Somatostatin is present in endocrine cells—known as the
D or delta cell—throughout the mucosa of the gastrointestinal tract and in the islets of Langerhans in the pancreas. It is also widely distributed in the central nervous
system, the autonomic nervous system, and the enteric
nervous system.
Structure and Synthesis
Somatostatin exists in two biologically active forms,
somatostatin-14 and somatostatin-28, so designated
because of the number of amino acid residues they
contain. The human somatostatin gene is located on chromosome 3. The predicted precursor of 116 amino acids
contains the somatostatin-28 sequence at its carboxyl terminus. Somatostatin-28 is cleaved from prosomatostatin,
and somatostatin-14 is enzymatically derived from
somatostatin-28 with the actions of an endopeptidase and
aminopeptidase. In the stomach, somatostatin-14 may be
formed directly from prosomatostatin. Somatostatin gene
expression studies have shown that chronic alkalinization
and GRP reduce somatostatin mRNA in the antrum, while
prolonged fasting increases it.
Release of Somatostatin
Feeding releases both somatostatin-14 and somatostatin28 from the gastrointestinal tract. Fat and protein are
stronger releasers than carbohydrates. Insulin hypoglycemia and isoproterenol release somatostatin from both
the pancreas and the gastrointestinal tract.
In the antrum, somatostatin is released by food,
adrenergic nerves, CGRP, and acidification of the lumen.
Antral acidification, the primary mechanism by which
gastrin release is turned off, is accomplished through
release of somatostatin from delta cells, and results in inhibition of G cells. Vagal stimulation inhibits somatostatin
release through both atropine-sensitive muscarinic nerves
and GRP release.
Receptors and Postreceptor Signaling
At least five somatostatin receptors have been cloned.
The multiplicity of the somatostatin receptors gives rise
to diverse signal transduction mechanisms. Both forms
of somatostatin bind to SSTR-1, SSTR-2, and SSTR-3,
but somatostatin-28 binds preferentially to SSTR-2 and
somatostatin-14 to SSTR-5. The receptors belong to the
G-protein-coupled, 7-transmembrane family of receptors,
but in different tissues, different G proteins are implicated.
The long-acting somatostatin analogue octreotide binds
with high affinity to SSTR-2, -3 and -4, but not to
SSTR-1 and -5.
Biological Actions of Somatostatin
Somatostatin is a pan-inhibitor of gastrointestinal
endocrine and exocrine secretion and has variable effects
on motility:
1. Inhibition of hormone and neurotransmitter secretion. Somatostatin inhibits the release of acetylcholine and
of all GI peptides.
2. Inhibition of exocrine secretion. Somatostatin inhibits gastric secretion of acid, pepsin, and ECL-cell histamine. It inhibits pancreatic enzyme and bicarbonate
secretion as well as the bile salt-independent bicarbonate
secretion in bile. It also inhibits intestinal water and electrolyte secretion.
3. Motility. Its effect on motility is variable. While it
stimulates the early phase of gastric emptying, somatostatin inhibits the late phase. While it simulates distal
intestinal migrating motor complexes, it inhibits those in
the gastroduodenum. It inhibits ileal and gallbladder
contraction.
4. Nutrient absorption. Somatostatin is an inhibitor of
nutrient absorption in the intestine.
5. Tissue responses. Through its antitrophic action on
tissues, somatostatin inhibits tissue response to growth
factors.
6. Blood flow. It inhibits splanchnic blood flow.
144 ............................................. Gastrointestinal P eptides and Peptide-S ecreting T umors (Apudomas)
7. Sensation. GRP has an antinociceptive effect and
causes decreased rectal sensation.
GASTRIC INHIBITORY POLYPEPTIDE
Gastric inhibitory polypeptide (GIP) was isolated by
Brown et al. from impure porcine CCK by its inhibitory
effect on acid secretion.
12
Subsequently, the peptide was
found to be more important for its insulin-releasing action
and was renamed glucose-dependent insulinotropic
peptide.
Distribution
GIP is produced by K cells, primarily in the duodenum
and jejunum.
Structure and Synthesis
A linear peptide of 42 amino acid residues, GIP is structurally related to glucagon. The human GIP gene consists
of six exons, with GIP being coded mainly in exon 3.
Release of GIP
GIP is released by oral but not by intravenous glucose and
by emulsified fat and amino acids.
Receptors and Postreceptor Signaling
The GIP receptor has been cloned and is a G-proteincoupled, adenylate cyclase-activating, 7-transmembrane
receptor.
Biological Actions of GIP
The major biological actions of GIP include the following:
1. Inhibition of gastric acid secretion. GIP inhibits
pentagastrin-stimulated acid secretion from denervated
gastric pouches. This inhibitory action can be reversed
by cholinergic agonists. The acidic inhibitory effect in
humans is relatively weak, and GIP is not considered a
major enterogastrone.
2. Intestinal secretion. GIP inhibits intestinal secretion
of water and electrolytes.
3. Stimulation of insulin release. Probably the most important action of GIP, insulin release is considered physiologic. The insulinotropic action of GIP occurs only when
the blood glucose level is raised to 125mg/dL or higher.
GIP also stimulates insulin release from isolated rat islets
in a glucose-dependent manner.
4. Simulation of somatostatin release. GIP releases
somatostatin from the gastric fundus and antrum. The
gastrin inhibitory action in antral mucosa in organ culture
is reversed by somatostatin antibody.
SUBSTANCE P
Substance P (SP) was the first gut peptide to be isolated.
This was accomplished in 1931 by Von Euler and
Gaddum.
13
It is an 11-amino acid peptide belonging to the
tachykinin family, which includes calcitonin gene-related
peptide (CGRP), neurokinin A, neurokinin B, physalaemin, kassinin, and eledoisin.
Distribution
SP is present in the central nervous system. In the GI tract,
it is found in both small-diameter spinal afferent neurons
and in the neurons of the ENS. SP neurons are present in
myenteric plexus and enter the circular muscle. The C
fibers that contain SP are thought to be sensory neurons
and can be lesioned with the sensory neurotoxin capsaicin.
Receptor and Postreceptor Processes
Three receptor subtypes have been characterized: NK1,
NK
2
, and NK3. The NK1receptor is the preferred receptor
for SP. These receptors are G-protein-coupled, 7transmembrane spanning receptors. When activated,
cytosolic inositol triphosphate and calcium are elevated.
Biological Actions of SP
SP and the other tachykinins have several biological
actions, including:
1. Pain. SP mediates central transmission of pain.
2. Neurogenic inflammation. SP and the other tachykinins regulate neurogenic inflammation (vasodilatation
and plasma extravasation) in the gut, airways, skin, and
joints.
3. Motility action. Orad contraction of the peristaltic
reflex (Figure 5.11) is mediated by SP and related peptides.
Excitation of smooth muscle occurs directly and through
the release of acetylcholine from neurons of the myenteric
plexus.
4. Secretion. SP stimulates salivary and intestinal
secretion.
5. Vasodilation. These peptides are potent vasodilators.
6. Sensory innervation. SP mediates sensory innervation of the gut.
CALCITONIN GENE-RELATED PEPTIDE
Calcitonin gene-related peptide (CGRP) is a 37-amino
acid peptide produced by alternative processing of the
glucagon gene in neural tissues. It is a member of the
tachykinin family.
Distribution
CGRP is widely distributed in the gut, both in sensory
afferent C fibers and in the neurons of the ENS. Like SP,
Biological Actions of CGRP
The major biological actions of CGRP include:
1. Sensory neurotransmission along with SP.
2. Gastric mucosal protection (cytoprotection).
3. Release of somatostatin.
4. Powerful vasodilatory action.
5. Potent inhibition of gastric acid secretion, probably
through release of somatostatin.
6. Relaxation of gastric smooth muscle and inhibition of
gastric emptying.
PANCREATIC POLYPEPTIDE FAMILY
Three peptides comprise the pancreatic polypeptide (PP)
family: PP, peptide YY (PYY), and neuropeptide Y (NPY).
Distribution
FIGURE 5.11. The peristaltic reflex. When a bolus of food distends the intestine, two reflex arcs are activated: Proximally,
neural release of ACh and substance P causes contraction; while
distally, peptidergic neurons release VIP, leading to relaxation of
the intestinal musculature. The effect is to propel the bolus of
food distally.
CGRP fibers are present in myenteric plexus, circular
smooth muscle, around submucosal blood vessels and in
the mucosa of the gut. CGRP is also present in the CNS.
Structure and Synthesis
The alternative processing that produces CGRP from
the calcitonin gene is shown in Figure 5.12. The CGRP so
produced is a-CGRP (or CGRP-I). A second CGRP, b-
CGRP (or CGRP-II) is also produced from a gene that
does not encode CGRP. The spinal afferent neurons
express a-CGRP, but both a- and b-CGRP are found in
the CNS and in the gut. CGRP is a 37-amino acid residue
peptide.
Release of CGRP
The islets of Langerhans, particularly in the head of the
pancreas, are the major site of production of PP. No PP
release occurs after total pancreatectomy. PYY cells are
located in the ileal and colonic mucosa.
Structure and Synthesis
PP, PYY, and NPY each contain 36 amino acid residues,
and each have 18 amino acid identities. The PP gene
contains four exons and three introns. Prepropancreatic
polypeptide contains 95 amino acids.
Release of PP
PP is released by protein meals and cholinergic reflexes.
The basal level increases with each myoelectric motor
CGRP is released by the sensory neurotoxin capsaicin. Low
doses of capsaicin stimulate CGRP release, but in high
doses, capsaicin destroys spinal afferent neurons. Little
information exists on the release of CGRP during normal
digestion.
FIGURE 5.12. Production of calcitonin gene-related peptide
Receptors and Postreceptor Signaling
The CGRP receptor is a G protein-coupled, 7-transmembrane receptor that predominantly activates adenylate
cyclase. The CGRP receptor has recently been cloned.
C lassification of Gastrointestinal P eptides ...................................................................................... 145
(CGRP) from the calcitonin gene. The calcitonin gene contains
within it the structure of not only calcitonin but also that of
another peptide, which came to be known as calcitonin generelated peptide. Post-translational processing in the thyroid produces calcitonin. In neurons in the gastrointestinal tract,
however, post-translational processing results in CGRP.
146 ............................................. Gastrointestinal P eptides and Peptide-S ecreting T umors (Apudomas)
complex (MMC). PP is also released by intravenous amino
acids and vagal simulation which occurs during sham
feeding or insulin hypoglycemia. Oleic acid and glucose
also release PP but to a smaller degree than amino acids.
Atropine pretreatment abolishes PP release in response to
vagal simulation. GRP (bombesin) is a potent stimulant of
PP release. Adrenergic and dopaminergic stimulation also
releases PP.
PYY is released by a mixed meal and oleic acid, but
there is no evidence that the vagus nerve releases PYY.
Postprandial PYY release is prolonged and lasts 5 to 6 h.
Receptors and Postreceptor Processes
At least three receptors have been cloned for PP, PYY,
and NPY. They are typical G-protein-coupled,
7-transmembrane receptors.
Biological Actions of the PP Family
The major biologic actions of the PP family include:
1. Gastric acid secretion. PP is a weak stimulant of acid,
but PYY is a potent inhibitor of acid and pepsin.
2. Pancreatic secretion. Both PP and PYY are potent inhibitors of pancreatic protein and bicarbonate
secretion.
3. Biliary motility. PP relaxes the gallbladder and stimulates choledochal sphincter tone.
4. Gastrointestinal motility. PP increases motility in the
stomach and intestine and accelerates gastric emptying
and intestinal transit. PYY inhibits gastric emptying and
the propagation of the interdigestive MMC; it also delays
intestinal transit of food.
5. Vascular effects. Both PYY and NPY are intestinal
and cerebral vasoconstrictors and raise systemic arterial
pressure.
NEUROTENSIN
Neurotensin is a tridecapeptide that was isolated from a
side fraction of the purification of SP from bovine
hypothalamus.
Distribution
Neurotensin is found in N cells, endocrine cells in the ileal
mucosa. N cells are of the open type and have microvilli.
Small quantities of neurotensin are found in jejunum,
stomach, duodenum, and colon. Neurotensin is also found
in the nerves of the ENS and in the brain.
Structure and Synthesis
Neurotensin is released by oleic acid, and fats are the
potent releasers of the peptide. Neurotensin release in
humans is abolished by ileal resection. In monolayer
culture, epinephrine and bombesin release neurotensin,
and somatostatin inhibits its release.
Biological Actions of Neurotensin
The major biological actions of neurotensin include:
1. Vasodilation, cyanosis, increased capillary permeability, and systemic hypertension.
2. Hypoinsulinemia, hypoglycemia, hyperglucagonemia,
and release of histamine.
3. Inhibition of pentagastrin-stimulated gastric acid and
pepsin (i.e., a strong enterogastrone).
4. Stimulation of pancreatic bicarbonate and protein
secretion.
5. Inhibition of gastric emptying.
6. Increased esophageal, intestinal, and colonic motility.
CLINICAL SIGNIFICANCE OF GASTROINTESTINAL PEPTIDES
Gastrointestinal peptides have clinical significance in
three areas, including: (1) peptide-secreting tumors
(apudomas), (2) use in diagnosis and imaging, and (3) use
in therapy.
APUD CONCEPT AND THE DIFFUSE
NEUROENDOCRINE SYSTEM
Before describing the clinical significance of peptides and
peptide-secreting tumors, this section briefly discusses the
inception of the seminal concepts of APUD and the diffuse
neuroendocrine system (DNES).
In 1968, Anthony Pearse (Hammersmith Hospital,
London, England, UK) described the endocrine cells in the
pancreas and the gastrointestinal tract as deriving from the
embryonic neural crest and sharing certain histochemical
characteristics.
14
The shared characteristics included
amine precursor uptake and presence of the enzyme
decarboxylase, which can act on the amine precursors to
convert them into amines and peptides, which endocrine
cells can secrete. Based on these shared features, Pearse
C linical S ignificance ......................................................................................................................... 147
coined the acronym APUD and put forth the hypothesis
that all cells with APUD characteristics are derived from
the neural crest of the embryo.
14
Subsequently, it was shown that the endocrine cells of
the pancreas and the GI tract derive not from the neural
crest but from the foregut endoderm of the embryo.
Nevertheless, the work of Pearse and others after him did
identify a diffuse neuroendocrine system of cells, widely
distributed within and outside the central nervous system.
The gastroenteropancreatic (GEP) family of endocrine
cells forms part of this diffuse neuroendocrine system
(DNES). A list of the component parts of the DNES is
given in Table 5.4.
PEPTIDE-SECRETING TUMORS
(APUDOMAS) OF THE GEP SYSTEM
Tumors arising from cells with APUD characteristics
have come to be known as apudomas. A list of the apudomas of the pancreas and GI tract is given in Table 5.5.
Histologically, all these tumors are carcinoid and, as
such, it is difficult to distinguish benign from malignant
tumors. Most tumors, perhaps more than 66% according
to some studies, are malignant and capable of local
invasion and metastasis. They are given a particular name
(e.g., gastrinoma, insulinoma) because of the predominant immunohistochemically stainable cell and/or peptide
secreted. However, any given apudoma may contain more
than one endocrine cell and may secrete more than one
peptide.
Metastasis is usually to regional lymph nodes and
the liver. These tumors can metastasize more diffusely
but rarely do so. Even when malignant, apudomas are
compatible with long survival. Hence, palliative and
symptomatic care is important in the treatment.
Apudomas may occur in the sporadic form or as part
of the familial condition known as multiple endocrine
neoplasia type 1 (MEN-1). When apudomas occur as part
of the MEN-1 syndrome, they tend to be multicentric,
contain more than one endocrine cell, and secrete more
than one peptide. A secondary peptide often secreted in
the MEN-1 syndrome is pancreatic polypeptide (PP).
Tumors frequently seen in the MEN-1 syndrome
are given in Table 5.6. Those most frequently associated
with islet cell tumors include parathyroid adenoma and
pituitary adenoma. The most common pituitary adenoma
in MEN-1 syndrome is prolactinoma.
Gastrinoma or Zollinger-Ellison Syndrome
In 1955, Drs. Zollinger and Ellison reported on two
patients with severe, intractable and complicated peptic
ulcer disease (PUD) in association with a tumor in the
pancreas.
15
Astutely, they suggested that the pancreatic
tumor was responsible for the peptic ulcer, and the syndrome now bears their names. The terms Zollinger–
Ellison syndrome (ZES) and gastrinoma syndrome are
used synonymously. The essentials of ZES are summarized
in Table 5.7.
Incidence
ZES is rare, occurring in about 1 in 1,000,000 of the
population. Its incidence in individuals with PUD has
been estimated at 1 in 1000 and, in those with ulcer recurrence following an ulcer-reducing surgical procedure, 1 in
50.
16
ZES occurs in two forms, sporadic and familial.
The sporadic form accounts for 70% to 80% of all cases.
The familial form occurs as part of the MEN-1 syndrome,
is transmitted as an autosomal dominant trait, and is due
to LOA on chromosome 11.
Secretory Products
ZES is caused by hypersecretion of gastrin from the tumor.
Gastrin is secreted in several molecular forms, including
G-34, G-17, and G-13. Indeed, these molecular forms of
gastrin were first purified from metastatic gastrinoma in
the liver. In addition to gastrin, the tumor may elaborate
TABLE 5.4. Diffuse Neuroendocrine System
Central division
Pineal gland
Pituitary gland
Hypothalamus
Peripheral division
Gastroenteropancreatic (GEP)
Ultimobranchial body
Parathyroid
Carotid body
Adrenal medulla
Sympathetics
TABLE 5.5. Apudomas of the GEP System
Gastrinoma (Zollinger–Ellison syndrome)
Insulinoma
Glucagonoma
VIPoma
Somatostatinoma
Others
TABLE 5.6. Tumors of the MEN-1 Syndrome
Parathyroid adenoma (90%)
Islet cell tumor (80%)
Pituitary adenoma (65%)
Carcinoid tumors
148 ............................................. Gastrointestinal P eptides and Peptide-S ecreting T umors (Apudomas)
other peptides, the most common being pancreatic
polypeptide (PP). The secretion of PP occurs most commonly when the tumor is part of the MEN-1 syndrome.
The primary effect of hypergastrinemia is acid
hypersecretion. In addition, however, long-term hypergastrinemia has important trophic actions, including:
1. Increased thickening of oxyntic mucosa can occur,
due to parietal cell and mucous neck cell hyperplasia.
2. ECL cell hyperplasia may occur.It is often simple but
can occasionally become micronodular, even adenomatous or dysplastic. Dysplastic hyperplasia is precarcinoid
and may progress to the development of infiltrating
carcinoid tumors of the stomach. The incidence of small
gastric carcinoids in ZES is 3% but increases to 13% when
associated with MEN-1 syndrome.
3. Increased thickening of duodenal mucosa may occur
due to crypt cell hyperplasia.
Gastrin is also trophic to colonic mucosa. A potential
but unproven consequence of long-term hypergastrinemia
may be growth and/or development of colonic polyps
and carcinoma. Epidemiologic studies of long-term hypergastrinemia, however, do not support association with
colonic neoplasia in humans.
Site of Tumor
Prior to the mid-1980s, it was believed that most gastrinomas arose in the pancreas. With the advent of better
imaging techniques and more careful exploration for duodenal gastrinoma, it is now known that 40% to 50% of all
gastrinomas arise in the duodenum. Most of the remainder develop in the pancreas, but 1% to 5% of tumors are
found only in lymph nodes. The latter observation has
provoked a debate as to whether these lymph node gastrinomas are primary or secondary arising from a small
primary in the pancreas or duodenum that cannot be
identified. Similarly, a few gastrinomas have been found in
the liver without any evidence of a primary tumor anywhere. Again, are these hepatic primary tumors? The
answer is unknown.
Clinical Features
ZES is characterized by a pentad of clinical features (Table
5.8).
TABLE 5.7. Essentials: Gastrinoma or Zollinger-Ellison
Syndrome
Incidence
Rare: 1:1,000,000 in U.S. population
Estimated 1:1000 in PUD; 1:50 in recurrent ulcer following
ulcer surgery
Two forms:
䊏
Sporadic form accounts for 70%–80% of cases
䊏
Familial form (autosomal dominant) associated with MEN-1
syndrome due to LOA on chromosome 11
Clinical picture (see Table 5.8)
PUD sometimes severe and intractable
Diarrhea and increased intestinal motility due to acid in
small intestine
Associated tumor in duodenum or pancreas
Etiology
Hypersecretion of gastrin from tumor causes acid
hypersecretion
Other effects include:
䊏
Oxyntic mucosa thickening
䊏
ECL-cell hyperplasia
䊏
Infiltrating carcinoid tumors of the stomach
䊏
Thickening of duodenal mucosa
Diagnosis
History
䊏
Recurrent ulcer despite surgery
䊏
PUD associated with diarrhea
䊏
Multiple ulcers in unusual locations
䊏
Family history of gastrinoma or other neuroendocrine
tumors
Elevated plasma gastrin levels
Positive secretin test
Ratio of basal to maximal acid secretion >0.6
Radiologic findings
䊏
Giant gastric folds
䊏
Marked gastric hypersecretion causing barium flocculation
䊏
Dilated and edematous duodenum
䊏
Ulcers in the jejunum
䊏
Evidence of intestinal hypermotility
MEN-1 syndrome must be ruled out
Tumor localization
Preoperative
䊏
Abdominal ultrasound
䊏
Endoscopic ultrasound
䊏
CT scan
䊏
Secretin or calcium angiography
䊏
125
I-octreotide
䊏
Transhepatic venous sampling
Intraoperative
䊏
Complete exploration
䊏
Intraoperative ultrasound
䊏
Duodenotomy and eversion
Treatment
In the absence of hepatic metastases: Surgical exploration and
resection
In the presence of hepatic metastases: Long-term PPI therapy
Advanced disease: Chemotherapy, debulking procedures
Abbreviations: CT, computerized tomography; ECL, enterochromaffinlike; MEN-1, multiple endocrine neoplasia type 1 syndrome; PPI, proton
pump inhibitor; PUD, peptic ulcer disease.
TABLE 5.8. ZES Pentad of Clinical Features
Peptic ulcer disease
Diarrhea
Acid hypersecretion (BAO/MAO ≥0.6)
Basal hypergastrinemia (>2 times normal)
Positive secretin test (rise in plasma gastrin to twice basal level)
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