1. HORMONAL CONTROL OF GIT SECRETIONS
The GIT produces a large number of hormones many of whose functions are not well
understood, although some of them, together with neuronal activities, are concerned
with coordinating the secretions of various digestive juices.
Endocrine cells are scattered throughout the entire GIT in clusters forming a diffuse
portion of the endocrine system (Chapter 7.(
Over 25 peptides have been extracted and characterized from the GIT.
No deficiency states are known for any of these peptides although hormone-secreting
tumors have been described.
The G cells in the antral and pyloric regions of the stomach produce gastrin.
Gastrin occurs in a number of molecular forms, for example gastrin17 and gastrin34
are composed of 17 and 34 amino acid residues respectively. Gastrin17 is the most
active and has a half-life of about 8 min. Its precursor, gastrin34, has a half-life of
approximately 40 min. The release of gastrin is stimulated by food entering the
stomach from the esophagus and its function is, in turn, to stimulate release of gastric
juice.
Gastric inhibitory peptide (GIP) is a peptide of 43 amino acid residues secreted by the
duodenum and upper jejunum. It stimulates insulin release (Chapter 7), reduces the
secretions of gastrin and pepsin and inhibits gastric movements.
The hormone, vasoactive intestinal peptide (VIP) is comprised of 28 amino acid
residues. It is released in response to distension of the GIT by food. It stimulates the
contraction of smooth muscle tissues of the GIT wall and pancreatic exocrine
secretions and it also inhibits gastrin and gastric acid release. Pancreatic polypeptide
is formed, as its name implies, by the pancreas and inhibits pancreatic hydrogen
carbonate and protein secretions.
Secretin is also produced in the duodenum and jejunum. It is a 27-amino acid residue
peptide with a half-life of 17 min. Its release is triggered by acid from the stomach
and it functions to stimulate the release of pancreatic juice, the hydrogen carbonate of
which helps neutralize the acid in chyme. Glucose-dependent insulinotrophic
polypeptide (gastric inhibitory polypeptide) is also released in the duodenum and
jejunum. It inhibits the secretion of gastric acid and stimulates insulin secretion.
Mucosal cells in the upper region of the small intestine secrete cholecystokinin
(CCK). Two molecular forms are produced consisting of 33 and 39 amino acid
residues respectively. The release of CCK is stimulated by peptides and fatty acids in
the food and, in turn, stimulates the release of pancreatic juice and contractions of the
gall bladder.
Motilin is a 22 amino acid residue peptide that is structurally unrelated to any other
GIT hormone produced in the upper small intestine. It controls GIT movements
during fasting.
The ileum and colon produce peptide YY and neurotensin. The former decreases
pancreatic and gastric secretions, while the latter may regulate peristalsis of the ileum.
The hormone called substance P is produced along the entire GIT. Its functions
include
Gastrin
Secreted mainly by cells in the stomach in response to eating food (especially protein),
gastrin causes the stomach to produce more acid and stimulates contraction of muscle in
the wall of part of the stomach, ileum, and colon. This contraction propels food through the
digestive tract.
2. Cholecystokinin
Released by the duodenum in response to fats and acid, cholecystokinin causes the
gallbladder to squeeze bile into the duodenum and stimulates the production of pancreatic
enzymes, which pass into the duodenum through the pancreatic duct.
Secretin
Secreted by the lining of the duodenum in response to acid entering from the stomach,
secretin acts on the pancreas to increase the output of bicarbonate, which neutralizes acid
from the stomach. It also increases the release of enzymes from the pancreas.
The secretin family—secretin, which stimulates production of watery, alkaline pancreatic
juices; glucose-dependent insulinotropic peptide, which stimulates insulin release in
response to a mixed meal; vasoactive intestinal peptide (VIP), a stimulator of small-
intestinal and colonic enterocyte secretion of water and electrolytes.
Peptide products of preproglucagon—enteroglucagon, which may be important in gut
adaptation; glucagon-like peptides 1 and 2 and oxyntomodulin, which induce satiety.
Peptide products of preproghrelin—ghrelin, which is the only hormone known to stimulate
food intake; obestatin, whose physiological function is uncertain; and motilin, which
accelerates intestinal transit.
Peptide tyrosine tyrosine (PYY), which slows intestinal transit, and neuropeptide Y, which is
a potent vasoconstrictor, inhibits intestinal secretion, and depresses colonic motility.
Others—bombesin and the gastrin-releasing peptides; opioids; tachykinins; other gut
peptides—neurotensin; somatostatin; chromogranin-derived peptides; and other peptide
neurotransmitters
Carcinoid syndrome
Carcinoid tumours are capable of producing serotonin (5-hydroxytryptamine; 5-HT).
Carcinoid syndrome occurs in about 10% of patients with carcinoid tumours, usually
midgut tumours that have metastasized to the liver. The cardinal feature is the carcinoid
flush; other characteristic symptoms are secretory diarrhoea, cramping abdominal pain,
nausea, and vomiting; and about 50% of patients have cardiac valve abnormalities. The
diagnosis is made on the basis of elevated concentrations of 5-hydroxyindoleacetic acid in
a 24-h urine collection, with localization by octreoscan (using radiolabelled octreotide),
ultrasonography/CT, or endoscopy. Treatment is with simple antidiarrhoeal agents and
octreotide, a long-acting, subcutaneously administered, somatostatin analogue. The 5-year
survival rates for carcinoids (depending on location) are 33 to 98%
At pharmacological doses, glucose-dependent insulinotropic peptide inhibits gastric
secretions, hence its original name of gastric inhibitory peptide (GIP). However, its
physiological role appears to be as a component of the enteroinsular axis, being released
in response to a mixed meal, particularly carbohydrates and long-chain fatty acids, and
stimulating insulin release. This incretin effect, also exerted by GLP1 (see later), has been
shown to be accompanied by increased levels of cAMP in islet β cells with consequent
increased cell mass and resistance to apoptosis.
Vasoactive intestinal peptide (VIP)
VIP is a 3326-Da peptide neurotransmitter of 28 amino acids widely distributed throughout
the central and peripheral nervous systems. Its highest concentrations occur in the
submucosa of the intestinal tract, where it is found in postganglionic intrinsic nerves. It is
3. a potent stimulator of small-intestinal and colonic enterocyte secretion of water and
electrolytes, acting via elevation of cAMP. Other important actions include smooth-muscle
relaxation, both in the alimentary tract and in the systemic vasculature; stimulation of
insulin release, counteracted by a direct glucagon-like effect of VIP in stimulating hepatic
gluconeogenesis and glycogenolysis; stimulation of pancreatic bicarbonate secretion; and
relaxation of the gallbladder, pyloric sphincter, and circular muscle of the small intestine
with contraction of the longitudinal muscle.
Peptide histidine methionine, a neuropeptide of 27 amino acids with considerable sequence
homology to VIP, is derived from the adjacent exon of the prepro-VIP gene. It mimics the
actions of VIP, probably acting via the same receptor, but is less potent.
Another peptide with considerable sequence homology to VIP is pituitary adenylate
cyclase-activating peptide, which occurs in forms with 27 and 38 amino acids. It has a
similar tissue distribution to VIP, sharing the same receptor outside the central nervous
system and pituitary gland, and similar actions on
Glucagon-like peptide 1
The most common circulating form of glucagon-like peptide 1 is as GLP-17–36 NH2. It is
released after a meal and, in humans, is the most potent incretin. It induces satiety,
inhibiting secretion of glucagon and potentiating the release of somatostatin.
Glucagon-like peptide 2
This appears to stimulate motility and absorption and has trophic effects on the intestine
Ghrelin
Studies on growth hormone (GH) secretagogues led to the identification of a specific G-
protein-coupled receptor termed the GH secretagogue receptor (GHSR). Subsequently, the
endogenous ligand for this receptor was identified as an acylated peptide of 28 amino
acids, called ghrelin, cleaved from a 117 amino acid precursor, preproghrelin. Ghrelin and
motilin (see below), along with their precursors and receptors, are structurally related,
leading to suggestions that they form a new family of peptides. Ghrelin is a circulating
hormone secreted predominantly from the oxyntic mucosa of the stomach but is found in
other areas of the gut. Its major action is to stimulate food intake. It is, to date, the only
known orexigenic hormone and, as such, it opposes the satiety signal leptin
Motilin
Motilin, a 2700-Da peptide of 22 amino acids, secreted by small intestinal M cells, was first
characterized in 1971. Peaks in motilin secretion coincide with initiation of the duodenal
myoelectric complex, and so motilin appears to control the reflex motor activity of the
small intestine, keeping the small intestine free of debris. Circulating amounts of motilin
rise after a meal or drinking water and it may have a physiological role in accelerating
gastric emptying and colonic transit. Macrolide antibiotics, e.g. erythromycin, are motilin
receptor agonists, hence their side effects of diarrhoea and abdominal cramps.
Peptide tyrosine tyrosine (PYY) and neuropeptide Y
The pancreatic polypeptide-fold (PP-fold) family includes the gut hormone peptide tyrosine
tyrosine, the neurotransmitter neuropeptide Y, and, in the pancreatic islets, pancreatic
polypeptide. All are 36 amino acid peptides that require C-terminal amidation for
bioactivity and share the PP-fold structural motif. They interact with the Y family of
receptors that couple to inhibitory G proteins and are probably derived from a common
ancestral gene.
Peptide tyrosine tyrosine
4. Peptide tyrosine tyrosine (PYY) is a 36 amino acid peptide found in the L cells of the distal
gut. It is released into the circulation following a meal, mostly as PYY3–36, and its levels are
reduced during fasting. Its main function appears to be to slow intestinal transit, allowing
more time for absorption. Other actions include delaying gastric emptying, decreasing
intestinal motility, and inhibiting gastric acid secretion. Clinical trials are testing the
efficacy of PYY3–36 as an antiobesity agent.
Neuropeptide Y
Neuropeptide Y is a 36 amino acid peptide neurotransmitter, which is often colocalized with
noradrenaline. It is found in both extrinsic adrenergic nerves to the myenteric plexus and
in intrinsic nerves in the myenteric and submucosal plexi, and highest concentrations occur
in the upper intestine and distal colon. It is a potent vasoconstrictor, inhibits intestinal
secretion, and depresses colonic motility
Somatostatin
Somatostatin was initially isolated from the hypothalamus as a 1640-Da peptide of 14
amino acids that inhibited the release of GH. It is widely distributed throughout the central
and peripheral nervous systems and is found in a variety of endocrine tissues. In the
gastrointestinal tract, it occurs in 14 and 28 amino acid forms secreted by specialized (D)
cells distributed throughout the gut mucosa and on the inner rim of the pancreatic islets.
D cells have all the characteristics of endocrine cells, but also possess axon-like basal
elongations along which the peptide can be transported and secreted directly on to local
cells. Somatostatin inhibits hormone release, blocks the response of the effector tissue and
inhibits a wide range of gastrointestinal functions (Table 1). Five human somatostatin
receptors have been identified and cloned, the type 1 receptor predominating in the
gastrointestinal tract. As gastrointestinal and other neuroendocrine tumours often possess
high-density somatostatin receptors, scintigraphy with radiolabelled somatostatin
analogues has been used for tumour localization
Characteristics of Prominent Forms of Principal Gut Regulatory Peptides[1]
Hormone/Peptide
Molecular
Weight (Da)
No. of
Amino
Acids
Main Gut
Localization
Principal Physiologic
Actions
Gastrin Family
Cholecystokinin 3918
33 (also
385, 59)
Duodenum and
jejunum, Enteric
nerves
Stimulates gallbladder
contraction and intestinal
motility; stimulates
secretion of pancreatic
enzymes, insulin,
glucagon, and pancreatic
polypeptides; has a role
5. in indicating satiety; the
C-terminal 8 amino acid
peptide cholecystokinin
(CCK)-8 retains full
activity
Little gastrin 2098 17
Both forms of
gastrin are
found in the
gastric antrum
and duodenum
Gastrins stimulate the
secretion of gastric acid,
pepsinogen, intrinsic
factor, and secretin;
stimulate intestinal
mucosal growth;
increase gastric and
intestinal motility
Big gastrin 3839 34
Secretin-
Glucagon Family
Secretin 3056 27
Duodenum and
jejunum
Stimulates pancreatic
secretion of HCO3,
enzymes and insulin;
reduces gastric and
duodenal motility, inhibits
gastrin release and
gastric acid secretion
Vasoactive
intestinal
polypeptide (VIP)
3326 28 Enteric nerves
Relaxes smooth muscle
of gut, blood vessels,
and genitourinary
system; increases water
and electrolyte secretion
from pancreas and gut;
releases hormones from
pancreas, gut, and
hypothalamus
