![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](https://image.slidesharecdn.com/hormonalcontrolofgitsecretions-160103225815/85/Hormonal-control-of-git-secretions-4-320.jpg)
Hormonal control of git secretions
- 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
- 6. Glucose- dependent insulinotropic 4976 42 Duodenum and jejunum Stimulates insulin release; reduces gastric and intestinal motility; increases fluid and electrolyte secretion from small intestin
- 7. Glucose- dependent insulinotropic 4976 42 Duodenum and jejunum Stimulates insulin release; reduces gastric and intestinal motility; increases fluid and electrolyte secretion from small intestin