Gastrointestinal Hormones - pediagenosis
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Tuesday, November 5, 2019

Gastrointestinal Hormones

Gastrointestinal Hormones
Clinical background
Neuroendocrine tumours of the gastrointestinal system are rare tumours that usually present with manifestations related to the actions of the peptide that they secrete. Functioning neuroendocrine tumours include: the pancreatic tumours insulinomas (insulin secreting), VIPomas (vasoactive intestinal polypeptide), glucagonomas (glucagon), gastrinomas (gastrin) and somatostatinomas (somatostatin) and the small bowel tumours carcinoids (5HIAA), gastrinomas (gastrin) and somatostatinomas (somatostatin). Pancreatic tumours may form part of the MEN 1 syndrome and sometimes secrete a number of other hormones including ACTH (presenting as Cushing’s syndrome), GHRH (causing acromegaly), and PTHrP (presenting with hypercalcaemia). Patients with insulinomas present with hypoglycaemic symptoms; those with gastrinomas have complex peptic ulcer disease with diarrhoea; VIPomas cause diarrhoea, acid–base disturbances and glucose intolerance and an erythematous rash; glucagonomas cause a typical necrolytic skin lesion associated with glucose intolerance, bowel disturbance, neuropsychiatric problems and venous thrombosis; and somatostatinomas present with steatorrhoea, gallstones and diabetes. Carcinoid tumours are the most common of the group, presenting with flushing, diarrhoea, bronchospasm, arthropathy and cardiac complications. All these tumours are extremely rare and require specialist management by multidisciplinary teams of endocrinologists, surgeons, radiologists and oncologists.

Gastrointestinal Hormones

Gastrointestinal endocrine hormones are principally peptides. Many peptides are synthesized by GIT cells but their role as hormones is unclear. The GIT hormones release enzymes necessary for digestion; they enhance enzyme activity by stimulating the release of bile acids, which provide an optimal acid pH for many enzymes, and the bile salts; some alter GIT motility. Possible mediators of acid secretion and duodenal pH control are shown in Table 43.1.
Biosynthesis, chemistry and release The GIT hormones are synthesized in ‘clear’ cells, named because of their selective staining with silver salts, and are widely diffused throughout the gut, thus giving rise to the DES, or diffuse endocrine system of the gut. Gut cells have been arbitrarily named, for example G cells (gastrin-secreting), S cells (secretin-secreting), D cells (somatostatin-secreting), K cells (gastric inhibitory peptide-secreting) and I cells (chole-cystokinin-secreting). The GIT hormones are conveniently grouped according to their structural similarities into two main families – the gastrin and secretin families (Fig. 43a).
The secretin family of peptides, namely secretin, glucagon, VIP and gastric inhibitory peptide (GIP) share sequence homology in many amino acids. Secretin and glucagon have 14 amino acids in common. The gastrin family is so-called because gastrin and cholecystokinin (CCK) have identical C-terminal sequences of the first five amino acids (Fig. 43b).
Gastrin is secreted by the G cells in the gastric antrum and the duodenum, and exists in the circulation in several forms, the major ones being G17 and G34, representing the numbers of amino acids in each. G17 is found in the stomach and G34 mainly in the duodenum, and, in humans, in the circulation. The main physiological actions of gastrin are to release HCl from the parietal cells of the stomach (Fig. 43a), and to regulate growth of the gastric mucosa. The acidic gastric juice produced by gastrin excites pepsinogen secretion from the chief cells and secretin release from the S cell. Gastrin release is stimulated mainly by food and to a lesser extent by free fatty acids, amino acids and peptides, but dietary sugars do not release gastrin. The hormone is also released following autonomic vagal stimulation. Gastrin increases motor activity in the GIT, stimulates enzyme secretion from the pancreas, relaxes the pyloric sphincter and increases lower oesophageal sphincter pressure. The mechanism of HCL release from the gastric parietal cell is shown in Fig. 43c. Cholecystokinin (CCK). CCK-secreting cells (I-cells) occur mainly in the duodenum and the proximal jejunum. CCK has also been described in neurones innervating the distal intestine. In the GIT, CCK is released in response to certain amino acids, particularly tryptophan and phenylalanine, lipids and free fatty acids. CCK contracts the gall bladder and stimulates the release of pancreatic enzymes. CCK stimulates glucagon release, as does VIP. CCK enhances the action of secretin in stimulating bicarbonate release from the pancreas, and it delays gastric emptying. CCK, or a related peptide, may serve as a satiety hormone.
Secretin. In humans, secretin is found predominantly in the granular S cells in the villi and crypts of the small intestinal mucosa. Secretin is released in response to acidification of the contents of the duodenum, that is the entry of gastric fluids. Secretin is not released above a pH of 4.5. Its major action is to stimulate bicarbonate secretion from the pancreas, and it potentiates CCK-invoked release of pancreatic enzymes. Clearly, there is a negative-feedback relationship between secretin and bicarbonate which inhibits secretin release.
Vasointestinal peptide (VIP). Human VIP is a strongly basic polypeptide of 28 amino acids, belonging to the secretin family of peptides. VIP is widely distributed throughout the body, but especially in the GIT, where it occurs from oesophagus to rectum. VIP-containing neurones are especially concentrated in the jejunum, ileum, colon, gall bladder wall, the sphincters and the pancreas. VIP release from cells is known to be modified by other neurones, which contain opioids or somatostatin as neurotransmitters. An important function of VIP within the gut may be to promote descending relaxation, as it is released only during relaxation.
Gastric inhibitory peptide (GIP) is a 42 amino acid poly- peptide of the secretin family, present in the GIT at highest concentrations in the duodenum and jejunum. GIP release is stimulated by glucose, amino acids and free fatty acids, and release may also be modified by other hormones. An important action of GIP is to enhance insulin secretion under conditions of hyperglycaemia. Glucose taken orally is more potent in stimulat- ing insulin release than when taken intravenously, and this may be explained by the stimulant effect of glucose on GIP release. Gastrin-releasing peptide (GRP) is a 27 amino acid (porcine) peptide present in the brain and GIT neurones. GRP, when introduced into rat brain, causes gastrin release from the G cell. GRP has been localized to nerve cells in the antral mucosa, and has been shown to produce a release of gastrin.
Enteroglucagon is the name given to a heterogeneous group of peptides within the gut. These are fragments of the proglucagon molecule, and include a peptide termed oxyntomodulin, and glicentin and GRP. The highest concentrations occur in the ileum and colon, and about 60–80% of the activity is accounted for by glicentin. The peptides are released by food in the gut, which is not the stimulus for glucagon release.
Ghrelin is a peptide hormone synthesized and released from the fundus of the stomach. Ghrelin potently stimulates growth hormone release from the pituitary. It is also orexigenic (promotes feeding behaviour) through an action in the hypothala- mus (see also Chapter 45) and is therefore part of the energy balance system.
Motilin is a peptide secreted in the small intestine and is chemically unrelated to other known GIT hormones. Motilin causes periodic contractions of the muscles of the upper GIT, and may perform ‘housekeeping’ duties to keep the GIT free of undigested material.

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