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Recent Advances in Pancreatic Hormone Research R. G. LONG M.D., M.R.C.P

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Recent Advances in Pancreatic Hormone Research R. G. LONG M.D., M.R.C.P Postgrad Med J: first published as 10.1136/pgmj.59.691.277 on 1 May 1983. Downloaded from Postgraduate Medical Journal (May 1983) 59, 277-282 LEADING ARTICLE Recent advances in pancreatic hormone research R. G. LONG M.D., M.R.C.P. Gastrointestinal Laboratory, St Thomas' Hospital, London SEI 7EH Introduction investigated has been gastric inhibitory polypeptide (also known as glucose-dependent insulinotropic The pancreas secretes 4 major polypeptide hor- polypeptide or GIP) which is a 43 amino acid mones: insulin from the beta cells; pancreatic gluca- polypeptide found in the K cells of the duodenum gon from the alpha cells; somatostatin from the D and jejunum. GIP is released after oral (but not cells in the islets of Langerhans, and pancreatic intravenous) glucose and infusion studies have polypeptide (PP) from the PP cells which are spread shown that, when the blood glucose level is raised more diffusely through pancreatic exocrine and above normal fasting levels, GIP releases insulin. It endocrine tissue. Some or all of these 4 hormones therefore appears that GIP is an incretin, but it may also have paracrine effects; this means that the probably does not explain the whole effect (Sarson peptide is secreted locally and has metabolic effects and Bloom, 1981). This means that the search for copyright. on neighbouring cells. Gastrin is synthesized in G other incretins continues and it seems likely that cells in the foetal pancreas, but these cells disappear interest will now be turned towards the newly postnatally. Certain other polypeptides such as vaso- isolated glicentin. active intestinal polypeptide (VIP) have also been The effects of glycogenolysis and gluconeogenesis demonstrated in human pancreas, but appear pre- of pancreatic glucagon and its release by hypoglycae- dominantly localized to nerves; these substances, mia and infusions of alanine and arginine are well which were initially classified as 'gut hormones', are known. It therefore antagonizes the action of insulin http://pmj.bmj.com/ now thought to be neurotransmitters or neuromodu- and, except in stress situations, its release is most lators of the non-adrenergic, non-cholinergic branch inhibited by a high blood glucose. Some 30 years ago, of the autonomic nervous system. In view of the gut glucagon-like immunoreactivity or enterogluca- multiple modes of actions of these peptides, the gon was recognized and it was subsequently shown descriptive term 'regulatory peptides' is now often that there were large amounts of this material in the used. Basic information about the peptides to be L cells of the terminal ileum, colon and rectum. One discussed is listed in Table 1, but it should be such peptide, probably the most important, was emphasized that many of them exist in multiple glicentin (so named because it has glucagon-like on September 27, 2021 by guest. Protected molecular forms. The purpose of this review is to immunoreactivity) and appeared to be composed of discuss some primarily non-diabetic aspects of the about 100 amino acids. In 1981, Thim and Moody physiology and pathophysiology of pancreatic poly- reported the 69 amino acid sequence of glicentin and peptides which have recently received attention. demonstrated that in the 29 residues 33-61, there was the entire sequence of pancreatic glucagon. Pure Physiology glicentin is now becoming available (Moody et al., The many metabolic functions of insulin are well 1981) and a study by Kirkegaard et al. (1982) in rats known. Recently, much attention has been directed showed that glicentin inhibits pentagastrin-stimu- towards mechanisms of release. When equivalent lated gastric acid secretion, but pancreatic glucagon amounts of glucose are given orally and intrave- does not. Another putative function for glicentin is as nously, a much larger plasma insulin response is seen a trophic factor, particularly on small intestinal with the oral stimulus. It has therefore been postu- villous growth. Glicentin is released into the plasma lated that there is a gut factor or 'incretin' which is in large amounts after a mixed meal and it seems released by the gut after glucose ingestion and causes likely that it will be found to have very different the enhanced insulin secretion. The main candidate physiological effects from pancreatic glucagon. 0032-5473/83/0500-0277 $02.00 © 1983 The Fellowship of Postgraduate Medicine Postgrad Med J: first published as 10.1136/pgmj.59.691.277 on 1 May 1983. Downloaded from 278 R G. Long TABLE 1: Basic information on pancreatic regulatory peptides Probable Molecular Number of main mode weight amino acids of action Main action Insulin 5807 51 Hormone Glucose lowering Pancreatic glucagon 3485 29 Hormone Glucose raising Somatostatin 1640 14 Paracrine Inhibition of hormone release Pancreatic polypeptide 4226 36 Hormone Inhibition of pancreaticobiliary secretions Gastrin 2098 17 Hormone Stimulation of gastric acid secretion Vasoactive intestinal polypeptide 3326 28 Neurotransmitter Noncholinergic, nonadrenergic, neurotransmitter The biological effects of somatostatin are very TABLE 2. Effects of somatostatin great and it has been demonstrated to have a marked inhibitory effect on the secretion of most gastrointes- Inhibition of hormone secretion tinal hormones and fluid secretions (Table 2). Such Site Hormone widespread inhibition has led to the concept that it Pancreas Insulin might be secreted by pancreatic D cells to have local Pancreatic glucagon Pancreatic polypeptide paracrine effects on neighbouring cells, for example, Stomach Gastrin the alpha and beta cells. Wass et al. (1980) have Gut Secretin found considerable plasma somatostatin rises after a Gastric inhibitory polypeptide standard breakfast whereas we have only found rises Motilin copyright. Enteroglucagon after a very large meal. Our demonstration that Neurotensin exogenous somatostatin infusion during a small Anterior Growth hormone meal, to mimic plasma levels seen after a large meal, .Pituitary Thyroid stimulating hormone inhibits plasma hormone secretion suggests that Adrenocorticotrophic hormone Other Calcitonin somatostatin may act via the circulation and fulfil the Renin criteria for being a hormone (Long et al., 1982). Finally, as somatostatin has also been demonstrated Inhibition of gastrointestinal secretion by immunocytochemistry in autonomic nerves, it Gastric acid and pepsin http://pmj.bmj.com/ Pancreatic juice seems possible that it may act as a neurotransmitter Bile flow or neuromodulator as well as a paracrine and Small intestine hormonal substance. This peptide is therefore of particular interest as it may act through all 3 of the Inhibition of other functions Splanchnic blood flow main modes of action attributed to pancreatic and Gall bladder contraction gastrointestinal regulatory peptides. LD5° of phenobarbitone Pancreatic polypeptide remains a hormone of on September 27, 2021 by guest. Protected uncertain function. In man, a large, rapid and Stimulation persistent rise in plasma pancreatic polypeptide Gastric emptying of glucose occurs after a mixed breakfast, but the best stimulus appears to be protein, for example, cod or beef. Pancreatic polypeptide is also released by insulin hypoglycaemia and gastric distension with either a in biliary and pancreatic juice secretion along with balloon or non-nutritive substances. Normal secre- reduced trypsin and bilirubin outputs. This experi- tion is almost entirely under parasympathetic control ment suggests that the persistent rise in plasma and can be inhibited by atropine or truncal vago- pancreatic polypeptide after a meal may be reducing tomy. In dogs, pancreatic polypeptide infusion causes late biliary and pancreatic secretion, but the physio- inhibition of basal and secretin-stimulated pancreatic logical significance of the early rise remains obscure. secretion (Lin et al., 1976). Greenberg et al. (1978) After birth, gastrin disappears from the pancreas, infused bovine pancreatic polypeptide into normal but this hormone keeps its interest as the great human subjects to levels similar to those seen after a majority of gastrin-secreting tumours arise in the standard breakfast and found a significant reduction pancreas. Postgrad Med J: first published as 10.1136/pgmj.59.691.277 on 1 May 1983. Downloaded from Recent advances in pancreatic hormone research 279 Vasoactive intestinal polypeptide (VIP) has been release. Krarup et al. (1979) showed a normal plasma demonstrated in the pancreas in the exocrine paren- pancreatic polypeptide response to insulin-induced chyma and around blood vessels, and VIP receptors hypoglycaemia in diabetes of short duration, but have been demonstrated on pancreatic membranes. found that this deteriorated with time and that the VIP stimulates pancreatic juice and bicarbonate deterioration correlated with parameters of peri- secretion on a dose-dependent basis. When the vagus pheral neuropathy such as reduced vibration sense. is stimulated, there is atropine-resistant, but somato- They concluded that pancreatic polypeptide release statin-sensitive, VIP release (Fahrenkrug et al., 1979). might be used as a test for peripheral neuropathy in These results suggest that VIP is acting as a neuro- diabetics. Two other types of autonomic neuropathy transmitter to control pancreatic exocrine secretion. have also been studied: in Chagas' disease, there is a destruction of post-ganglionic intrinsic cell bodies due to infection with Trypanosoma cruzi, and in Deficiency syndromes chronic autonomic failure (the Shy-Drager syn- Chronic pancreatitis
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