710 Proc. roy. Soc. Med. Volume 68 November 1975 Dr S R Bloom (RoyalPostgraduate Medical School, Hammersmith Hospital, London W12)
Gastrointestinal Hormones Gastrointestinal endocrinology is a poorly developed subject with, as yet, little clinical application. This is in spite of the fact that the first hormone discovered, secretin (Bayliss & Starling 1902) was from the gut. The reasons for this slow development are mainly technical. The endocrine system of the gut is, anatomically, both large and complex. Electron microscopists have agreed that there are at least eleven different types of endocrine cell present in the gastrointestinal mucosa and their total mass is very considerable perhaps exceeding all other endocrine systems (Pearce 1973). The proper understanding of an endocrine cell, however, must await the isolation of its hormone product and it is here that difficulties arise. The endocrine cells of the gut are not gathered together as a single gland but are widely scattered; thus purification of their product is very much more difficult than with glandular hormones. Further the gut endocrine cells produce mainly polypeptide hormones which are very susceptible to proteolysis. The gut mucosa is, of course, rich in proteolytic enzymes and once released they result in very rapid destruction of the hormones. A final difficulty in isolation is the problem of knowing what to look for. It is not enough to see a certain endocrine cell present in profusion in electron micrographs. In order to purify the product one must first find out what its hormone does so as to have the means of locating it in an extract. In the last fifteen years, however, some of these technical difficulties have been overcome. First in 1961 secretin was isolated, then in 1964 gastrin and also cholecystokinin-pancreozymin (CCK-PZ), in 1969 a gastric inhibitory peptide (GIP), in 1970 a vasoactive intestinal peptide (VIP) and in 1972 motilin was isolated (Bloom 1974). With hormone purification a breakthrough in understanding can occur because production of specific antibodies allows the identification of the producing cell (immunocytochemistry) and also the measurement of the concentration in blood (radioimmunoassay). There are, thus, seven gut hormones whose role in physiology can be assessed by direct blood measurement: namely, secretin, GIP, VIP, enteroglucagon (using cross-reacting pancreatic glucagon antibodies), gastrin, CCK-PZ and motilin. One of the first features to become apparent was the possession of overlapping or identical actions (Bloom 1974). For example the first three hormones mentioned above all inhibit -
34
gastric acid production and stimulate insulin release. Both gastrin and CCK-PZ stimulate gastric acid and pancreatic enzyme production and both motilin and CCK-PZ have powerful gut motor activity. Similarly the hormones are often released by overlapping or identical stimuli. For instance GIP and enteroglucagon are best released by glucose and fat while gastrin and CCK-PZ are best released by protein breakdown products. The gut hormones are, therefore, more complex to study than such hormones as ACTH or ADH which have well defined actions, free from any significant interfering factors. The gut hormones, par excellence, illustrate the importance of studying hormonal interrelations. The first example of the complexity of the hormonal interrelationships of the gut is in the control of gastric acid. It is necessary to understand this clinically in order to identify any failures in such acid control, as the resulting peptic ulcers are both common and troublesome (Wormsley 1974). Taking first the factors which stimulate acid production, these are recognized to be at least four in number: (1) Food constituents and ambient pH act directly on the gastric parietal cell to control acid output. (2) Acetyl choline from both vagal and local innervation can powerfully stimulate acid production, though there is probably also an inhibitory component to the innervation. (3) Histamine, produced locally in the mucosa, plays an important but ill understood role in acid production and agents which block H2 receptors almost abolish gastric acid production. (4) The classical hormone gastrin, in either the short acting (G17), or long acting (G34) form, is a powerful acid stimulator. The complex details of the control of gastrin release occupy a large and rapidly growing literature but in essence the G or gastrin cell is stimulated by distension and food and inhibited by acid, while its innervation can be either stimulatory or inhibitory. The factors which inhibit gastric acid production are also numerous. As mentioned above these include acid itself and also under certain circumstances the innervation. The hormones secretin, VIP and GIP, the first two released by intestinal acid and the third by glucose and fat, are powerful inhibitors of gastric acid and also greatly reduce gastrin release. The presence of yet further acid inhibitory hormones such as gastrone, bulbogastrone and enterogastrone is postulated. Once the acid is produced it needs to be neutralized and this is accomplished both by a specialized bicarbonate producing gland, the pancreas, or more directly by the intestinal mucosa. Two hormones, secretin and VIP, stimulate pancreatic bicarbonate production, and in some species vagal innervation is also important. Stimulation
35
of the local duodenal mucosal glands (Brunner's glands) is an action of pancreatic glucagon and it can therefore be postulated that this may also be an action of the homologous gut hormone enteroglucagon. There is thus a galaxy of known factors controlling acid production and neutralization and possibly many more yet undiscovered. It is apparent that it is their correct interrelationship which is the all-important factor in achieving the right result, and that the 'cause' of hyperacidity in duodenal ulcer may be no more than a very subtle imbalance. A second example of the importance of interrelationships in connexion with gut hormones is the gut-islet of Langerhans' axis. It has been apparent for a long time that oral glucose causes a far greater release of insulin than the same amount of glucose given intravenously (Rehfeld 1972). Similarly oral glucose causes a greater suppression of pancreatic glucagon release, while oral amino acids result in higher plasma glucagon levels than if given i.v. (Lefebvre & Unger 1972). These effects appear to be hormonally mediated and incretin, insulin releasing peptide, and GIP have been postulated as responsible for the f cell stimulation, while secretin and CCK-PZ may possibly be responsible for the a cell effects. These actions illustrate the general principle of gut hormone metabolic effects. As the gut is the first organ to recognize the definite presence and nature of ingested food it is in a good position to alter the body's metabolic setting to handle it correctly. The consequences of failure in this system are unknown. The recent finding that growth hormone release inhibiting hormone (GH-RIH) was a potent inhibitor, not only of GH but also of TSH, insulin, glucagon and gastrin release (Bloom et al. 1974), has been given added point by the discovery of the presence of GH-RIH in the gut (Luft et al. 1974) as well as the hypothalamus. The suggestion can be made that GH-RIH is a local hormone, perhaps akin to the prostaglandins or substance P, and its role may be analogous to that of histamine in the stomach. Control of body functions is thus highly complex, with both central and local innervation and circulating and local hormonal influences. It may be postulated that if one were actually able to measure all these influences the aid of computers would be needed to handle the results effectively and integrate the resulting mass of data. On the other hand, anything less is inadequate. REFERENCES
Bayliss W M & Starling E H (1902) Proceedings of the Royal Society 69, 352-353 Bloom S R (1974) Gut 15, 502-510 Bloom S R, Mortimer C H, Thorner M 0, Besser G M, Hall R, Gomez Pan A, Roy V M, Russell R C G, Coy D H, Kastin A J & Schally AV (1974) Lancet ii, 1106-1108
Section of Endocrinology
711
Lefebvre P J & Unger R H (1972) Glucagon: Molecular Physiology, Clinical and Therapeutic Implications. Pergamon Press, Oxford Luft R, Efendic S, Hukfelt T, Johansson D & Arimura A (1974) Medical Biology 52, 428-430 Pearce A G E (1973) In: Ninth Symposium on Advanced Medicine. Ed. G Walker. Pitman Medical, London; pp 400-409 Rehfeld J F (1972) Scandinavian Journal of Gastroenterology 7, 289-292 Wormsley K G (1974) Gut 15, 59-81
The following papers were also read: Vitamin D, Parathyroid Hormone and Calcitonin Professor I Maclntyre (Royal Postgraduate Medical School, Hammersmith Hospital, London W12) REFERENCES Evans I M A, Colston K W, Galante L & Maclntyre I (1975) Clinical Science and Molecular Medicine 48, 227-230 Galante L, Colston K W, Evans I M A, Byfield P G H, Matthews E W & Maclntyre I (1973) Nature (London) 244, 438-440 Foster G V, Byfield P G H & Gudmundsson T V (1972) In: Clinics in Endocrinology and Metabolism. Ed. I Maclntyre. W B Saunders, London; pp 93-124
Hypothalamic Hormones Dr C H Mortimer
(St Bartholomew's Hospital, London EC1) Human Thyroid Stimulators Dr B R Smith (Royal Victoria Infirmary, Alewcastle upon Tyne 1) REFERENCE Hall R, Smith B R & Mukhtar E D (1975) Clinical Endocrinology 4, 213
Meeting 11 December 1974 The following short papers were read: Diagnosis of Insulinomas: Value of C-peptide Assay During Insulin-induced Hypoglycaemia Dr R C Turner, Dr L Heding and Dr E Harris (Radcliffe Infirmary, Oxford) Thyroid Uptake of Macromolecules Dr A M Zalin (Department of Experimental Pathology, The Medical School, Birmingham, B15 2TJ) Endocrine Profiles in Amenorrhaea: Incidence and Significance of Hyperprolactin2mia Dr S Franks, Miss A M Jequier, Mr S J Steele, Dr J D N Nabarro (Department of Nuclear Medicine, Middlesex Hospital and Medical School, London WI) Dr M A F Murray and Dr H S Jacobs (St Mary's Hospital Medical School, London W2) Hypothalamic Control of Growth Hormone Secretion Dr J B Ferriss, Dr Judith Bollinger and Dr S Reichlin (Western Infirmary, Glasgow, and Tuft's New England Medical Center, Boston, USA)
Gastrointestinal Hormones Gastrointestinal endocrinology is a poorly developed subject with, as yet, little clinical application. This is in spite of the fact that the first hormone discovered, secretin (Bayliss & Starling 1902) was from the gut. The reasons for this slow development are mainly technical. The endocrine system of the gut is, anatomically, both large and complex. Electron microscopists have agreed that there are at least eleven different types of endocrine cell present in the gastrointestinal mucosa and their total mass is very considerable perhaps exceeding all other endocrine systems (Pearce 1973). The proper understanding of an endocrine cell, however, must await the isolation of its hormone product and it is here that difficulties arise. The endocrine cells of the gut are not gathered together as a single gland but are widely scattered; thus purification of their product is very much more difficult than with glandular hormones. Further the gut endocrine cells produce mainly polypeptide hormones which are very susceptible to proteolysis. The gut mucosa is, of course, rich in proteolytic enzymes and once released they result in very rapid destruction of the hormones. A final difficulty in isolation is the problem of knowing what to look for. It is not enough to see a certain endocrine cell present in profusion in electron micrographs. In order to purify the product one must first find out what its hormone does so as to have the means of locating it in an extract. In the last fifteen years, however, some of these technical difficulties have been overcome. First in 1961 secretin was isolated, then in 1964 gastrin and also cholecystokinin-pancreozymin (CCK-PZ), in 1969 a gastric inhibitory peptide (GIP), in 1970 a vasoactive intestinal peptide (VIP) and in 1972 motilin was isolated (Bloom 1974). With hormone purification a breakthrough in understanding can occur because production of specific antibodies allows the identification of the producing cell (immunocytochemistry) and also the measurement of the concentration in blood (radioimmunoassay). There are, thus, seven gut hormones whose role in physiology can be assessed by direct blood measurement: namely, secretin, GIP, VIP, enteroglucagon (using cross-reacting pancreatic glucagon antibodies), gastrin, CCK-PZ and motilin. One of the first features to become apparent was the possession of overlapping or identical actions (Bloom 1974). For example the first three hormones mentioned above all inhibit -
34
gastric acid production and stimulate insulin release. Both gastrin and CCK-PZ stimulate gastric acid and pancreatic enzyme production and both motilin and CCK-PZ have powerful gut motor activity. Similarly the hormones are often released by overlapping or identical stimuli. For instance GIP and enteroglucagon are best released by glucose and fat while gastrin and CCK-PZ are best released by protein breakdown products. The gut hormones are, therefore, more complex to study than such hormones as ACTH or ADH which have well defined actions, free from any significant interfering factors. The gut hormones, par excellence, illustrate the importance of studying hormonal interrelations. The first example of the complexity of the hormonal interrelationships of the gut is in the control of gastric acid. It is necessary to understand this clinically in order to identify any failures in such acid control, as the resulting peptic ulcers are both common and troublesome (Wormsley 1974). Taking first the factors which stimulate acid production, these are recognized to be at least four in number: (1) Food constituents and ambient pH act directly on the gastric parietal cell to control acid output. (2) Acetyl choline from both vagal and local innervation can powerfully stimulate acid production, though there is probably also an inhibitory component to the innervation. (3) Histamine, produced locally in the mucosa, plays an important but ill understood role in acid production and agents which block H2 receptors almost abolish gastric acid production. (4) The classical hormone gastrin, in either the short acting (G17), or long acting (G34) form, is a powerful acid stimulator. The complex details of the control of gastrin release occupy a large and rapidly growing literature but in essence the G or gastrin cell is stimulated by distension and food and inhibited by acid, while its innervation can be either stimulatory or inhibitory. The factors which inhibit gastric acid production are also numerous. As mentioned above these include acid itself and also under certain circumstances the innervation. The hormones secretin, VIP and GIP, the first two released by intestinal acid and the third by glucose and fat, are powerful inhibitors of gastric acid and also greatly reduce gastrin release. The presence of yet further acid inhibitory hormones such as gastrone, bulbogastrone and enterogastrone is postulated. Once the acid is produced it needs to be neutralized and this is accomplished both by a specialized bicarbonate producing gland, the pancreas, or more directly by the intestinal mucosa. Two hormones, secretin and VIP, stimulate pancreatic bicarbonate production, and in some species vagal innervation is also important. Stimulation
35
of the local duodenal mucosal glands (Brunner's glands) is an action of pancreatic glucagon and it can therefore be postulated that this may also be an action of the homologous gut hormone enteroglucagon. There is thus a galaxy of known factors controlling acid production and neutralization and possibly many more yet undiscovered. It is apparent that it is their correct interrelationship which is the all-important factor in achieving the right result, and that the 'cause' of hyperacidity in duodenal ulcer may be no more than a very subtle imbalance. A second example of the importance of interrelationships in connexion with gut hormones is the gut-islet of Langerhans' axis. It has been apparent for a long time that oral glucose causes a far greater release of insulin than the same amount of glucose given intravenously (Rehfeld 1972). Similarly oral glucose causes a greater suppression of pancreatic glucagon release, while oral amino acids result in higher plasma glucagon levels than if given i.v. (Lefebvre & Unger 1972). These effects appear to be hormonally mediated and incretin, insulin releasing peptide, and GIP have been postulated as responsible for the f cell stimulation, while secretin and CCK-PZ may possibly be responsible for the a cell effects. These actions illustrate the general principle of gut hormone metabolic effects. As the gut is the first organ to recognize the definite presence and nature of ingested food it is in a good position to alter the body's metabolic setting to handle it correctly. The consequences of failure in this system are unknown. The recent finding that growth hormone release inhibiting hormone (GH-RIH) was a potent inhibitor, not only of GH but also of TSH, insulin, glucagon and gastrin release (Bloom et al. 1974), has been given added point by the discovery of the presence of GH-RIH in the gut (Luft et al. 1974) as well as the hypothalamus. The suggestion can be made that GH-RIH is a local hormone, perhaps akin to the prostaglandins or substance P, and its role may be analogous to that of histamine in the stomach. Control of body functions is thus highly complex, with both central and local innervation and circulating and local hormonal influences. It may be postulated that if one were actually able to measure all these influences the aid of computers would be needed to handle the results effectively and integrate the resulting mass of data. On the other hand, anything less is inadequate. REFERENCES
Bayliss W M & Starling E H (1902) Proceedings of the Royal Society 69, 352-353 Bloom S R (1974) Gut 15, 502-510 Bloom S R, Mortimer C H, Thorner M 0, Besser G M, Hall R, Gomez Pan A, Roy V M, Russell R C G, Coy D H, Kastin A J & Schally AV (1974) Lancet ii, 1106-1108
Section of Endocrinology
711
Lefebvre P J & Unger R H (1972) Glucagon: Molecular Physiology, Clinical and Therapeutic Implications. Pergamon Press, Oxford Luft R, Efendic S, Hukfelt T, Johansson D & Arimura A (1974) Medical Biology 52, 428-430 Pearce A G E (1973) In: Ninth Symposium on Advanced Medicine. Ed. G Walker. Pitman Medical, London; pp 400-409 Rehfeld J F (1972) Scandinavian Journal of Gastroenterology 7, 289-292 Wormsley K G (1974) Gut 15, 59-81
The following papers were also read: Vitamin D, Parathyroid Hormone and Calcitonin Professor I Maclntyre (Royal Postgraduate Medical School, Hammersmith Hospital, London W12) REFERENCES Evans I M A, Colston K W, Galante L & Maclntyre I (1975) Clinical Science and Molecular Medicine 48, 227-230 Galante L, Colston K W, Evans I M A, Byfield P G H, Matthews E W & Maclntyre I (1973) Nature (London) 244, 438-440 Foster G V, Byfield P G H & Gudmundsson T V (1972) In: Clinics in Endocrinology and Metabolism. Ed. I Maclntyre. W B Saunders, London; pp 93-124
Hypothalamic Hormones Dr C H Mortimer
(St Bartholomew's Hospital, London EC1) Human Thyroid Stimulators Dr B R Smith (Royal Victoria Infirmary, Alewcastle upon Tyne 1) REFERENCE Hall R, Smith B R & Mukhtar E D (1975) Clinical Endocrinology 4, 213
Meeting 11 December 1974 The following short papers were read: Diagnosis of Insulinomas: Value of C-peptide Assay During Insulin-induced Hypoglycaemia Dr R C Turner, Dr L Heding and Dr E Harris (Radcliffe Infirmary, Oxford) Thyroid Uptake of Macromolecules Dr A M Zalin (Department of Experimental Pathology, The Medical School, Birmingham, B15 2TJ) Endocrine Profiles in Amenorrhaea: Incidence and Significance of Hyperprolactin2mia Dr S Franks, Miss A M Jequier, Mr S J Steele, Dr J D N Nabarro (Department of Nuclear Medicine, Middlesex Hospital and Medical School, London WI) Dr M A F Murray and Dr H S Jacobs (St Mary's Hospital Medical School, London W2) Hypothalamic Control of Growth Hormone Secretion Dr J B Ferriss, Dr Judith Bollinger and Dr S Reichlin (Western Infirmary, Glasgow, and Tuft's New England Medical Center, Boston, USA)
