Progress Report Hormonal Control of Pancreatic Endocrine and Exocrine Secretion

Gut: first published as 10.1136/gut.13.2.154 on 1 February 1972. Downloaded from

Gut, 1972, 13, 154-161

Progress report Hormonal control of pancreatic endocrine and exocrine secretion

The known inhibitory effect of glucagon on pancreatic exocrine secretion has recently been applied to the treatment of acute pancreatitis'. The use of this promising therapeutic agent follows considerable advances made in recent years in the understanding of the hormonal control of pancreatic endocrine and exocrine secretion. Mechanisms of autonomic nervous control and of neuro-hormonal interactions in the pancreas have recently been reviewed by Brooks2 and Dupr63. Three questions about the hormonal control of pancreatic secretion need to be asked: How do pancreatic hormones (insulin and glucagon) affect exocrine pancreatic function (endocrine-exocrine interactions); how do hormones from the gastrointestinal mucosa affect endocrine function of the pancreas (entero-endocrine reactions); how do gastrointestinal hormones affect exocrine pancreatic function (entero-exocrine interactions)? Endocrine-exocrine Interactions http://gut.bmj.com/ There is evidence that the pancreatic hormones, insulin and glucagon, influence enzyme synthesis and release in the exocrine pancreas. Acinar cells in the rat pancreas show progressive degranulation and atrophy after repeated injections of glucagon4,5 6. The inhibitory effect of glucagon on pancreatic exocrine secretion was first demonstrated by Zajtchuck and colleagues7.

Intravenous glucagon given to two subjects with pancreatic fistulae caused a on September 24, 2021 by guest. Protected copyright. 90% reduction in pancreatic juice volume and amylase. Dyck and his associates gave physiological doses of glucagon intravenously to the dog8 and mang while stimulating pancreatic secietion with secretin and pancreozymin. Marked inhibition ofenzyme output was noted and there was some reduction in volume flow while electrolyte concentrations were unchanged. The effect occurred within a few minutes, indicating inhibition of enzyme release rather than of synthesis. Knight and his coworkers' treated three attacks of acute pancreatitis occurring in two patients with intravenous glucagon and the clinical condition of the patients improved rapidly. One patient received two intravenous injections of glucagon and the abdominal pain disappeared after four hours and the plasma amylase fell after seven hours. The second patient received a loading dose of glucagon followed by a glucagon infusion on two separate occasions. The pain was relieved and the plasma amylases fell after one hour. Although the trial was not controlled and the number of subjects small the results are promising and suggest that further use of the drug in the treatment of acute pancreatitis is indicated. Progressive damage to pancreatic acinar cells is caused by insulin deficiency. The pancreatic exocrine tissue in diabetic man becomes fibrosed and shows reduced response to hormonal stimulation10""1 and reduced pancreatic 154 Gut: first published as 10.1136/gut.13.2.154 on 1 February 1972. Downloaded from

Hormonal control ofpancreatic endocrine and exocrine secretion 155 uptake of selenomethionine12"13 the changes being partictlarly marked in insulin-dependent diabetics. Dogs rendered diabetic with anterior pituitary extract14 or alloxanl5 show damage to exocrine tissue, and alloxan given to rats results in a twenty-fold reduction in pancreatic amylase which returns to normal with insulin treatment'6. Insulin also increases synthesis of chymotrypsinogen in the pancreas of normal rats on an exclusively protein diet'6, and it was suggested that insulin controls the synthesis of chymotrypsinogen by favouring the entry of amino acids into the acinar cells and the synthesis of amylase by favouring the entry of glucose. Certainly insulin has been shown to promote amino acid incorporation and protein synthesis in isolated muscle'7 and secreting mammary gland'8. The role of insulin in protein synthesis has recently been reviewed by Wool'9 and Manchester20. There is some morphological evidence to indicate that pancreatic exocrine function may be influenced by pancreatic endocrine hormones. Henderson2' has suggested that the endocrine tissue of the pancreas is fragmented into islets throughout the exocrine tissue thereby ensuring high concentrations of pancreatic hormones around the acinar cells which might have been of evolutionary advantage. In the human pancreas blood in the lobular arterioles first passes to the endocrine islet tissue and then forms a capillary plexus among the externally secreting acini2",22. Henderson suggests that blood from the islets bathes the acinar cells by way of an islet-exocrine portal system. This relationship is found in reptiles, birds, and mammals. Primitive fish have a separate endocrine pancreas but cartilaginous fish show some endo- exocrine integration in having a double layer of cells lining the pancreatic ducts, a luminal layer of exocrine cells and an outer layer of endocrine cells. The fatty fibrosis of pancreatic exocrine tissue which follows diabetes http://gut.bmj.com/ mellitus is not reversed by therapeutic doses of insulin and Henderson argues that this is evidence in favour of acinar cell integrity depending on locally high concentrations of insulin delivered via the islet-exocrine portal system. Hansson23 has provided further evidence which may indicate pancreatic endocrine-exocrine interaction. Autoradiographs of mouse pancreas prepared

after intravenous injection of 35S-methionine show that the amino acid is on September 24, 2021 by guest. Protected copyright. taken up markedly more strongly by the acinar cells surrounding the endocrine islets than by the cells remote from the islets. Kramer and Tan24 have confirmed this observation and have shown that zymogen granules are more abundant in the periinsular acini but decrease to the levels of normal acini after islet destruction by alloxan. This suggests that insulin exerts a trophic effect on the periinsular acini by promoting amino acid uptake. Cells which have the ultrastructural features of both endocrine and exocrine cell types (intermediate cells) have recently been demonstrated25. The fact that the intermediate cells occur mainly in the islets and periinsular acini and contain insulin and glucagon as well as secretory enzymes may indicate that the islet and periinsular acinar cells have a common origin and that functional endocrine-exocrine interactions are more complex than previously thought. The significance, in this context, of the hypothesis26 that the islet cells and the polypeptide hormone-secreting cells of the gastrointestinal tract have a common origin from the neural crest of the embryo remains to be evaluated. There is thus some phylogenetic, embryological, morphological, patho- physiological, and biochemical evidence of interaction between the endocrine and exocrine pancreas. The enhancement by insulin of amino acid uptake and synthesis would be highly relevant in the pancreas, for the pancreatic Gut: first published as 10.1136/gut.13.2.154 on 1 February 1972. Downloaded from

156 Giles Youngs acinar cells take up amino acids from the blood for enzyme synthesis more avidly than any other organ in the body23'27. Promotion of amino acid uptake by insulin may explain why the uptake of amino acids is most pronounced in the acinar cells surrounding the islets and such an endocrine-exocrine interaction would fit Henderson's hypothesis. The role of the intermediate cells and the physiological significance of exocrine inhibition by pancreatic glucagon remain to be clarified. Entero-endocrine Interactions Pancreatic insulin and glucagon secretion is influenced by many hormones, including those released from the gastrointestinal tract. It is known that insulin28 and glucagon29 release from the pancreas is directly and reciprocally controlled by the blood glucose concentration. In addition insulin secretion is directly stimulated both by amino acids30 and fatty acids31 and glucagon is released by amino acids32. Although the direct effects of nutrients on the endocrine pancreas appear to stimulate or inhibit release ofinsulin or glucagon appropriate to the physiological need it is becoming increasingly evident that hormonal control of insulin secretion plays an equal if not more important role. Glucagon is known to be a potent stimulus to insulin release~3'34'35 and adrenaline is a powerful inhibitor36'37. Insulin, in turn, affects glucagon secretion, for Unger and his associates38,39,40 have recently shown that normal suppression of glucagon secretion by hyperglycaemia does not occur when severe insulin deficiency is produced and this may explain the high levels of glucagon in the blood of subjects with diabetes mellitus. It is possible that http://gut.bmj.com/ these high levels of glucagon are partly responsible for the depressed exocrine function in this disease. Glucose given by mouth is cleared more rapidly from the blood than glucose injected intravenously41. McIntyre and his associates42 showed that delivery of glucose into the intestine in man is followed byhigher blood levels of insulin than those reached when similar levels of blood glucose are produced by intravenous infusion. Since this enhancement ofinsulin release is not abolished on September 24, 2021 by guest. Protected copyright. by portacaval anastomosis43 it appears that the higher levels of insulin and enhanced glucose tolerance following absorption of glucose from the gut are due to an intestinal factor, possibly a hormone. The suggestion that there is a hormone in the gastrointestinal mucosa which stimulates insulin secretion is not a new one. Moore and his colleagues44 in 1906 suggested that the duodenum elaborates a hormone which excites the internal secretion of the pancreas. La Barre and his coworkers45'46'47 showed that the intravenous injection of a duodenojejunal extract into dogs causes hypoglycaemia and this effect is mediated by the pancreas. La Barre suggested the name 'incretin' for this intestinal factor which promotes glucose disposal. These early studies have been reviewed by Babkin48 and McIntyre49. Several of the hormones released from the intestinal mucosa are capable of stimulating insulin release but it is not yet known which hormone is the main stimulus to insulin secretion after glucose ingestion. The main candi- dates are secretin, pancreozymin-cholecystokinin, and enteroglucagon, a glucagon-like hormone found in the gastrointestinal mucosa. Blood concentration of a substance with glucagon-like immunoreactivity increases after absorption ofglucose from the gut ofman'50'5 and dog52 but after intravenous glucose infusion immunoreactive glucagon levels fall51. This suggests that Gut: first published as 10.1136/gut.13.2.154 on 1 February 1972. Downloaded from

Hormonal control ofpancreatic endocrine and exocrine secretion 157 oral glucose stimulates release of immunoreactive glucagon from the gut but that intravenous glucose inhibits release of pancreatic glucagon by a direct effect on the pancreas. A substance with glucagon-like immunoreactivity has been found in the gastrointestinal mucosa53 and has been called 'gut glucagon' or 'enteroglucagon'. This substance has been shown to stimulate insulin release52 and could therefore be the intestinal factor which promotes glucose disposal during absorption from the gut. Cells containing a substance with glucagon-like immunoreactivity have been localized in the gastric fundus and jejunum of the dog using an immunofluorescent technique54. Entero- glucagon can be distinguished from pancreatic glucagon by immunoassay"3'5 and has twice the molecular weight and lacks the effects of pancreatic glucagon on liver glycogenolysis. Other gastrointestinal hormones may also enhance glucose disposal in response to food in the gut lumen. Ingestion of glucose causes a rapid and large increase in circulating secretin-like activity56 and purified secretin given into the portal vein of the dog57 and man58 or into a peripheral vein59,60 causes a significant rise in insulin release from the pancreas. The role ofsecretin in the normal physiological response to oral glucose has been cast in doubt by studies which fail to show a rise in plasma insulin after duodenal infusion of acid6'62 and no evidence of exocrine pancreatic stimulation (secretin effect) after intraduodenal glucose in man63. More recently Chisholm and his associates64 have shown that an infusion of hydrochloric acid into the duodenum of man causes elevation of serum secretin and insulin levels. Further studies65 showed that the peak insulin response occurs 30 minutes after the peak secretin level and that the rise in blood insulin is greater and more prolonged than would be expected from the glycaemic stimulus alone or from the short-lived rise in blood secretin level. A continuous secretin http://gut.bmj.com/ infusion before the glucose ingestion was found greatly to potentiate the insulin response. This suggests that secretin has a dual role in insulin release, an early direct stimulation associated with raised secretin levels in the blood, followed by a prolonged potentiation of the glycaemic stimulus to insulin release which continues well after peripheral secretin levels have declined. It has also been shown studies in vitro66'67 that secretin does not release

by on September 24, 2021 by guest. Protected copyright. insulin unless the exocrine pancreas is intact and this could be a further example of the mutual relationship mentioned earlier between the endocrine and exocrine pancreas. Pancreozymin-cholecystokinin is the third intestinal hormone which may be responsible for the release of insulin after oral glucose68, the stimulus to insulin release in this case being independent of the integrity of the exocrine pancreas67. In addition, pancreozymin-cholecystokinin is the only gastrointestinal hormone that has been shown to stimulate glucagon release from the pancreas57'69. As pancreatic glucagon is a potent stimulus to insulin release"3'34'35, pancreozymin-cholecystokinin could act as the stimulus for insulin secretion by a dual mechanism. It is possible that pancreatic glucagon released by pancreozymin-cholecystokinin partly counteracts insulin promotion of hepatic glycogen synthesis, allowing glucose to be acted on by insulin at peripheral sites. Thus enteroglucagon, secretin, pancreozymin-cholecystokinin (and probably the chemically similar gastrin) may all fulfil the role of the hypothetical hormone, 'incretin', and act as signals for the release ofinsulin on the arrival of food in the gastrointestinal tract. Such an action would fillaphysiological need. Gut: first published as 10.1136/gut.13.2.154 on 1 February 1972. Downloaded from

158 Giles Youngs Entero-exocrine Interactions The actions of gastrin, secretin, and pancreozymin-cholecystokinin on the pancreas are well documented but incompletely understood. The mechanisms of release of these hormones have been reviewed recently by Wormsley70. It is known that these hormones have multiple and overlapping effects and the probability that gastrin serves as a direct stimulus to the release of secretin"4 and secretin appears to inhibit gastrin release7' directly makes it likely that pancreatic exocrine secretion is serially controlled by more than one hormone. The synergistic actions between hormones72 73,74 and the difficulty of choos- ing physiological doses and administering them by way of the physiological portal venous route further complicates investigation. Chemical identification of the major gastrointestinal hormones has led to the develop- ment of radioimmunoassay of gastrin75, secretin58, and pancreozymin- cholecystokinin76, and this technique will be ofundoubted value in our further understanding of the physiological roles of these hormones. The possible role ofenteroglucagon in stimulating insulin release has already been mentioned and it seems possible that enteroglucagon, like pancreatic glucagon, inhibits pancreatic exocrine secretion. Dyck and his associates77 gave intrajejunal glucose to man while stimulating pancreatic secretion with secretin and pancreozymin. Bicarbonate concentration fell by 25% and volume by 50% and the fall was paralleled by a rise in blood levels of immunoreactive glucagon, presumed to be enteroglucagon. There was no change in enzyme concentration, contrasting with the marked fall in enzyme concentration after the intravenous infusion of pancreatic glucagon mentioned earlier8. It was postulated that pancreatic http://gut.bmj.com/ glucagon inhibits enzyme release while enteroglucagon inhibits volume flow and electrolyte secretion by the pancreas. The stimulus for this possible feedback mechanism would be the arrival of food in the intestine. The enteroglucagon released would regulate volume and electrolyte secretion while pancreozymin-cholecystokinin would, as mentioned earlier, stimulate release of pancreatic glucagon which in turn would regulate secretion of enzymes. However, the intrajejunal glucose used in this experiment was in 50% on September 24, 2021 by guest. Protected copyright. solution and the physiological relevance of the findings remains to be substantiated. Grossman78 has postulated that gastrin, pancreozymin-cholecystokinin, secretin, and probably glucagon act on one receptor. The receptor has two interacting sites-one with affinity for the chemically similar gastrin and pancreozymin-cholecystokinin and one for secretin and probably the chemically similar glucagon. The hypothesis predicts that all targets that react to one of these hormones will react to the other two and probably glucagon as well. Simultaneous action of two hormones leads to competitive or non- competitive augmentation or inhibition, depending on whether the hormones are acting on the same or different interaction sites and whether the hormones acting on the receptor are stimulating or inhibitory. Glucagon appears to act on the receptor in a similar fashion. It shares with secretin choleretic79 and insulinotropic333435 effects and the inhibitory influence on gastric acid secretion80 but the effects of glucagon on hepatic glycogenolysis and gluconeogenesis are not shared by the other gastrointestinal hormones81. Examples of all these forms of interaction have been found in the study of several of the target sites in the gastrointestinal tract. With the information Gut: first published as 10.1136/gut.13.2.154 on 1 February 1972. Downloaded from

Hormonal control ofpancreatic endocrine and exocrine secretion 159 provided by radioimmunoassay of levels of individual hormones, Grossman's hypothesis should enable a more detailed analysis ofgastrointestinal hormonal action to be made. Conclusion The evidence reviewed demonstrates the complexity of the regulation of pancreatic exocrine and endocrine secretions and the difficulty of deciding which of the observed effects are of physiological importance. The hormones stimulating pancreatic exocrine and endocrine secretions interact by com- peting at the receptor site, by directly stimulating or inhibiting the release of other hormones, and, in the case of insulin, by controlling a-cell responsive- ness to hyperglycaemia. It is suggested that hormonal control of insulin release is more important than the direct effect of blood glucose level and that the close anatomical relationship between the pancreatic islets and acinar cells enables locally high concentrations of insulin to promote uptake of amino acids by the acinar cells. The exocrine deficiency in diabetes mellitus may be due in part to lack of the trophic effect of insulin and in part to the raised blood glucagon levels found in this disease.

GILES YOUNGS Department of Medicine, Royal Free Hospital, London

References

'Knight, M. J., Condon, J. R., and Smith, R. (1971). Possible use of glucagon in the treatment of pancreatitis. http://gut.bmj.com/ Brit. med. J., 2, 440-442. 2Brooks, F. P. (1970). Control of Gastrointestinal Function. Macmillan, New York. 3Dupr6, J. (1970). Regulation of the secretions of the pancreas. Ann. Rev. Med., 21, 299-316. "Salter, J. M., Davidson, I. W. F., and Best, C. H. (1957). The pathologic effects of large amounts of glucagon. Diabetes, 6, 248-255. 5Lacy, P. E., Cardeza, A. F., and Wilson, W. D. (1959). Electron microscopy of the rat pancreas: effects of glucagon administration. Diabetes, 8, 36-44. 'Jarett, L., and Lacy, P. E. (1962). Effect of glucagon on the acinar portion of the pancreas. Endocrinology, 70, 867-873.

'Zajtchuk, R., Amato, J. J., Paloyan, E., and Baker, R. J. (1967). Inhibition of pancreatic exocrine secretion on September 24, 2021 by guest. Protected copyright. by glucagon. Surg. Forum, 18, 410-411. 8Dyck, W. P., Rudick, J., Hoexter, B., and Janowitz, H. D. (1969). Influence ofglucagon on pancreatic exocrine secretion. Gastroenterology, 56, 531-537. "Dyck, W. P., Texter, E. C., Jr., Lasater, J. M., and Hightower, N. C., Jr. (1970). Influence of glucagon on pancreatic exocrine secretion in man. Gastroenterology, 58, 532-539. "Chey, W. Y., Shay, H., and Shuman, C. R. (1963). External pancreatic secretion in diabetes mellitus. Ann. intern. Med., 59, 812-821. "Vacca, J. B., Henke, W. J., and Knight, W. A., Jr. (1964). The exocrine pancreas in diabetes mellitus. Ann. intern. Med., 61, 242-247. "Lahdevirta, J. (1967). Testing of exocrine function of pancreas in diabetes mellitus by use of 7"Se-methionine and of secretin. Acta. med. scand., 182, 345-351. "3Melmed, R. N., Agnew, J. E., and Bouchier, I. A. D. (1968). The normal and abnormal pancreatic scan. Quart. J. Med., 37, 607-624. "Richardson, K. C., and Young, F. G. (1938). Histology of diabetes induced in dogs by injection of anterior- pituitary extracts. Lancet, 1, 1098-1101. "Grossman, M. I., and Ivy, A. C. (1946). Effect of alloxan upon external secretion of the pancreas. Proc. Soc. exp. Biol. (N. Y.), 63, 62-63. "Palla, J. C., Abdeljlil., A. ben, and Desnuelle, P. (1968). Effect of insulin on the rate of biosynthesis of some pancreatic enzymes. (Abstr). Gut, 9, 254. 7Manchester, K. L., and Young, F. G. (1959). Hormones and protein biosynthesis in isolated rat diaphragm. J. Endocr., 18, 381-394. "Mayne, R., Barry, J. M., and Rivera, E. M. (1966). Stimulation by insulin of the formation of ribonucleic acid and protein by mammary tissues in vitro. Biochem. J., 99, 688-693. "Wool, I. G. (1969). Action of insulin on protein synthesis. In Diabetes (Excerpta Med. Int. Cong. Ser., No. 172), edited by J. Ostman and R. D. G. Milner, pp. 16-24. Excerpta Medica Foundation, Amsterdam. 2"Manchester, K. L. (1970). Sites of hormonal regulation of protein metabolism. In Mammalian Metabolism. edited by H. N. Munro, Vol. IV, pp. 229-298. Academic Press, New York and London. 2"Henderson, J. R. (1969). Why are the Islets of Langerhans? Lancet, 2, 469-470. 22Clark, W. E. Le G. (1971). The Tissues of the Body. 6th ed., p. 291. Clarendon Press, Oxford. Gut: first published as 10.1136/gut.13.2.154 on 1 February 1972. Downloaded from

160 Giles Yoitngs "3Hansson, E. (1959). The formation of pancreatic juice proteins studied with labelled amino acids. Acta physiol. scand., 46, Suppl. 161, pp. 1-99. 24Kramer, M. F., and Tan, H. T. (1968). The peri-insular acini of the pancreas of the rat. Z. Zellforsch, 86, 163-170. 2"Melmed, R. N., and Holt, S. J. (1971). Personal communication. (Courtauld Institute of Biochemistry, Middlesex Hospital, London.) 2"Pearse, A. G. E., and Polak, J. M. (1971). Neural crest origin of the endocrine polypeptide (APUD) cells of the gastrointestinal tract and pancreas. Gut, 12, 783-788. 2'Wheeler, J. E., Lukens, F. D. W., and Gyorgy, P. (1949). Studies on the localisation of tagged methionine within the pancreas. Proc. Soc. exp. Biol. (N. Y.), 70, 187-189. 28Metz, R. (1960). The effect of blood glucose concentration on insulin output. Diabetes, 9, 89-93. 29Unger, R. H., Eisentraut, A. M., McCall, M. S., and Madison, L. L. (1961). Glucagon antibodies and an immunoassay for glucagon. J. clin. Invest., 40, 1280-1289. 3°Edgar, P., Rabinowitz, D., Merimee, T. J., and Almogela, E. (1969). Effect of arginine on insulin release in vitro. Metabolism, 18, 84-86. "'Montague, W., and Taylor, K. W. (1968). Regulation of insulin secretion by short chain fatty acids. Nature (Lond.), 217, 853. 3'Assan, R., Rosselin, G., and Dolais, J. (1967). Effets sur la glucagonemie des perfusions et des ingestions d'acides amin6s. Journees. ann. Diabet. Hotel Dieu, 7, 2541. 33Samols, E., Marri, G., and Marks, V. (1965). Promotion of insulin secretion by glucagon. Lancet, 2, 415-416. "Turner, D. S., and McIntyre, N. (1966). Stimulation by glucagon of insulin release from rabbit pancreas in vitro. Lancet, 1, 351-352. 35Grodsky, G. M., Bennett, L. L., Smith, D. F., and Schmid, F. G. (1967). Effect ofpulse administration ofglucose or glucagon on insulin secretion in vitro. Metabolism, 16, 222-233. 3"Coore, H. G., and Randle, P. J. (1964). Regulation of insulin secretion studied with pieces of rabbit pancreas incubated in vitro. Biochem. J., 93, 66-78. 37Porte, D., Jr., Graber, A., Kuzuya, T., and Williams, R. H. (1965). Epinephrine inhibition of insulin release. (Abstr.) J. clin. Invest., 44, 1087. 38Unger, R. H., Aguilar-Parada, E., Muller, W. A., and Eisentraut, A. M. (1970). Studies of pancreatic alpha cell function in normal and diabetic subjects. J. clin. Invest., 49, 837-848. 39Muller, W. A., Faloona, G. R., Aguilar-Parada, E., and Unger, R. H. (1970). Abnormal alpha cell function in diabetes: response to carbohydrate and protein ingestion. New Engl. J. Med., 283, 109-115. 4"Muller, W. A., Faloona, G. R., and Unger, R. H. (1971). The effect of experimental insulin deficiency on glucagon secretion. J. clin. Invest., 50, 1992-1999. 4"Scow, R. O., and Cornfield, J. (1954). Quantitative relations between the oral and intravenous glucose tolerance curves. Amer. J. Physiol., 179, 435438. "1McIntyre, N., Holdsworth, C. D., and Turner, D. S. (1964). New interpretation of oral glucose tolerance. Lancet, 2, 20-21. 43McIntyre, N., Holdsworth, C. D., and Turner, D. S. (1965). Intestinal factors in the control of insulin

secretion. J. clin. Endocr., 25, 1317-1324. http://gut.bmj.com/ 44Moore, B., Edie, E. S., and Abram, J. H. (1906). On the treatment of diabetes mellitus by acid extract of duodenal mucous membrane. Biochem. J., 1, 28-38. 45Zunz, E., and La Barre, J. (1929). Contributions a l'6tude des variations physiologiques de la s6cr6tion interne du pancr6as: relations entre les s6cretions externe et interne du pancr6as. Arch. int. Physiol., 31, 2044. "'La Barre, J., and Still, E. U. (1930). Studies on the physiology ofsecretin. III. Further studies on the effects of secretin on the blood sugar. Amer. J. Physiol., 91, 649-653. 4"La Barre, J. (1936). La Secritine: Son Role Physiologique, Ses Proprietes Thtrapeutiques. Masson, Paris. 4"Babkin, B. P. (1950). Secretory Mechanism ofthe Digestive Glands, 2nd ed., pp. 601-607. Hoeber, New York. 49McIntyre, N. (1969). The intestinal control of insulin secretion: an historical introduction. In Diabetes,

edited by J. Ostman, and R. D. G. Milner, pp. 425432. Excerpta Medica Foundation, Amsterdam. on September 24, 2021 by guest. Protected copyright. 5"Samols, E., Tyler, J., Marri, G., and Marks, V. (1965). Stimulation of glucagon secretion by oral glucose. Lancet, 2, 1257-1259. "IShima, K., and Foa, P. P. (1968). A double antibody assay for glucagon. Clin. chim. Acta., 22, 511-520. "2Unger, R. H., Ohneda, A., Valverde, I., Eisentraut, A. M., and Exton, J. (1968). Characterisation of the re- sponses of circulating glucagon-like immunoreactivity to intraduodenal and intravenous administration of glucose. J. clin. Invest., 47, 48-65. 5"Samols, E., Tyler, J., Megyesi, C., and Marks, V. (1966). Immunochemical glucagon in human pancreas, gut and plasma. Lancet, 2, 727-729. "Polak, J. M., Bloom, S., Coulling, I., and Pearse, A. G. E. (1971). Immunofluorescent localization of enteroglucagon cells in the gastrointestinal tract of the dog. Gut, 12, 311-318. "Valverde, I., Rigopoulou, D., Exton, J., Ohneda, A., Eisentraut, A. M., and Unger, R. H. (1968). Demon- stration and characterization of a second fraction of glucagon-like immunoreactivity in jejunal extracts. Amer. J. med. Sci., 255, 415-420. 56Young, J. D., Lazarus, L., and Chisholm, D. J. (1968). Radioimmunoassay of secretin in human serum. J. nucl. Med., 9, 641-642. "7Unger, R. H., Ketterer, H., Dupr6, J., and Eisentraut, A. M. (1967). The effects ofsecretin, pancreozymin, and gastrin on insulin and glucagon secretion in anesthetised dogs. J. clin. Invest., 46, 630-645. 3"White, J. J., and Dupr6, J. (1968). Regulation of insulin secretion by intestinal hormone, secretin: studies in man via transumbilical portal vein catheterisation. Surgery, 64, 204-213. "Dupr6, J., Rojas, L., White, J. J., Unger, R. H., and Beck, J. C. (1966). Effects of secretin on insulin and glucagon in portal and peripheral blood in man. Lancet, 2, 26-28. "Unger, R. H., Ketterer, H., Eisentraut, A., and Dupr6, J. (1966). Effect of secretin on insulin secretion. Lancet, 2, 24-26. '"Boyns, D. R., Jarrett, R. J., and Keen, H. (1967). Intestinal hormones and plasma insulin: an insulinotrophic action of secretin. Brit. med. J., 2, 676-678. 62Mahler, R. J., and Weisberg, H. (1968). Failure of endogenous stimulation of secretin and pancreozymin release to influence serum insulin. Lancet, 1, 448-451. "3Sum, P. T., and Preshaw, R. M. (1967). Intraduodenal glucose infusion and pancreatic secretion in man. Lancet, 2, 340-341. Gut: first published as 10.1136/gut.13.2.154 on 1 February 1972. Downloaded from

Hormonal control ofpancreatic endocrine and exocrine secretion 161 "'Chisholm, D. J., Young, J. D., and Lazarus, L. (1969). The gastrointestinal stimulus to insulin release. I. Secretin. J. clin. Invest., 48, 1453-1460. '5Kraegen, E. W., Chisholm, D. J., Young, J. D., and Lazarus, L. (1970). The gastrointestinal stimulus to insulin release. II. A dual action of secretin. J. clin. Invest., 49, 524-529. "Guidoux-Grassi, L., and Felber, J. P. (1968). Effect of secretin on insulin release by rat pancreas. (Abstr.). Diabetologia, 4, 391-392. "Hinz, M., Katsilambros, N., Schweitzer, B., Raptis, S., and Pfeiffer, E. F. (1971). The role of the exocrine pancreas in the stimulation of insulin secretion by intestinal hormones. I. The effect of pancreozymin, secretin, gastrin-pentapeptide and of glucagon upon insulin secretion of isolated islets of rat pancreas. Diabetologia, 7, 1-5. "IDupr6, J., Curtis, J. D., Unger, R. H., Waddell, R. W., and Beck, J. C. (1969). Effects of secretin, pancreozymin or gastrin on the response of the endocrine pancreas to administration of glucose or arginine in man. J. clin. Invest., 48, 745-757. "Buchanan, K. D., Vance, J. E., Morgan, A., and Williams, R. H. (1968). Effect of pancreozymin on insulin and glucagon levels in blood and bile. Amer. J. Physiol., 215, 1293-1298. 7"Wormsley, K. G. (1971). Reactions to acid in the intestine in health and disease. Gut, 12, 67-84. 71Hansky, J., Soveny, C., and Korman, M. G. (1971). Effect ofsecretin on serum gastrin as measured by immunoassay. Gastroenterology, 61, 62-68. 12Henriksen, F. W., and Worning, H. (1967). The interaction of secretin and pancreozymin on the external pancreatic secretion in dogs. Acta physiol. scand., 70, 241-249. 73Brown, J. C., Harper, A. A., and Scratcherd, T. (1967). Potentiation of secretin stimulation of the pancreas. J. Physiol. (Lond.), 190, 519-530. "Wormsley, K. G. (1969). A comparison of the response to secretin, pancreozymin and a combination of these hormones in man. Scand. J. Gastroent., 4, 411-417. 75McGuigan, J. E., and Trudeau, W. L. (1968). Immunochemical measurement of elevated levels of gastrin in the serum of patients with pancreatic tumors of the Zollinger-Ellison variety. New Engl. J. Med., 278, 1308-1313. 7Young, J. D., Lazarus, L., and Chisholm, D. J. (1969). Radioimmunoassay of pancreozymin-cholecystokinin in human serum. J. nucl. Med., 10, 743-745. 77Dyck, W. P. (1971). Influence ofintrajejunal glucose on pancreatic exocrine function in man. Gastroenterology, 60, 864-869. "'Grossman, M. I. (1970). Gastrin, cholecystokinin, and secretin act on one receptor. Lancet, 1, 1088-1089. "'Jones, R. S., Geist, R. E., and Hall, A. D. (1971). The choleretic effects of glucagon and secretin in the dog. Gastroenterology, 60, 64-68. "OLin, T. M., and Spray, G. F. (1968). Effect of glucagon on gastric HCI secretion. (Abstr.). Gastroenterology, 54, 1254. "'Sokal, J. E. (1966). Glucagon, an essential hormone. Amer. J. Med., 41, 331-341. http://gut.bmj.com/ on September 24, 2021 by guest. Protected copyright.