control endocrine and exocrine secretionhormonalcontrolofpancreatic endocrine andexocrine secretion...

Gut, 1972, 13, 154-161

Progress reportHormonal control of pancreaticendocrine and exocrine secretion

The known inhibitory effect of glucagon on pancreatic exocrine secretion hasrecently been applied to the treatment of acute pancreatitis'. The use of thispromising therapeutic agent follows considerable advances made in recentyears in the understanding of the hormonal control of pancreatic endocrineand exocrine secretion. Mechanisms of autonomic nervous control and ofneuro-hormonal interactions in the pancreas have recently been reviewed byBrooks2 and Dupr63.Three questions about the hormonal control of pancreatic secretion need

to be asked: How do pancreatic hormones (insulin and glucagon) affectexocrine pancreatic function (endocrine-exocrine interactions); how dohormones from the gastrointestinal mucosa affect endocrine function of thepancreas (entero-endocrine reactions); how do gastrointestinal hormonesaffect exocrine pancreatic function (entero-exocrine interactions)?

Endocrine-exocrine Interactions

There is evidence that the pancreatic hormones, insulin and glucagon, in-fluence enzyme synthesis and release in the exocrine pancreas. Acinar cellsin the rat pancreas show progressive degranulation and atrophy after repeatedinjections of glucagon4,5 6. The inhibitory effect of glucagon on pancreaticexocrine secretion was first demonstrated by Zajtchuck and colleagues7.Intravenous glucagon given to two subjects with pancreatic fistulae caused a90% reduction in pancreatic juice volume and amylase. Dyck and hisassociates gave physiological doses of glucagon intravenously to the dog8 andmang while stimulating pancreatic secietion with secretin and pancreozymin.Marked inhibition of enzyme output was noted and there was some reductionin volume flow while electrolyte concentrations were unchanged. The effectoccurred within a few minutes, indicating inhibition of enzyme release ratherthan of synthesis. Knight and his coworkers' treated three attacks of acutepancreatitis occurring in two patients with intravenous glucagon and theclinical condition of the patients improved rapidly. One patient received twointravenous injections of glucagon and the abdominal pain disappearedafter four hours and the plasma amylase fell after seven hours. The secondpatient received a loading dose of glucagon followed by a glucagon infusionon two separate occasions. The pain was relieved and the plasma amylasesfell after one hour. Although the trial was not controlled and the number ofsubjects small the results are promising and suggest that further use of thedrug 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 showsreduced response to hormonal stimulation10""1 and reduced pancreatic

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Hormonal control ofpancreatic endocrine and exocrine secretion

uptake of selenomethionine12"13 the changes being partictlarly marked ininsulin-dependent diabetics. Dogs rendered diabetic with anterior pituitaryextract14 or alloxanl5 show damage to exocrine tissue, and alloxan givento rats results in a twenty-fold reduction in pancreatic amylase whichreturns to normal with insulin treatment'6. Insulin also increases synthesis ofchymotrypsinogen in the pancreas of normal rats on an exclusively proteindiet'6, and it was suggested that insulin controls the synthesis of chymotryp-sinogen by favouring the entry of amino acids into the acinar cells and thesynthesis of amylase by favouring the entry of glucose. Certainly insulin hasbeen shown to promote amino acid incorporation and protein synthesis inisolated muscle'7 and secreting mammary gland'8. The role of insulin inprotein synthesis has recently been reviewed by Wool'9 and Manchester20.

There is some morphological evidence to indicate that pancreatic exocrinefunction may be influenced by pancreatic endocrine hormones. Henderson2'has suggested that the endocrine tissue of the pancreas is fragmented intoislets throughout the exocrine tissue thereby ensuring high concentrations ofpancreatic hormones around the acinar cells which might have been ofevolutionary advantage. In the human pancreas blood in the lobular arteriolesfirst passes to the endocrine islet tissue and then forms a capillary plexusamong the externally secreting acini2",22. Henderson suggests that blood fromthe islets bathes the acinar cells by way of an islet-exocrine portal system.This relationship is found in reptiles, birds, and mammals. Primitive fish havea separate endocrine pancreas but cartilaginous fish show some endo-exocrine integration in having a double layer of cells lining the pancreaticducts, a luminal layer of exocrine cells and an outer layer of endocrine cells.The fatty fibrosis of pancreatic exocrine tissue which follows diabetesmellitus is not reversed by therapeutic doses of insulin and Henderson arguesthat this is evidence in favour of acinar cell integrity depending on locallyhigh concentrations of insulin delivered via the islet-exocrine portal system.

Hansson23 has provided further evidence which may indicate pancreaticendocrine-exocrine interaction. Autoradiographs of mouse pancreas preparedafter intravenous injection of 35S-methionine show that the amino acid istaken up markedly more strongly by the acinar cells surrounding the endo-crine islets than by the cells remote from the islets. Kramer and Tan24 haveconfirmed this observation and have shown that zymogen granules are moreabundant in the periinsular acini but decrease to the levels of normal aciniafter islet destruction by alloxan. This suggests that insulin exerts a trophiceffect on the periinsular acini by promoting amino acid uptake. Cells whichhave the ultrastructural features of both endocrine and exocrine cell types(intermediate cells) have recently been demonstrated25. The fact that theintermediate cells occur mainly in the islets and periinsular acini and containinsulin and glucagon as well as secretory enzymes may indicate that the isletand periinsular acinar cells have a common origin and that functionalendocrine-exocrine interactions are more complex than previously thought.The significance, in this context, of the hypothesis26 that the islet cells and thepolypeptide hormone-secreting cells of the gastrointestinal tract have acommon 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 endocrineand exocrine pancreas. The enhancement by insulin of amino acid uptakeand synthesis would be highly relevant in the pancreas, for the pancreatic

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acinar cells take up amino acids from the blood for enzyme synthesis moreavidly than any other organ in the body23'27. Promotion of amino acid uptakeby insulin may explain why the uptake of amino acids is most pronounced inthe acinar cells surrounding the islets and such an endocrine-exocrineinteraction would fit Henderson's hypothesis. The role of the intermediatecells and the physiological significance of exocrine inhibition by pancreaticglucagon 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 thatinsulin28 and glucagon29 release from the pancreas is directly and reciprocallycontrolled by the blood glucose concentration. In addition insulin secretionis directly stimulated both by amino acids30 and fatty acids31 and glucagon isreleased by amino acids32. Although the direct effects of nutrients on theendocrine pancreas appear to stimulate or inhibit release of insulin or glucagonappropriate to the physiological need it is becoming increasingly evident thathormonal control of insulin secretion plays an equal if not more importantrole. Glucagon is known to be a potent stimulus to insulin release~3'34'35 andadrenaline is a powerful inhibitor36'37. Insulin, in turn, affects glucagonsecretion, for Unger and his associates38,39,40 have recently shown that normalsuppression of glucagon secretion by hyperglycaemia does not occur whensevere insulin deficiency is produced and this may explain the high levels ofglucagon in the blood of subjects with diabetes mellitus. It is possible thatthese high levels of glucagon are partly responsible for the depressed exocrinefunction in this disease.

Glucose given by mouth is cleared more rapidly from the blood than glucoseinjected intravenously41. McIntyre and his associates42 showed that deliveryof glucose into the intestine in man is followed byhigher blood levels of insulinthan those reached when similar levels of blood glucose are produced byintravenous infusion. Since this enhancement of insulin release is not abolishedby portacaval anastomosis43 it appears that the higher levels of insulin andenhanced glucose tolerance following absorption of glucose from the gut aredue to an intestinal factor, possibly a hormone. The suggestion that there is ahormone in the gastrointestinal mucosa which stimulates insulin secretion isnot a new one. Moore and his colleagues44 in 1906 suggested that theduodenum elaborates a hormone which excites the internal secretion of thepancreas. La Barre and his coworkers45'46'47 showed that the intravenousinjection of a duodenojejunal extract into dogs causes hypoglycaemia andthis effect is mediated by the pancreas. La Barre suggested the name 'incretin'for this intestinal factor which promotes glucose disposal. These early studieshave been reviewed by Babkin48 and McIntyre49.

Several of the hormones released from the intestinal mucosa are capableof stimulating insulin release but it is not yet known which hormone is themain stimulus to insulin secretion after glucose ingestion. The main candi-dates are secretin, pancreozymin-cholecystokinin, and enteroglucagon, aglucagon-like hormone found in the gastrointestinal mucosa. Blood concen-tration of a substance with glucagon-like immunoreactivity increases afterabsorption of glucose from the gut of man'50'5 and dog52 but after intravenousglucose infusion immunoreactive glucagon levels fall51. This suggests that

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oral glucose stimulates release of immunoreactive glucagon from the gut butthat intravenous glucose inhibits release of pancreatic glucagon by a directeffect on the pancreas. A substance with glucagon-like immunoreactivity hasbeen found in the gastrointestinal mucosa53 and has been called 'gut gluca-gon' or 'enteroglucagon'. This substance has been shown to stimulate insulinrelease52 and could therefore be the intestinal factor which promotes glucosedisposal during absorption from the gut. Cells containing a substance withglucagon-like immunoreactivity have been localized in the gastric fundusand jejunum of the dog using an immunofluorescent technique54. Entero-glucagon can be distinguished from pancreatic glucagon by immuno-assay"3'5 and has twice the molecular weight and lacks the effects ofpancreatic glucagon on liver glycogenolysis.

Other gastrointestinal hormones may also enhance glucose disposal inresponse to food in the gut lumen. Ingestion of glucose causes a rapid andlarge increase in circulating secretin-like activity56 and purified secretin giveninto the portal vein of the dog57 and man58 or into a peripheral vein59,60causes a significant rise in insulin release from the pancreas. The role of secretinin the normal physiological response to oral glucose has been cast in doubtby studies which fail to show a rise in plasma insulin after duodenal infusionof acid6'62 and no evidence of exocrine pancreatic stimulation (secretineffect) after intraduodenal glucose in man63. More recently Chisholm andhis associates64 have shown that an infusion of hydrochloric acid into theduodenum of man causes elevation of serum secretin and insulin levels.Further studies65 showed that the peak insulin response occurs 30 minutesafter the peak secretin level and that the rise in blood insulin is greater andmore prolonged than would be expected from the glycaemic stimulus aloneor from the short-lived rise in blood secretin level. A continuous secretininfusion before the glucose ingestion was found greatly to potentiate theinsulin 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 insulinrelease which continues well after peripheral secretin levels have declined. Ithas also been shown by studies in vitro66'67 that secretin does not releaseinsulin unless the exocrine pancreas is intact and this could be a furtherexample of the mutual relationship mentioned earlier between the endocrineand exocrine pancreas.

Pancreozymin-cholecystokinin is the third intestinal hormone which maybe responsible for the release of insulin after oral glucose68, the stimulus toinsulin release in this case being independent of the integrity of the exocrinepancreas67. In addition, pancreozymin-cholecystokinin is the only gastro-intestinal hormone that has been shown to stimulate glucagon release fromthe pancreas57'69. As pancreatic glucagon is a potent stimulus to insulinrelease"3'34'35, pancreozymin-cholecystokinin could act as the stimulus forinsulin secretion by a dual mechanism. It is possible that pancreatic glucagonreleased by pancreozymin-cholecystokinin partly counteracts insulin pro-motion of hepatic glycogen synthesis, allowing glucose to be acted on by in-sulin at peripheral sites.Thus enteroglucagon, secretin, pancreozymin-cholecystokinin (and prob-

ably the chemically similar gastrin) may all fulfil the role of the hypotheticalhormone, 'incretin', and act as signals for the release of insulin on the arrival offood in the gastrointestinal tract. Such an action would fill aphysiological need.

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Entero-exocrine Interactions

The actions of gastrin, secretin, and pancreozymin-cholecystokinin on thepancreas are well documented but incompletely understood. The mechanismsof release of these hormones have been reviewed recently by Wormsley70. Itis known that these hormones have multiple and overlapping effects and theprobability that gastrin serves as a direct stimulus to the release of secretin"4and secretin appears to inhibit gastrin release7' directly makes it likely thatpancreatic 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 physio-logical portal venous route further complicates investigation. Chemicalidentification of the major gastrointestinal hormones has led to the develop-ment of radioimmunoassay of gastrin75, secretin58, and pancreozymin-cholecystokinin76, and this technique will be of undoubted value in our furtherunderstanding of the physiological roles of these hormones.The possible role of enteroglucagon in stimulating insulin release has already

been mentioned and it seems possible that enteroglucagon, like pancreaticglucagon, inhibits pancreatic exocrine secretion.Dyck and his associates77 gave intrajejunal glucose to man while stimulating

pancreatic secretion with secretin and pancreozymin. Bicarbonate con-centration fell by 25% and volume by 50% and the fall was paralleled by arise in blood levels of immunoreactive glucagon, presumed to be entero-glucagon. There was no change in enzyme concentration, contrasting withthe marked fall in enzyme concentration after the intravenous infusion ofpancreatic glucagon mentioned earlier8. It was postulated that pancreaticglucagon inhibits enzyme release while enteroglucagon inhibits volume flowand electrolyte secretion by the pancreas. The stimulus for this possiblefeedback mechanism would be the arrival of food in the intestine. Theenteroglucagon released would regulate volume and electrolyte secretion whilepancreozymin-cholecystokinin would, as mentioned earlier, stimulate releaseof pancreatic glucagon which in turn would regulate secretion of enzymes.However, the intrajejunal glucose used in this experiment was in 50%solution and the physiological relevance of the findings remains to besubstantiated.

Grossman78 has postulated that gastrin, pancreozymin-cholecystokinin,secretin, and probably glucagon act on one receptor. The receptor has twointeracting sites-one with affinity for the chemically similar gastrin andpancreozymin-cholecystokinin and one for secretin and probably the chem-ically similar glucagon. The hypothesis predicts that all targets that react toone of these hormones will react to the other two and probably glucagon aswell. Simultaneous action of two hormones leads to competitive or non-competitive augmentation or inhibition, depending on whether the hormonesare acting on the same or different interaction sites and whether the hormonesacting on the receptor are stimulating or inhibitory. Glucagon appears to acton the receptor in a similar fashion. It shares with secretin choleretic79 andinsulinotropic333435 effects and the inhibitory influence on gastric acidsecretion80 but the effects of glucagon on hepatic glycogenolysis andgluconeogenesis are not shared by the other gastrointestinal hormones81.Examples of all these forms of interaction have been found in the study ofseveral of the target sites in the gastrointestinal tract. With the information

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Hormonal control ofpancreatic endocrine and exocrine secretion 159

provided by radioimmunoassay of levels of individual hormones, Grossman'shypothesis should enable a more detailed analysis ofgastrointestinal hormonalaction to be made.

Conclusion

The evidence reviewed demonstrates the complexity of the regulation ofpancreatic exocrine and endocrine secretions and the difficulty of decidingwhich of the observed effects are of physiological importance. The hormonesstimulating pancreatic exocrine and endocrine secretions interact by com-peting at the receptor site, by directly stimulating or inhibiting the release ofother hormones, and, in the case of insulin, by controlling a-cell responsive-ness to hyperglycaemia. It is suggested that hormonal control of insulinrelease is more important than the direct effect of blood glucose level and thatthe close anatomical relationship between the pancreatic islets and acinarcells enables locally high concentrations of insulin to promote uptake ofamino acids by the acinar cells. The exocrine deficiency in diabetes mellitusmay be due in part to lack of the trophic effect of insulin and in part to theraised blood glucagon levels found in this disease.

GILES YOUNGSDepartment of Medicine,

Royal Free Hospital, London

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