Postgraduate Medical Journal (May 1983) 59, 277-282

LEADING ARTICLE

Recent advances in pancreatic hormone research

R. G. LONGM.D., M.R.C.P.

Gastrointestinal Laboratory, St Thomas' Hospital, London SEI 7EH

Introduction

The pancreas secretes 4 major polypeptide hor-mones: insulin from the beta cells; pancreatic gluca-gon from the alpha cells; somatostatin from the Dcells in the islets of Langerhans, and pancreaticpolypeptide (PP) from the PP cells which are spreadmore diffusely through pancreatic exocrine andendocrine tissue. Some or all of these 4 hormonesmay also have paracrine effects; this means that thepeptide is secreted locally and has metabolic effectson neighbouring cells. Gastrin is synthesized in Gcells in the foetal pancreas, but these cells disappearpostnatally. Certain other polypeptides such as vaso-active intestinal polypeptide (VIP) have also beendemonstrated in human pancreas, but appear pre-dominantly localized to nerves; these substances,which were initially classified as 'gut hormones', arenow thought to be neurotransmitters or neuromodu-lators of the non-adrenergic, non-cholinergic branchof the autonomic nervous system. In view of themultiple modes of actions of these peptides, thedescriptive term 'regulatory peptides' is now oftenused. Basic information about the peptides to bediscussed is listed in Table 1, but it should beemphasized that many of them exist in multiplemolecular forms. The purpose of this review is todiscuss some primarily non-diabetic aspects of thephysiology and pathophysiology of pancreatic poly-peptides which have recently received attention.

PhysiologyThe many metabolic functions of insulin are well

known. Recently, much attention has been directedtowards mechanisms of release. When equivalentamounts of glucose are given orally and intrave-nously, a much larger plasma insulin response is seenwith the oral stimulus. It has therefore been postu-lated that there is a gut factor or 'incretin' which isreleased by the gut after glucose ingestion and causesthe enhanced insulin secretion. The main candidate

investigated has been gastric inhibitory polypeptide(also known as glucose-dependent insulinotropicpolypeptide or GIP) which is a 43 amino acidpolypeptide found in the K cells of the duodenumand jejunum. GIP is released after oral (but notintravenous) glucose and infusion studies haveshown that, when the blood glucose level is raisedabove normal fasting levels, GIP releases insulin. Ittherefore appears that GIP is an incretin, but itprobably does not explain the whole effect (Sarsonand Bloom, 1981). This means that the search forother incretins continues and it seems likely thatinterest will now be turned towards the newlyisolated glicentin.The effects of glycogenolysis and gluconeogenesis

of pancreatic glucagon and its release by hypoglycae-mia and infusions of alanine and arginine are wellknown. It therefore antagonizes the action of insulinand, except in stress situations, its release is mostinhibited by a high blood glucose. Some 30 years ago,gut glucagon-like immunoreactivity or enterogluca-gon was recognized and it was subsequently shownthat there were large amounts of this material in theL cells of the terminal ileum, colon and rectum. Onesuch peptide, probably the most important, wasglicentin (so named because it has glucagon-likeimmunoreactivity) and appeared to be composed ofabout 100 amino acids. In 1981, Thim and Moodyreported the 69 amino acid sequence of glicentin anddemonstrated that in the 29 residues 33-61, there wasthe entire sequence of pancreatic glucagon. Pureglicentin is now becoming available (Moody et al.,1981) and a study by Kirkegaard et al. (1982) in ratsshowed that glicentin inhibits pentagastrin-stimu-lated gastric acid secretion, but pancreatic glucagondoes not. Another putative function for glicentin is asa trophic factor, particularly on small intestinalvillous growth. Glicentin is released into the plasmain large amounts after a mixed meal and it seemslikely that it will be found to have very differentphysiological effects from pancreatic glucagon.

0032-5473/83/0500-0277 $02.00 © 1983 The Fellowship of Postgraduate Medicine

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TABLE 1: Basic information on pancreatic regulatory peptides

ProbableMolecular Number of main modeweight amino acids of action Main action

Insulin 5807 51 Hormone Glucose loweringPancreatic glucagon 3485 29 Hormone Glucose raisingSomatostatin 1640 14 Paracrine Inhibition of

hormone releasePancreatic polypeptide 4226 36 Hormone Inhibition of

pancreaticobiliarysecretions

Gastrin 2098 17 Hormone Stimulation ofgastric acidsecretion

Vasoactive intestinal polypeptide 3326 28 Neurotransmitter Noncholinergic,nonadrenergic,neurotransmitter

The biological effects of somatostatin are verygreat and it has been demonstrated to have a markedinhibitory effect on the secretion of most gastrointes-tinal hormones and fluid secretions (Table 2). Suchwidespread inhibition has led to the concept that itmight be secreted by pancreatic D cells to have localparacrine effects on neighbouring cells, for example,the alpha and beta cells. Wass et al. (1980) havefound considerable plasma somatostatin rises after astandard breakfast whereas we have only found risesafter a very large meal. Our demonstration thatexogenous somatostatin infusion during a smallmeal, to mimic plasma levels seen after a large meal,inhibits plasma hormone secretion suggests thatsomatostatin may act via the circulation and fulfil thecriteria for being a hormone (Long et al., 1982).Finally, as somatostatin has also been demonstratedby immunocytochemistry in autonomic nerves, itseems possible that it may act as a neurotransmitteror neuromodulator as well as a paracrine andhormonal substance. This peptide is therefore ofparticular interest as it may act through all 3 of themain modes of action attributed to pancreatic andgastrointestinal regulatory peptides.

Pancreatic polypeptide remains a hormone ofuncertain function. In man, a large, rapid andpersistent rise in plasma pancreatic polypeptideoccurs after a mixed breakfast, but the best stimulusappears to be protein, for example, cod or beef.Pancreatic polypeptide is also released by insulinhypoglycaemia and gastric distension with either aballoon or non-nutritive substances. Normal secre-tion is almost entirely under parasympathetic controland can be inhibited by atropine or truncal vago-tomy. In dogs, pancreatic polypeptide infusion causesinhibition of basal and secretin-stimulated pancreaticsecretion (Lin et al., 1976). Greenberg et al. (1978)infused bovine pancreatic polypeptide into normalhuman subjects to levels similar to those seen after astandard breakfast and found a significant reduction

TABLE 2. Effects of somatostatin

Inhibition of hormone secretionSite Hormone

Pancreas InsulinPancreatic glucagonPancreatic polypeptide

Stomach GastrinGut Secretin

Gastric inhibitory polypeptideMotilinEnteroglucagonNeurotensin

Anterior Growth hormone.Pituitary Thyroid stimulating hormone

Adrenocorticotrophic hormoneOther Calcitonin

Renin

Inhibition of gastrointestinal secretionGastric acid and pepsinPancreatic juiceBile flowSmall intestine

Inhibition of other functionsSplanchnic blood flowGall bladder contractionLD5° of phenobarbitone

StimulationGastric emptying of glucose

in biliary and pancreatic juice secretion along withreduced trypsin and bilirubin outputs. This experi-ment suggests that the persistent rise in plasmapancreatic polypeptide after a meal may be reducinglate biliary and pancreatic secretion, but the physio-logical significance of the early rise remains obscure.

After birth, gastrin disappears from the pancreas,but this hormone keeps its interest as the greatmajority of gastrin-secreting tumours arise in thepancreas.

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Recent advances in pancreatic hormone research

Vasoactive intestinal polypeptide (VIP) has beendemonstrated in the pancreas in the exocrine paren-chyma and around blood vessels, and VIP receptorshave been demonstrated on pancreatic membranes.VIP stimulates pancreatic juice and bicarbonatesecretion on a dose-dependent basis. When the vagusis stimulated, there is atropine-resistant, but somato-statin-sensitive, VIP release (Fahrenkrug et al., 1979).These results suggest that VIP is acting as a neuro-transmitter to control pancreatic exocrine secretion.

Deficiency syndromes

Chronic pancreatitis is a common cause of pan-creatic endocrine dysfunction. The usual order ofdestruction of hormone cells is firstly pancreaticpolypeptide, secondly insulin and thirdly pancreaticglucagon. The early loss of pancreatic polypeptidepresumably reflects the presence of PP cells in theexocrine tissue as well as in the islets. In patients withchronic pancreatitis with steatorrhoea, the pancreaticpolypeptide response to a mixed meal is highlysignificantly reduced compared to normal controlswho have similar responses to patients with chronicpancreatitis and no steatorrhoea. The plasma pan-creatic polypeptide response to intravenous Boot'ssecretin and to insulin hypoglycaemia is also usuallyreduced in patients with chronic pancreatitis withsteatorrhoea. However, as occasional patients withchronic pancreatitis and steatorrhoea have normalpancreatic polypeptide responses, this test cannot beused for diagnostic purposes (Adrian et al., 1979;Valenzuela, Taylor and Walsh, 1979). Insulin failuredue to beta cell destruction may occur, as well asreduced pancreatic glucagon responses to stimulisuch as intravenous arginine (Long, Adrian andBloom, 1981a).

Children with cystic fibrosis have a poor meanplasma pancreatic polypeptide response to a milkdrink. Interestingly, these children also have im-paired glucose tolerance associated with a reducedplasma gastric inhibitory polypeptide response. Thisresult suggests that there is a defect on the enteric sideof the enteroinsular axis as well as an element of betacell failure (Adrian et al., 1980).

Pancreatic glucagon is thought to be essential forrecovery from hypoglycaemia and it together withadrenaline are thought to be more important for thispurpose than other counter-regulatory hormonessuch as growth hormone and cortisol. Recently, adiabetic patient was described who had recurrentsevere hypoglycaemic episodes and, in response toinsulin-induced hypoglycaemia, there was a poorresponse of plasma pancreatic glucagon, adrenaline,growth hormone and cortisol (Boden et al., 1981).

Pancreatic glucagon and pancreatic polypeptideare both dependent on an intact vagus for their

release. Krarup et al. (1979) showed a normal plasmapancreatic polypeptide response to insulin-inducedhypoglycaemia in diabetes of short duration, butfound that this deteriorated with time and that thedeterioration correlated with parameters of peri-pheral neuropathy such as reduced vibration sense.They concluded that pancreatic polypeptide releasemight be used as a test for peripheral neuropathy indiabetics. Two other types of autonomic neuropathyhave also been studied: in Chagas' disease, there is adestruction of post-ganglionic intrinsic cell bodiesdue to infection with Trypanosoma cruzi, and inchronic autonomic failure (the Shy-Drager syn-drome), there is destruction of brain cell nuclei andintermediolateral spinal column cells. Both thesegroups of patients have a significant reduction ofpancreatic polypeptide and pancreatic glucagon re-lease to insulin-induced hypoglycaemia compared tocontrols (Long et al., 1980; Barnes et al., 1980). Thereis therefore a functional failure of pancreatic hor-mone release in each of the 3 types of autonomicneuropathy tested.

Bovine insulin treatment may be associated withlarge amounts of impurities which include otherpancreatic peptides such as pancreatic polypeptideand VIP. In contrast, the newer porcine and humaninsulins are free from these contaminants. Manypatients treated with bovine insulin preparationshave been found to have developed antibodies topancreatic polypeptide and VIP and, consequently,these peptides no longer circulate. The significance ofthis finding is unknown, but it has been postulatedthat the presence of VIP antibodies might encouragethe development of autonomic neuropathy (Bloom etal., 1979).

Nesidioblastosis is a rare disease of neonatescharacterized by prolonged periods of hypoglycae-mia and the presence of circulating endogenousinsulin which in normal people would be unmeasur-able in the presence of a low blood glucose. In 1977,Hirsch et al. demonstrated that the hypoglycaemiacould be reversed by small amounts of intravenoussomatostatin. Subsequently, it has been shown thatthere are reduced amounts of pancreatic somatostatincells in children with nesidioblastosis. It has thereforebeen concluded that this condition is due to pan-creatic somatostatin deficiency.

Pancreatic endocrine tumours

Glucagonomas, PP-omas, somatostatinomas andvipomas became recognized in the 1970's and someof the basic background of these important, if rare,tumour syndromes is reviewed in Table 3. Pancreatictumours secreting 5-hydroxytryptamine (serotonin),adrenocorticotrophic hormone and parathyroid hor-mone may also be seen (Friesen, 1982). It is

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TABLE 3. Features of major pancreatic endocrine tumour syndromes

Tumoursyndrome Reference Symptoms Diagnostic features

Insulinoma Friesen, 1982 Hypoglycaemia Hypoglycaemia with hyperinsulinaemiaGlucagonoma Mallinson et al., 1974 Necrotizing, Migrating erythema; Hyperglucagonaemia

diabetesPP-oma Polak et aL., 1976 None recognized Raised fasting plasma pancreatic polypeptideSomatostatinoma Krejs et al., 1979 Diabetes; cholelithiasis; steatorrhoea Raised plasma somatostatinGastrinoma Friesen, 1982 Duodenal ulcers; malabsorption Raised fasting gastrin with gastric hyperacidityVipoma Long et al., 198 lb Watery diarrhoea; weight loss Raised plasma VIP; hypokalaemic acidosis

important to remember that these syndromes andtheir diagnosis can then usually be made by plasmaradioimmunoassay of the suspected peptide. Onoccasions, supplementary investigations may be use-ful; these include the intravenous secretin test todemonstrate a paradoxical rise in plasma gastrin ingastrinoma patients, or the atropine test to demon-strate that pancreatic polypeptide is not undercholinergic control and therefore comes from atumour. The anatomical site of the primary tumourcan usually be demonstrated by selective pancreaticarteriography or portal venous sampling and subse-quent radioimmunoassay of the tumour hormone toshow a peak corresponding to the tumour venousoutflow (Bloom and Long, 1982).As discussed later in this issue, it is not uncommon

for pancreatic endocrine tumours to produce mult-iple peptides (Dawson, Bloom and Cockel, 1983;Manche et al., 1983). Combinations reported includegastrin and glucagon, insulin and gastrin, insulin andglucagon, gastrin and vasoactive intestinal polypep-tide and pancreatic polypeptide with vasoactiveintestinal polypeptide, glucagon, insulin and gastrin.Another feature is that the tumour may secretemultiple molecular forms of a peptide and, in onecase, metoclopramide abolished diarrhoea in a vi-poma patient by altering VIP secretion from theusual 28 amino acid form to a larger molecularweight form which appeared metabolically inactive(Long et al., 198 lc). The possibility of Wermer'ssyndrome (multiple endocrine adenomatosis, Type 1)must also be considered as sometimes pancreaticendocrine tumours, primary hyperparathyroidismand functioning pituitary tumours may all coexistsimultaneously in a patient.

Surgical removal of pancreatic endocrine tumoursis the treatment of choice, but is impractical inmany patients because of large extensive primarytumours, multiple primary tumours or metastasis toliver and lymph nodes. H2 receptor antagonists aregaining acceptance as a treatment for gastrinomas,but large doses causing an increased incidence of sideeffects may be required to control gastric acidsecretion (McCarthy, 1980). The rash of glucagono-

mas may respond to zinc supplements. Vipomadiarrhoea has been reported to respond to a variety oftreatments including indomethacin, metoclopramide,lithium, loperamide and trifluoperazine. Cytotoxictreatment with streptozotocin and 5-fluorouracilproduces worthwhile remissions in many patients(Moertel, Hanley and Johnson, 1980). Arterial em-bolization of functioning tumour mass similarly maybe dramatically helpful in some patients and isusually not associated with undue risk (Manche et al.,1983).

Treatment with somatostatinIn view of its widespread biological effects (Table

2), somatostatin is of potential therapeutic use inmany different clinical situations. Major problems ofsomatostatin as a treatment are its short plasma half-life (less than 5 min) and its broad spectrum of action.Subcutaneous protamine zinc somatostatin wasfound not to prolong, in a significant manner, theduration of action of somatostatin (Tannenbaum andColle, 1980). At the Salk Institute, solid phasesynthesis techniques have been used to developpeptides which have had aminoacids 1, 2, 4, 5, 12 andsometimes 13 deleted from the parent 14 amino acidsomatostatin. These 2 somatostatin analogues havebeen found to be hydrophobic, to be released slowlyfrom subcutaneous tissues into the plasma and tohave a prolonged duration of action in animals andman when given subcutaneously. In contrast, theparent molecule is hydrophilic, rapidly absorbed andhas a short duration of action; as a result, prolongedeffects can only be produced by continuous intrave-nous (or possibly subcutaneous or intraperitoneal)infusion. Numerous attempts have also been made tosynthesize analogues with specific actions, but ana-logues, which were shown to have insulin or glucagonspecificity in rats, have been shown to have no suchspecificities in man (Adrian et al., 1981).A beneficial effect of somatostatin might be

expected in diabetes mellitus as it delays intestinalglucose absorption, inhibits the secretion of counter-

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Recent advances in pancreatic hormone research 281

regulatory hormones such as growth hormone andpancreatic glucagon and, in normal fasting subjects,lowers blood glucose concentrations. In insulin-dependent diabetics, insulin requirements were re-duced by simultaneous insulin and somatostatininfusions (Gerich and Patton, 1978). However, whensomatostatin and insulin were infused together inpatients with established ketoacidosis, plasma glu-cose, pancreatic glucagon, free fatty acids andketone-body levels fell as rapidly during insulinalone as during insulin and somatostatin infusion(Lundbaek et al., 1976). In maturity onset diabetes,somatostatin worsens diabetic control by increasingplasma glucose, ketone and branched-chain aminoacid concentrations (Tamborlane et al., 1977). Oneclinical situation where continuous somatostatin in-fusion might be beneficial, is the rare acute diabeticretinopathy which is known to be growth hormonesensitive and to respond to hypophysectomy. It ispossible that such patients might be spared theproblems of hypophysectomy by this approach, butotherwise somatostatin treatment appears to havelittle to offer in patients with diabetes mellitus.Treatment with somatostatin and its analogues has

been studied in patients with various hormone-secreting tumours. In insulinoma, gastrinoma andglucagonoma patients, somatostatin reduces tumourpeptide levels and in 2 patients improved the rash ofthe glucagonoma syndrome (Sohier et al., 1980).Subcutaneous injections of 5 mg Des AA' 2. 4, 5, 12, 13somatostatin lowered tumour hormone levels below50% of basal for 3-24 hr in 8 patients with pancreaticendocrine tumours (Long et al., 1979), but subse-quently it was shown that this analogue also inhibitedthe secretion of growth hormone and non-tumour-derived pancreatic and gastrointestinal hormones(Barnes et al., 1981). In patients with the carcinoidsyndrome, somatostatin abolishes spontaneous flush-ing and flushing due to alcohol, noradrenaline andpentagastrin; twice daily subcutaneous injections ofDes AA' 2. 4, 5, 12 somatostatin greatly reduced flushingand lacrimation in a patient with severe carcinoidsymptoms (Frolich et al., 1978; Long et al., 1981d).Somatostatin can also successfully control carcinoiddiarrhoea (Dharmsathaphorn et al., 1980). The longterm use of somatostatin or its analogues is apotentially exciting new area of therapeutic advancein a variety of tumour syndromes.

Somatostatin has been used in the treatment ofbleeding peptic ulcers on the basis that it bothreduces gastric acid and pepsin secretion and splan-chnic blood flow. In a randomized controlled study ofpatients with bleeding ulcers, somatostatin stoppedthe bleeding in 8 of 10 patients whereas cimetidinedid in only I of 10 (Kayasseh et al., 1980). In anotherstudy, somatostatin was effective in 17 of 23 patientswho had previously failed to respond to cimetidine.

Preliminary studies suggested that somatostatinmight have a role in the treatment of bleeding gastro-oesophageal varices (Thulin et al., 1979), but theeffect of somatostatin on portal blood flow andwedged hepatic vein pressure in patients with cirrho-sis is now controversial (Sonnenberg et al., 1981;Bosch, Kravetz and Rodes, 1981) and a propercontrolled trial is awaited.The great potential for somatostatin therapy in

many endocrine and gastrointestinal problems isobvious. Other potential uses include patients withacute pancreatitis (where a double-blind multicentreEuropean trial should report soon and provide moredefinitive evidence) and to reduce leaking and hastenhealing in postoperative abdominal fistulas (Gyr,Kayasseh and Keller, 1981). To date, almost nosignificant side effects have been encountered atstandard dose rates, but careful metabolic studies areneeded before more definite conclusions on long termsafety can be reached.

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(Received 1 December 1982)

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