6 Gut hormones and intestinal function

6 Gut hormones and intestinal function JENS JUUL HOLST PETER SCHMIDT

This chapter deals with endocrine regulation exerted by hormones secreted from the gut, with particular emphasis on effects on the gut itself and on the pancreas. However, other targets for the gut hormones will also be briefly described. The actions of the gut hormones on gastric functions are described in Chapter 5. For a discussion of the role of peptides in neural and paracrine regulation of gut functions the reader is referred to Chapter 2 and to a number of recent reviews (Dockray, 1987; Furness and Costa, 1987; Yamada, 1987; Makhlouf, 1989; Daniel, 1991). As hormones, we shall consider peptides secreted from endocrine cells and released into the bloodstream. In fact, the gut is thought to be the largest endocrine organ in the body, i.e. with the largest number of endocrine cells. In contrast to other endocrine organs, the endocrine cells are scattered and the number of different endocrine cells is very large (see Chapter 1). Traditionally, the term 'gut hormones' covers both peptides with a proven hormonal function and a number of peptides with many of the characteristics of a hormone but for which an endocrine function has not yet been proven. In addition, a number of humorally regulated functions have been identified for which the responsible hormone is not yet known with certainty. The peptides for which an endocrine function has been proven include the following: gastrin (see Chapter 5), secretin and cholecystokinin (CCK). Peptides for which a hormonal role is very likely, but perhaps not unequivocally proven, include: gastric inhibitory polypeptide (GIP), intestinal somatostatin (other functions of somatostatin are discussed in Chapters 5 and 9; here), motilin and glucagon-like peptide-1 (GLP-1). Peptides secreted from typical endocrine cells, but for which an endocrine function has not yet been identified with certainty, include: neurotensin, peptide YY (PYY), the enteroglucagons and glucagon-like peptide 2 (GLP-2). Substance P has been described as being produced in endocrine cells (in addition to neurones of the enteric nervous system), but this is a controversial observation. The amine, serotonin, may also have hormonal functions. The endocrine functions believed to be exerted by gastrointestinal hormones are listed in Table 1. The table includes established endocrine Baillidre' s Clinical Endocrinology and Metabolism--

Vol. 8, No. 1, January 1994 ISBN 0-7020-1817-1

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J. J. HOLST AND P. SCHMIDT Table 1. Functions regulated (at least partly) by gastrointestinal hormones.

Function

Action

Hormone

Pancreatic secretion of fluid and bicarbonate Pancreatic secretion of enzymes Pancreatic secretion of fluid, bicarbonate and enzymes Pancreatic secretion of hormones

Stimulation Stimulation Inhibition

Secretin Pancreozymin Pancreotone

Inhibition or stimulation Stimulation Stimulation Stimulation Inhibition Stimulation

Enteroinsular axis; for insulin:incretin Cholecystokinin Secretin Gastrin, entero-oxyntin Enterogastrone, antral chalone, bulbogastrone Villikinin

Inhibition

Enterogastrone

Stimulation Stimulation

Motilin Enterocrinin, duocrinin

Gall bladder emptying Choleresis Gastric secretion Villous motility Lower oesophageal sphincter motility Gastric motility Trophic effects on gastrointestinal tract Intestinal motility Intestinal secretion and absorption

The left-hand column lists the regulated functions; the centre column indicates whether regulation is stimulatory or inhibitory or both; the right-hand column lists designations coined to the (often hypothetical) responsible humoral agent.

regulations such as acid-induced regulation of pancreatic fluid and bicarbonate secretion. The responsible substance, the first to be designated a h o r m o n e , was called secretin but it took approximately 60 years of work to isolate and characterize chemically the peptide responsible for this regulation (Jorpes and Mutt, 1973). Thus, what Bayliss and Starling (1902) discovered was not a h o r m o n e but an endocrine regulation. Indeed, subsequent research has demonstrated that not all of the effects of acid on pancreatic secretion are due to the peptide secretin. Also note that the two h o r m o n e s thought to be responsible for the endocrine regulation of gall bladder emptying and pancreatic enzyme secretion, C C K and pancreozymin, were revealed to be one and the same h o r m o n e , when it was finally isolated and chemically characterized after 50 years of work (Jorpes and Mutt, 1973). The message is that hormonally regulated functions and biologically active h o r m o n e s should not be confused; the physiological demonstration of an endocrine function says nothing about the responsible h o r m o n e , and the fact that a peptide has certain biological actions does not indicate that it is responsible for the physiological control of that activity. A r e the gastrointestinal h o r m o n e s important? Their role in growth and d e v e l o p m e n t (see Chapter 8) may turn out to be of particular importance. Traditionally, for the adult individual the importance of an endocrine system has b e e n evaluated from clinical conditions of excess and deficiencies. Conditions with excess production of the various h o r m o n e s m a y be encountered in patients with endocrine tumours. Selective deficiencies are not known with certainty. Loss of intestinal tissue would have to be extensive to cause deficiency because of the scattered occurrence of the endocrine cells, and adaptive changes would tend to restore the lost functions. H o w e v e r , in

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view of the many effects of this group of hormones it is probably justified to assume that they modulate secretory and motor functions throughout the gastrointestinal tract, whereby defects such as intestinal stasis, gallstones, ulcers and maldigestion and malabsorption are avoided. Furthermore, their role in regulation of pancreatic endocrine secretion and in providing signals from the gut to the CNS may be of considerable importance in the overall regulation of metabolism and body weight. Finally, some of the hormones may have important actions outside the gastrointestinal tract, e.g. as transmitters in the CNS. The endocrine regulation of the functions listed in Table 1 is discussed below. In addition, some of the actions of the 'endocrine' peptides, for which hormonal status is still uncertain, will be described. PANCREATIC SECRETION OF FLUID AND BICARBONATE

Pancreatic secretion is highly regulated in most mammals and varies markedly with the digestive state. In the pig pancreas it is possible to elicit near maximal fluid secretion by stimulation of the vagus nerves in a secretinfree system (Holst et al, 1993), but the secretory response to near threshold frequencies of vagus stimulation is greatly potentiated by simultaneous acidification of the duodenal bulb. This effect cannot be reproduced in an isolated perfused duodenopancreatic preparation, indicating that long reflexes or duodenal hormones released by acid are responsible for the effect. In fact, sufficient amounts of secretin are liberated by the acidification to explain the potentiation, which can also be reproduced by exogenous secretin. The endocrine element in acid-induced secretion has been documented by classical denervation experiments, and by crosscirculation studies (Jorpes and Mutt, 1973). The hormonal role of the peptide, secretin, in acid-induced pancreatic secretion has been established by the classical procedure, mimicry, whereby endocrine responses are mimicked by exogenous hormone infusion. Thus, infusion of small amounts of HC1, mimicking the emptying of boluses of gastric chyme into the duodenum, has been demonstrated to cause a significant release of secretin and to cause a certain pancreatic bicarbonate secretion. When the secretin response was mimicked by infusion of synthetic secretin a similar pancreatic bicarbonate secretion ensued (Schaffalitzky de Muckadell, 1980). Thus, it was reasonable to claim that secretin was responsible for the acid-induced bicarbonate response. The role of secretin in the control of meal-induced pancreatic secretion has, however, been questioned (Wormsley, 1980) because meal ingestion is not necessarily associated with a significant release (measured as increases in secretin concentration in peripheral venous plasma). Furthermore, in response to meals, duodenal pH rarely decreases below the threshold for secretin release. In agreement with this it has become apparent that secretin release in humans is clearly related to the gastric emptying of 'free acid' into the duodenum (Schaffalitzky de Muckadell et al, 1981) (Figure 1).

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What frequently happens during meal ingestion is that the buffer capacity of the meal increases the pH of the chyme above the threshold for secretin release (other meals may result in a higher intragastric acidity). Later in the digestive process, when part of the gastric contents have been emptied, the pH decreases again and a secretin release ensues. According to this view, secretin is a hormone of fasting, capable of maintaining a neutral pH when P-secretin (pmol/I)

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unbuffered gastric chyme enters the duodenum. Recent investigation of the mechanism of acid disappearance in the duodenum suggest that pancreatic bicarbonate secretion is but one of several important mechanisms that include buffering by bicarbonate in bile and duodenal juice and diffusion of H + through the duodenal epithelium (Ainsworth et al, 1992). In fact, the disappearance of acid operates almost unimpaired in severe pancreatic insufficiency (Fahrenkrug et al, 1978). Thus, the prime function of pancreatic bicarbonate seems to be to ensure an optimal pH for the pancreatic enzymes under all conditions. Recent research has addressed the question of neural involvement in the pancreatic secretory response to acid (for review, see Holst, 1993). Whilst it has been clearly demonstrated that neither nerve stimulation, denervation nor atropine influence the secretin response to intraduodenal acid, it has been clearly shown (Singer et al, 1986; Niebel et al, 1988) that both denervation and atropine inhibit the secretory response to low, physiological doses of hydrochloric acid. As the secretory response to low doses of secretin were also reduced by these treatments, it was concluded that part of the pancreatic response to duodenal acidification depends on neural mechanisms, in particular intrapancreatic cholinergic mechanisms. Intraduodenal acid may also activate vasoactive intestinal polypeptide (VIP)-producing neurones that may affect pancreatic secretion of fluid and bicarbonate (Schaffalitzky de Muckadell et al, 1977). However, the role of secretin in meal- and acid-induced secretion has been very clearly demonstrated in immunoneutralization studies (Chey et al, 1979). A recent report describes the development of secretin receptor antagonists (Haffar et al, 1991). Availability of potent antagonists may greatly facilitate future studies of hormonal functions of secretin. The recent molecular cloning of nucleotides encoding the secretin receptor (Ishihara et al, 1991) should facilitate studies of the sites and mechanisms of secretin actions. Intraduodenal administration of oleate induces a significant secretin (and CCK) release and is also associated with pancreatic bicarbonate secretion (Schaffalitzky de Muckadell et al, 1986). It has been clearly shown that the release of the two hormones (with the potentiation of the secretin response caused by CCK) can fully account for the secretory response (Olsen et al, 1986). It is of interest, however, that a neural component is also involved in the response to oleate (Jo et al, 1992). PANCREATIC SECRETION OF ENZYMES

Denervation experiments paved the way for the extraction of a substance from the duodenal mucosa that increased the pancreatic secretion of enzymes (Harper and Raper, 1943). This discovery undermined the prevailing view that control of protein secretion was exclusively neural. Subsequent research established that the pancreozymin activity was contained in the peptide, CCK, isolated and sequenced by Jorpes and Mutt (1973). The physiology of CCK has been revolutionized by two recent developments: the development of potent and apparently specific CCK-receptor antagonists (Jensen et al,

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1989) and the characterization and clon~ingof the CCK receptors (Wank et al, 1992; see also Chapter 4). It is now known that at least two types of CCK receptors exist: the CCK-preferring A receptors, and the B receptors which do not discriminate between gastrin and CCK. For both receptors highly potent and specific antagonists have become available. With these tools it has been possible to map to a considerable extent the spectrum of actions for which CCK is responsible under physiological circumstances. Enzyme secretion may be stimulated by intraduodenal administration of protein hydrolysate, essential amino acids, in particular phenylalanine and tryptophan, and by digested lipids in micellar or at least emulsified form (Solomon, 1987; Walsh, 1987). As noted above, oleic acid elicits not only bicarbonate secretion but also enzyme secretion. All of these substances cause secretion of cholecystokinin (Walsh, 1987). The development of assays for CCK was particularly difficult (Cantor, 1989). The concentrations of CCK in plasma, as it turned out, are in the low picomolar range, posing great demands on the radioimmunological technique employed (see Chapter 2). The molecular heterogeneity of circulating CCK was another formidable problem (Cantor, 1989). Ideally, a CCK assay should detect all biologically active molecular forms of the hormone. Because the biological activity resides in the C-terminal octapeptide, the C-terminal pentapeptide of which is identical to that of gastrin, most antisera against CCK also cross-react with gastrin. Certain antibodies, however, cross-react with the N-terminal region of the CCK-octapeptide, where its unique structural feature, the sulphated tyrosine residue, resides. With such antisera it is possible to perform meaningful measurements of CCK immunoreactivity in plasma. Relatively lower cross-reactivity with the larger forms of CCK, CCK-33 and CCK-58 frequently remains a problem, however. To circumvent these problems several authors have employed bioassays for CCK based on its ability to stimulate amylase secretion from pancreatic acinar cells (Liddle et al, 1984). Such assays have turned out to be surprisingly sensitive, although their specificity may be doubted. In recent studies, however, a very high correlation between results obtained with bioassays and radioimmunoassays has been reported (Hocker et al, 1992). When stimulus-induced increases in the concentration of CCK in plasma, determined with the modern assays described above, are mimicked in humans with infusions of sulphated CCK-octapeptide (CCK-8), perhaps the most important molecular form of CCK, a secretion of enzymes from the pancreas ensues. The observed changes in CCK concentration may, therefore, account for the changes in enzyme secretion elicited by intraduodenal administrations of lipids and protein hydrolysates. However, apart from this indirect approach to the physiological actions of CCK, more direct evidence has been obtained with the aid of the specific CCK antagonists. With these, of which the most widely used are L 364,781 or MK-329 and loxiglumide or lorglumide, the secretory responses to intraduodenal or intragastric instillation of mixed meals (i.e. predominantly intestinal and gastric phases of pancreatic secretion; Solomon, 1987) decrease by about 50--70% (Hildebrand et al, 1990; Adler et al, 1991; Schmidt et al, 1991), whereas during 'normal' ingestion of a meal (with a preserved cephalic phase), enzyme

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secretion was inhibited by only 15% (Cantor et al, 1992) (Figure 2). In contrast, infusion of atropine virtually abolished the secretory effects of intraduodenal meal instillation and inhibited the response to CCK infusion (Adler et al, 1991). This and a large number of other findings suggest that CCK plays a significant but limited role in meal-induced pancreatic enzyme secretion, which is mainly regulated by neural mechanisms (Hoist, 1993), and that, furthermore, the effect of CCK is dependent on such neural mechanisms. It was also concluded that CCK is not responsible for pancreatic fluid secretion

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(regardless of its synergistic interactions with secretin) (Schwarzendrube et al, 1991). In this connection it may be of relevance that, in pigs, higher concentrations than those that circulate are required to stimulate pancreatic enzyme secretion (Cuber et al, 1989), questioning the role of CCK for pancreatic secretion in this species. Small discrepancies between the effects obtained with antagonists from the two major groups, the benzodiazepine derivatives (like MK-329) and the glutaramic acid derivatives (like loxiglumide) indicate that the specificity of the antagonists may deserve further investigation. A feedback regulation of pancreatic secretion seems to exist in humans as well as in experimental animals (Ihse et al, 1977). It is the intraduodenal enzymatic activity that regulates pancreatic enzyme secretion. Thus, administration of trypsin inhibitors or diversion of pancreatic juice increase secretion. In rats, a CCK-releasing peptide, the monitor peptide, which is inactivated by trypsin seems to be responsible for secretion of CCK, which in turn regulates pancreatic protein secretion (Iwai et al, 1988). The peptide, which has been cloned (Fukuoka and Scheele, 1990), interacts directly with CCK-producing cells in the rat duodenum (Liddle et al, 1992). In humans, however, the feedback regulation does not involve CCK secretion and seems to be mediated by a cholinergic mechanism (Adler et al, 1989). The impressive potency and specificity of the CCK-receptor antagonists have allowed studies of the involvement of CCK in other functions of the body as well. Its role in gall bladder motility will be discussed below. Here we shall address other functions that have been investigated in the same, mainly human, studies in which pancreatic function was evaluated. There are many obstacles in evaluating the endocrine functions of CCK. It has been known for a long time that injected CCK has effects other than those on the gall bladder and the pancreas (Walsh, 1987). Thus, CCK has been suspected of having effects on gastric emptying, bowel motility, lower oesophageal sphincter (relaxation), sphincter of Oddi pressure and pancreatic polypeptide and insulin secretion. However, in view of the low concentrations in plasma it has also been suspected that most of these were pharmacological effects. Another problem is that CCK also exists in peptidergic nerves, where it may function as a neurotransmitter both centrally and in the enteric nervous system (see Chapter 3). Furthermore, it seems that CCK may affect other neurones and thus have indirect effects. Among these should be considered effects of CCK on afferent nerves relaying information to the CNS, or effects exerted directly on the CNS via leaks in the blood-brain barrier in the circumventricular organ. The effectiveness of the antagonists in interacting with neuronal CCK receptors is not known. These important features should be remembered when evaluating the results obtained with the receptor antagonists. Future precise mapping of the occurrence of CCK receptors, made possible by the cloning of the receptors, will help define the targets of CCK. Most of the studies cited agree that the CCK antagonists cause hypersecretion of CCK. The mechanism is not known, but as with other endocrine systems, CCK-producing cells might possess inhibitory CCK receptors that are blocked by the antagonist.

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There is good agreement that gastric emptying is accelerated by the CCK antagonists (Meyer et al, 1989; Fried et al, 1991a,b; Cantor et al, 1992), and Schmidt et al (1991) found slightly increased mouth-to-caecum transit time, but others found no effects on intestinal peristalsis (Bartho et al, 1989; Meyer et al, 1989, Cantor et al, 1992) and colonic motor activity (Niederau et al, 1992). Schmidt et al (1991) found a 72% increase in stool weight and a 186% increase in faecal fat excretion after loxiglumide, but these could be secondary to the effects on gall bladder. Brazer et al (1990) found no effects of antagonist treatment on lower oesophageal sphincter activity. All investigators report inhibitory effects of CCK antagonists on pancreatic polypeptide responses to a meal (Adler et al, 1990; Meier et al, 1990; Fried et al, 1991b; Hildebrand et al, 1991), but again the CCK effect must involve cholinergic pathways because atropine abolishes both CCK effects and meal-induced response (Adler et al, 1990). With receptor antagonists it has not been possible to substantiate the suggested role in insulin secretion (Liddle et al, 1990; Fried et al, 1991b; Hildebrand et al, 1991; Schwarzendrube et al, 1991). In studies of the much debated role of CCK in feeding behaviour and satiety, there was no effect of receptor antagonists in humans (Drewe et al, 1992; see also Greenberg et al, 1992). Careful infusion studies were also negative (Schick et al, 1991). The effects of CCK on gastric secretion is discussed in Chapter 5. Gastrin has CCK-like effects on pancreatic exocrine secretion, and a role for gastrin in meal-induced pancreatic secretion has been suspected. However, under physiological circumstances the concentrations are rarely sufficient to influence pancreatic secretion, and recent studies with CCK-B receptor antagonists would argue against an important role for gastrin in pancreatic secretion (Konturek et al, 1991). Neurotensin, secreted from N cells in the ileal mucosa (Armstrong and Leeman, 1988), may stimulate pancreatic secretion (Gullo et al, 1992). Neurotensin is rapidly degraded to smaller fragments, but fragments of neurotensin may also stimulate secretion (Trimble et al, 1987; Nustede et al, 1989). The effect is most pronounced in rats and dogs. In other species it is less effective (Cuber et al, 1990). Its effect on isolated pancreas is weaker than the effect in vivo, possibly because it acts indirectly (Feurle and Niestroj, 1991; Iwatsuki et al, 1991). At any rate, luminal stimulation of the lower small intestine, from where neurotensin is secreted, causes inhibition rather than stimulation of pancreatic secretion (see below). Furthermore, recent studies indicate that the neurotensin response to ingestion of mixed meals has been overestimated (Ferris et al, 1991). INHIBITION OF PANCREATIC EXOCRINE SECRETION

It has been known for a long time that infusions of metabolic substrates and hypertonic solutions into the lumen of the distal gut inhibits pancreatic secretion (Harper et al, 1979a). The inhibition persists after pancreatic denervation and must therefore be humoral. The responsible substance, a polypeptide extractable from the ileal and colonic mucosa, was named

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pancreotone (Harper et al, 1979b), but the chemical nature of the peptide has not yet been established with certainty. The known hormones from the distal gut include neurotensin, the glucagon-related peptides (see below), PYY and possibly somatostatin. As mentioned above, neurotensin stimulates rather than inhibits pancreatic secretion and is, therefore, an unlikely candidate. PYY, secreted from the L cells where it is often co-stored with the glucagon-related peptides, is a more likely candidate (Sheikh, 1991). PYY inhibits pancreatic secretion in almost all species investigated. In humans (Adrian et al, 1985), however, PYY had no effect on pancreatic secretion when infused in a dose that clearly inhibited gastric secretion. In recent studies in humans, where pancreatic secretion was studied during ileal perfusions with carbohydrate and lipids in amounts that might be expected to occur during light malabsorption or after large meals, plasma levels of PYY changed very little and did not reach levels that would be expected to influence pancreatic secretion (Layer et al, 1991). Recently, a truncated form of PYY, PYY (3~-36), reacting mainly with Y2 receptors thought to be responsible for the pancreatic inhibition, has been identified (Grandt et al, 1992). The relevance of this discovery for pancreatic secretion is not yet established. In rats, PYY immunoneutralization increased pancreatic secretory responses to pancreatic juice diversion (i.e. feedback stimulation; Guan et al, 1991). The inhibitory effect is indirect, and probably involves interactions with the CNS, possibly through receptors in the brain (Sheikh, 1991). The glucagon-related peptides result from processing of proglucagon, which is produced in large amounts in the distal intestinal mucosa, and are stored in the granules of the L cells (Holst and Orskov, 1993). Two of the products, namely oxyntomodulin and GLP-1, are biologically active, and both have been reported to inhibit pancreatic secretion (Schjoldager et al, 1989; Wettergren et al, 1993). Whereas the concentrations of oxyntomodulin in human plasma are probably not sufficient to influence pancreatic secretion, GLP-1 concentrations exhibit appreciable increases after ileal perfusion with physiological amounts of lipids or carbohydrates and these may have pronounced effects on pancreatic secretion (Layer et al, 1991). Again, the effect is indirect and probably involves central nervous mechanisms (Holst et al, 1993). Further studies are required for the final identification of the physiological 'pancreotone', and studies of interactions between the inhibitory hormones from the ileum are clearly of interest. Somatostatin (Walsh, 1987) is utilized in the body as circulating hormone, as paracrine transmitter and as neurotransmitter (see also Chapter 9). In the distal gut somatostatin is found mainly in neuronal structures and is likely to exert local functions. However, open-type endocrine cells producing somatostatin are found scattered along the entire gastrointestinal tract, and a considerable fraction of the circulating somatostatin appears to be derived from the gut. In plasma, somatostatin is present in two molecular forms: somatostatin-14 and somatostatin-28, the latter clearly originating from intestinal endocrine cells (Baldissera et al, 1985), and both have pronounced inhibitory effects on the pancreas. The concentration of somatostatin-28

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increases in relation to certain meals, and in studies where plasma levels of somatostatin-28 have been mimicked by infusion there were marked inhibitory effects on the pancreas (Hildebrand et al, 1992). Thus, somatostatin-28 may indeed play a regulatory role, but its relation to digestive physiology is still not yet clear. Again, somatostatin does not directly inhibit pancreatic secretion, but seems to do so by interfering with neuronal transmission within the pancreas (Holst et al, 1993). PANCREATIC SECRETION OF HORMONES

The pancreatic hormones comprise the products of the four cell types of the islets of Langerhans: the insulin-producing [3 cells, the glucagon-producing o~cells, the somatostatin-producing g cells, and the pancreatic polypeptideproducing PP cells. Their secretion is regulated by nutritional, metabolic and neural mechanisms, but here we shall address only endocrine regulation exerted by the gut in what has been named the enteroinsular axis (reviewed by Creutzfeldt and Ebert, 1993). It has been known for many years that enteric signals influence insulin secretion, and thereby glucose metabolism; the responsible hormone was named 'incretin'. The chemical nature of incretin is not yet fully established but recent developments suggest that two intestinal hormones, GIP and GLP-1, are together responsible for the 'incretin effect'. The incretin effect is frequently studied by comparison of insulin secretory responses (measured as changes in peripheral concentrations or, more precisely, by determination of insulin secretory rate on the basis of C-peptide determinations and kinetics) to oral and intravenous glucose administration adjusted to yield identical (arterial) blood glucose responses. The difference is due to incretin. Studied by this method, incretin is restricted to being a hormone released by glucose, and because glucose is rapidly absorbed in the proximal small intestine, the incretin studied by this method will also be a hormone from the upper intestine. However, physiological nutrients (complex carbohydrates and lipids), as present in mixed meals, influence insulin secretion via release of intestinal hormones derived both from the upper and the lower intestine. GIP was originally isolated because of its effects on gastric secretion, but seems to be much more important as a stimulator of insulin secretion (Walsh, 1987; Brown et al, 1988). GIP secretion is released by glucose, carbohydrates and fat and therefore by mixed meals. When meal-induced increases are mimicked by infusion, insulin secretion is increased, provided that the plasma glucose concentrations are also elevated over basal levels, e.g. to levels equivalent to those induced by the mimicked meals (Nauck et al, 1989). In other words, the glucose-induced insulin secretion is greatly potentiated by GIP, but GIP has little effect at euglycaemia. There is general agreement that GIP is responsible for part of the incretin effect, as also demonstrated in immunoneutralization studies in experimental animals (Lauritsen et al, 1981), and because GIP is also released in response to ordinary meals which elevate blood glucose sufficiently to stimulate insulin

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secretion, GIP is probably also responsible for part of the insulin response to a mixed meal. However, both immunoneutralization studies and studies in humans after small bowel resection indicate that an additional incretin is secreted from the distal gut (Lauritsen et al, 1980; Ebert et al, 1983). The distal incretin seems to be glucagon-like peptide-1 (GLP-1), a product of proglucagon secreted from the L cells of the ileum (see also Chapter 7) and colon in response to mixed, but in particular fat-rich or carbohydrate-rich, meals (Orskov, 1992; Holst and Orskov, 1993). This peptide is more potent than GIP and, although its effect on insulin secretion is also dependent of the blood glucose concentrations, it stimulates insulin secretion even at euglycaemia (Nauck et al, 1993). In addition, and in contrast to GIP, GLP-1 significantly inhibits glucagon secretion. The dual effect on insulin and glucagon secretion means that the molar ratio of the concentrations of the two hormones in the portal venous plasma increases markedly during GLP-1 stimulation. This in turn decreases the hepatic glucose production whereby plasma glucose decreases (Hvidberg et al, 1993). However, because the GLP-1 effect on insulin secretion decreases as plasma glucose falls, the glucose lowering effect ceases at 3.5--4.0mmol/1. Because of its pronounced effect on hepatic glucose production, GLP-1 is currently being evaluated for treatment of the hyperglycaemia of noninsulin dependent diabetics in whom infusion of the peptide completely normalizes the elevated blood glucose levels. Little is known about an endocrine regulation of pancreatic somatostatin secretion (Walsh, 1987). The increase in plasma somatostatin sometimes observed in response to meals seems to be, as noted above, due to intestinal secretion of mainly somatostatin-28. In contrast, the secretion of pancreatic polypeptide is markedly enhanced by meal ingestion, and part of this response may be mediated by duodenal release of CCK, as discussed above. Most of the response, however, depends on vagal, parasympathetic impulses (Schwartz, 1983), and the entire meal response can be abolished by atropine pretreatment. GALL BLADDER EMPTYING

The existence of an endocrine regulation of gall bladder emptying was established early in this century in cross-circulation experiments (Ivy and Oldberg, 1928) and the presence in the duodenal mucosa of a gall bladder contracting substance was established. The hormone, CCK, was isolated and purified to homogeneity on the basis of its cholecystokinetic properties (Jorpes and Mutt, 1973). The cholecystokinin radioimmunoassays have established a clear relationship between elevated plasma concentrations of cholecystokinin and gall bladder emptying, and mimicking of meal-induced concentrations of CCK by infusion consistently causes gall bladder emptying (Walsh, 1987; Cantor, 1989). The assumption from these studies that CCK is indeed responsible for meal-induced gall bladder emptying has been substantiated through studies with specific CCK-A receptor antagonists. Unanimously, such studies have shown that the antagonist completely

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prevents meal-induced gall bladder emptying and increases the resting volume of the gall bladder, suggesting that CCK regulates not only emptying but also gall bladder resting tone (Liddle et al, 1989; Meyer et al, 1989; Niederau, 1989; Hildebrand et al, 1990; Hopman et al, 1990; Malesci et al, 1990; Schmidt et al, 1991; Schwarzendrube et al, 1991; Cantor et al, 1992) (Figure 3). As with other gastrointestinal functions, however, gall bladder motor activity is also subjected to neuronal regulation (Schjoldager and Holst, 1993). In fact, it seems that atropine strongly inhibits the effect of small, physiological doses of CCK, as well as the effects of intraduodenal meal instillation, without affecting the release of CCK (Hopman et al, 1990; Takahashi et al, 1991). Therefore, in spite of the clear demonstration of CCK receptors on the gall bladder muscularis, and the fact that contractile responses can be elicited on isolated gall bladder muscle strips (Schjoldager, 1993), it seems that neuronal components are involved in both meal-induced and CCK-induced gall bladder contraction. As might be expected, gastrin in high concentrations may influence gall bladder motility by interacting with CCK-A receptors, but gastrin has no effect in physiological concentrations. Motilin (see below) has been reported to contract the gall bladder in humans (Vantrappen et al, 1979), but it seems that this hormone is released in response to gall bladder emptying, rather than causing it (Nilsson et al, 1993). An endocrine inhibition of gall bladder 120-

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Time following ingestion of MK-239 (minutes) Figure 3. Effect of a CCK-A receptor antagonist (MK-329) on gall bladder volumes in normal volunteers after ingestion of a mixed meal. Results are presented as a percentage of initial (premeal) gall bladder volume (mean + SEM). **P < 0.01. From Liddle et al (1989).

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motility might also be suspected to exist, and PYY has been demonstrated to inhibit gall bladder emptying in some species, but not in others (Schjoldager, 1993). Somatostatin inhibits gall bladder emptying (Fisher et al, 1987) and this may explain the high incidence of gallstones in patients with somatostatinproducing tumours (Krejs et al, 1979) and the cholestasis observed in patients treated wi.th long-acting somatostatin analogues (Gorden et al, 1989). The physiological role of endocrine inhibition is not established.

CHOLERESIS

The bile, as it emerges from the common bile duct, is partly of canalicular and partly of ductal origin. The canalicular bile is produced partly by a bile acid dependent mechanism and partly by a mechanism that depends on electrolyte secretion, but there is little evidence that these processes are regulated by gastrointestinal hormones (Erlinger, 1987). The bicarbonaterich ductal secretion seems to be subject to endocrine control. Thus, in numerous studies secretin has been demonstrated to increase bile flow (Waitman et al, 1969; Glass, 1982). A stimulated electrolyte secretion can also be demonstrated in isolated segments of ducts, and several other observations, including studies of erythritol clearance (which parallels bile acid dependent, canalicular secretion, but not secretin-induced secretion), support the assumption that it is mainly the ductular secretion that is stimulated (Erlinger, 1987). Duodenal acidification also increases choleresis, and infusions of secretin in doses that produce similar increases in the plasma concentrations stimulate bile secretion (Ainsworth et al, 1992). It has been demonstrated that denervation of the liver does not influence the response to secretin and modifies, but does not eliminate, the response to feeding (Cucchiaro et al, 1992). Glucagon, CCK and insulin have also been reported to increase bile flow, but the physiological importance of this is unclear (Kaminski et al, 1988). Both somatostatin and pancreatic polypeptide have been found to inhibit bile secretion (Nyberg, 1990; Langlois et al, 1990). Pancreatic polypeptide strongly inhibited bile acid output in conscious pigs (Langlois et al, 1990). The physiological relevance of these observations is unclear.

GASTRIC SECRETION The regulation of gastric secretion is discussed in Chapter 5. Endocrine regulation includes: (1) the well-defined stimulatory actions of antral hormones; (2) enteric hormones that stimulate secretion (entero-oxyntin) (Grossman, 1974); (3) antral hormones that inhibit secretion (antral chalone); (4) duodenal inhibitory hormones (bulbogastrone); and (5) the enteric inhibitory hormone, enterogastrone. Today, the endocrine role of gastrin is well worked out and its importance established. The nature of entero-oxyntin, the name suggested by Grossman (1974) for an enteric

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hormone or hormones that stimulate gastric secretion, is not established. A peptide, named gastrotrophin, has been isolated from porcine intestine (Walz et al, 1988; Defize et al, 1988), but its hormonal role has been questioned (Gantz et al, 1989). The existence of an antral chalone, an inhibitory hormone released by acidification of the antrum, has been suspected since the turn of the century, but remained elusive for many years (Thompson, 1974). Today it is well established that acidification of the antrum causes a release of somatostatin that strongly inhibits gastrin secretion (Holst et al, 1992) (see also Chapter 9). If sufficient amounts are released to increase the concentrations in plasma, antral somatostatin may also inhibit acid secretion in an endocrine manner, being exceedingly potent as an inhibitor of acid secretion. The efficiency of acidification of the duodenal bulb (bulbogastrone) in inhibiting gastric acid secretion was first demonstrated in 1961 and the endocrine nature of the inhibition was soon confirmed (Andersson, 1974). We now know that acidification of the bulb causes a release of both secretin and somatostatin, both of which may very potently inhibit acid secretion. Possibly these hormones are responsible for the bulbogastrone effect. The question of the enteric inhibitory hormones, enterogastrone, is complex (Grossman, 1974). Both duodenal hormones and ileal hormones may influence gastric acid secretion. Most probably the term enterogastrone covers the actions of several hormones, including somatostatin (Seal et al, 1988), neurotensin (Seal et al, 1988), PYY (Sheikh, 1991) and GLP-1 (Orskov, 1992; Wettergren et al, 1993).

VILLOUS MOTILITY, VILLIKININ A hormonal regulation of the contractions and relaxations of the villi of the small intestine elicited by acidification of the duodenal mucosa was postulated in 1933 (Kokas, 1974). More recent studies, however, did not confirm the existence of a humoral stimulant, but confirmed the important regulation of villous motility by the autonomic nervous system (Womack et al, 1988).

LOWER OESOPHAGEAL SPHINCTER MOTILITY

A hormonal regulation of lower oesophageal sphincter motility has been suspected for a long time (Wienbeck and Erkenbrecht, 1982). In particular, gastrin was suspected to be involved. More recent investigations, however, involving careful mimicry and immunoneutralization have excluded such a function for gastrin (Goyal and McGuigan, 1979; McCallum et al, 1983). As discussed above, CCK has also been suspected, but recent studies seem to have excluded such a function (Brazer et al, 1990). Motilin increases lower oesophageal sphincter motility (see below) (Meissner et al, 1976), but apart from this the evidence for an endocrine regulation seems weak.

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GASTRIC MOTILITY This is discussed in Chapter 5. The concept of intestinal inhibitory hormones, enterogastrones, regulating gastric function also applies to gastric motility. Presumably a similar complexity of regulatory substances as seen for secretion apply to the control of motility.

TROPHIC EFFECTS

The trophic effects of the gastrointestinal hormones are discussed in Chapters 7 and 8.

INTESTINAL MOTILITY A hormonal regulation of intestinal motility has been suspected for many years, especially because many of the gastrointestinal hormones have pronounced effects on intestinal motility (Wienbeck and Erkenbrecht, 1982). Nevertheless, convincing evidence that an endocrine regulation is essential is lacking. One reason is that intestinal motility is difficult to define in operational terms and therefore difficult to measure. Another reason is the variability of most of the parameters of motility recorded; this means that changes must be profound to appear significant. As a consequence minor modulatory effects, as would be expected to result from endocrine regulation, may be difficult to detect. The methods of registration of motility are numerous and range from electrical recordings (intracellular as well as extracellular), electronically recorded signals from strain-gauge transducers sewn on to the intestinal serosa, manometry recordings, radiographic examinations of enemas, scintigraphic detection of radioactive pellets added to ingested materials or recording of radiosignals from radiopellets, and determination of fluid propulsion, to transit time determination for either segments of the intestine or for the entire intestine. The problem is, however, that the motility pattern recorded by one of these methods is not easily related to the patterns recorded by the other methods. For instance, does a pattern with a high frequency of high amplitude pressure excursions result in a high rate of propulsion? Is a high frequency of spikes in the electromyogram related to an increased or a decreased transit? Because of the complex nature of the parameters of motility, it is not surprising that diverse and often conflicting results regarding the role of the hormones have often been reported. It is important to distinguish between motility patterns registered in the fasting state and in the fed state (Weisbrodt, 1987). It seems that in the fasting state the motility pattern is dominated by the migrating motility complex (MMC), with its characteristic four phases: phase I, with no contractile or electrical spike activity; phase II, with scattered spike/ contractile activity; phase III, with maximum contractile and spike activity;

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and phase IV, a short phase in which the motility approaches that of phase I. The cycle length varies between species, but is 1.5-2 h in humans with phase III lasting for about 10% of the cycle length. The motility after feeding is characterized by replacement of the MMC with a more or less continuous but rather low level of activity, the fed pattern. A disproportionate interest has been devoted to the study of the MMC pattern, presumably because of the difficulties in analysing and understanding the fed pattern. Obviously, the fed pattern characterizing the period when the chyme is mixed with the gastrointestinal secretions and exposed to the absorptive mucosal surfaces, while being at the same time propelled along the intestine, is a more important pattern from the digestive point of view. The MMC has been characterized as the 'housekeeper' of the gut, rapidly transporting cell debris and other interdigestive intestinal contents to the colon. In this context it is important to realize that a totally isolated, extrinsically denervated small intestine is capable of carrying out net aboral propulsive motor activity, whereby large amounts of intestinal contents may be propelled over great distances, in the absence of hormones in the perfusion medium (Schmidt et al, 1993). This phenomenon is in agreement with other observations that the gut exerts near normal transport functions in spite of extrinsic denervation (Weisbrodt, 1987), and with observations that the motility pattern of autotransplanted segments of the gut, not in series with the main gut, may be dissociated from the motility pattern of the main gut during feeding (Sarr and Kelly, 1981). Thus, it may be concluded that important motor functions of the gut are performed independently of endocrine and extrinsic nervous regulation. However, as already mentioned, this in no way excludes the existence of modulatory actions of hormones on motility. Thus, interdigestive MMCs have also been demonstrated to occur synchronously with duodenal MMCs in a denervated gastric pouch transplanted to the pelvis (Thomas and Kelly, 1979), pointing to the existence of an endocrine regulation. The hormone that has attracted widest interest in this respect is motilin (Walsh, 1987; McIntosh and Brown, 1988). Motilin, a peptide of 22 amino acids, for which both precursor structure and gene structure are known (Yano et al, 1989), was isolated on the basis of the observation that alkalinization of the duodenum stimulates gastric emptying. A substance with a stimulatory effect on gastric emptying was isolated from intestinal extracts (Brown et al, 1972). In fact, the name motilin had already been coined for a hypothetical hormone capable of enhancing intestinal motility at the beginning of the century (Mclntosh and Brown, 1988). Ironically, subsequent research has established that it is acidification rather than alkalinization that causes a release of motilin from the duodenum in humans. Similarly, meal ingestion is generally associated with a decrease rather than an increase in plasma motilin levels. The effects of motilin, which is secreted from specialized motilin (M) cells (and not, as previously believed, predominantly from enterochromaffin (EC) cells), on intestinal motility depends on species and study environment (McIntosh and Brown, 1988; Allescher and Ahmad, 1991). It has little effect in vitro but increases motor activity, at least in dogs, by a complex mechanism that includes nervous pathways (the effect is

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blocked by tetrodotoxin) and which may include endogenous opiates. It has also been demonstrated to increase gastric emptying and shorten intestinal transit. The greatest interest, however, has been focused on its relation to the generation of the MMC. Plasma levels show a cyclic pattern in all mammals studied. Peak levels occur when phase III of the MMC passes through the duodenum. The mechanism that generates the cyclic secretion of motilin is not known, although considerable effort has been made to elucidate this. There is recent evidence that the emptying of bile into the duodenum is responsible (Nilsson et al, 1993). This would render motilin secretion secondary to the nervous activity responsible for gall bladder emptying and the other interdigestive events that show a similar periodicity. Infusions of motilin in the fasted state cause premature MMCs in the upper gastrointestinal tract (Vantrappen et al, 1979). In the fed state motilin has little effect. In two studies in dogs, immunoneutralization of motilin abolished spontaneous MMCs in the upper (but not in the distal) intestinal tract (Lee et al, 1983; Poitras, 1984). Under all circumstances the effect of motilin depends on normal intrinsic and extrinsic innervation of the gut. The antibiotic, erythromycin, which has effects on intestinal motility similar to motilin, was originally believed to cause the release of motilin. More recent studies have shown that erythromycin interacts with motilin receptors, as demonstrated in receptor binding studies (Peeters et al, 1989). Such receptors have been demonstrated in various preparations of muscular tissue, and even on isolated gastric muscle cells. These observations may be of considerable clinical interest because both motilin (Peeters et at, 1992) and erythromycin (Janssens et al, 1990; Tack et al, 1992) and more potent derivatives of erythromycin may be used to treat motility disorders, e.g. in diabetic gastroparesis (Figure 4). Gastrin may, under certain circumstances, be demonstrated to influence intestinal motility, but patients with hypergastrinaemia do not seem to suffer from motility disturbances that can be ascribed to hypergastrinaemia. The major effects of gastrin, if any, would be on gastric motility. CCK has clear effects on gastric emptying, as demonstrated with the use of CCK-A receptor antagonists as discussed above, but its effect on intestinal motility is modest or negligible (Meyer et al, 1989; Niederau et al, 1992). Neurotensin, released particularly by fat ingestion, has inhibitory effects on gastrointestinal motility (Rosell et al, 1984). Its physiological role has not been established (see above), but it remains a candidate for slowing down the intestinal passage of chyme by increasing antiperistaltic activity (Siegle and Ehrlein, 1989). Another inhibitor is PYY. PYY inhibits gastric emptying and also retards jejunal and colonic motility (Sheikh, 1991), but the physiological importance of these observations has not yet been established. As mentioned above, PYY is often secreted in parallel with the proglucagon-derived peptide, GLP-1. This peptide also has pronounced delaying effects, at least on gastric emptying (Wettergren et al, 1993). Possibly the two hormones act in concert as the so-called 'ileal brake', inhibiting both gastric and intestinal functions.

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Figure 4. Speed of gastric emptying in diabetic patients taking placebo or erythromycin and in healthy subjects. (a) The rate of emptying of the solid part of the test meal, expressed as the mean (+ SEM) percentage of the isotope remaining in the stomach at various times after the ingestion of the meal, in ten patients with diabetes after the intravenous administration of placebo (solid line, open symbols) or 200 mg of erythromycin (solid line, closed symbols) and in ten healthy subjects (dotted line). (b) The rate of emptying of the liquid part of the test meal. From Janssens et al (1990).

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ENTERIC SECRETION AND ABSORPTION

The epithelial cells in the intestinal mucosa are polarized and highly specialized for the transport of water, electrolytes and nutrients. Net transport of electrolytes and water across the epithelium is the result of two counteracting processes: absorption (transport from lumen to the blood) and secretion (transport from the blood to the lumen). The absorptive cells appear to be localized primarily on the villi and the secretory cells, mainly in the crypts (Jodal et al, 1988; Cooke, 1989; Rangachari, 1991). Absorption and secretion may occur at the same time, and net absorption may, therefore, be accomplished by both increasing absorption and decreasing secretion, while net secretion may result from both decreased absorption and increased secretion. Hormonal effects on intestinal transport include effects on both secretion and absorption, but in most experiments only the net effect on transport has been determined. Numerous studies (for review, see Cooke, 1987) have documented that most of the gastrointestinal hormones alter intestinal transport in pharmacological doses, but their role in the physiological control of electrolyte and water transport is difficult to determine. This is due both to the lack of potent and specific antagonists for most of the peptides and to the dual localization of some of the hormones in both nerves and in endocrine cells. Effects of the hormones on intestinal transport could be exerted directly on the enterocytes, or the peptides could act as paracrine transmitters, but the effects could also be mediated via secretory nerves innervating the epithelium (see Chapters 1 and 3). Furthermore, most of the gastrointestinal hormones have effects on mucosal blood flow and gastrointestinal motility, both of which may indirectly influence intestinal transport. Many of the gastrointestinal hormones are released simultaneously postprandially but the cooperative effects of combinations of hormones have generally not been studied. Endocrine regulation of Brunner's gland secretion was proposed in 1935 by Florey and Harding, who showed that feeding caused a flow of juice from the duodenum in spite of extrinsic denervation. The name 'duocrinin' was suggested by Grossman (1974). Several peptides have since been shown to cause a similar secretory response (see below), but a specific hormone responsible for the secretion is not known. The duodenal mucosal bicarbonate secretion has attracted considerable interest because of its potential importance in the mucosal defence mechanisms (Flemstr6m, 1987). As mentioned above, duodenal acidification stimulates bicarbonate secretion (Flemstr6m, 1987; Ainsworth et al, 1992), and the mechanism seems to involve peptidergic nerves in the mucosa and prostaglandins, whereas the hormones secretin and glucagon had no effect in humans (Wolosin et al, 1989). Transplanted segments of jejunum have been used to demonstrate humoral control of the secretion of enteric succus and the name 'enterocrinin' was suggested for the responsible factor (Nasset, 1974), but it has never been chemically identified. Most of the gastrointestinal hormones cause net intestinal secretion both in vivo and vitro (Cooke, 1987; Armstrong and Leeman, 1988; Spokes et al, 1990). Thus, secretin has been

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shown to stimulate enteric secretion, but seems unlikely to do so under physiological circumstances (Binder et al, 1980). Glucagon also has secretory effects on the small intestine, but infusion studies indicate that supraphysiological concentrations are required to elicit secretion (Patel et al, 1979). CCK has been found to inhibit the absorption of water and electrolytes in humans (Moritz et al, 1973; Cooke, 1987). However, as discussed above, recent antagonist studies have not revealed any convincing effects for CCK or gastrin on intestinal transport, but generally this topic has not been specifically addressed. Neurotensin has been demonstrated to stimulate net fluid secretion in rat small intestine (Spokes et al, 1990), but recent studies indicate that in physiological concentrations neurotensin has little influence on ileal output in humans (MacKay et al, 1990). PYY enhances electrolyte and water absorption by the colon (Okuno et al, 1992) and has been proposed for treatment of secretory diarrhoea (Playford et al, 1990). Because PYY cells are present in the colonic mucosa this could point to a role for PYY, particularly in a local control of absorption. Somatostatin does not seem to alter basal intestinal transport in dogs and humans, but reduces intestinal secretion induced by VIP, prostaglandins and glucagon (Cooke, 1987). In fact, a long-acting analogue has been used for the treatment of watery diarrhoea syndromes (Anderson and Bloom, 1986). In such patients, however, the effect is most likely to be due to inhibition of release of the agent responsible for the diarrhoea. Somatostatin has also been shown to inhibit absorption of nutrients, but the extent to which this is due to its effect on splanchnic blood flow is not known. Passive immunization against somatostatin increased postprandial fatty acid levels in dogs (Schusdziarra et al, 1980), but possible changes in pancreaticobiliary secretion were not considered. The large network of neurones and nerve fibres throughout the gastrointestinal tract, the enteric nervous system, plays an important role in the control of intestinal transport, being responsible for the intestinal reflexes (see also Chapter 3). These intestinal secretory reflexes may be initiated by bacterial toxins, bile salts and distension of the gut wall (Caren et al, 1974; Cassuto et al, 1981; Eklund et al, 1985; Karlst6m, 1986). It is possible that the acute effects brought about by the enteric nervous system could be modulated by more long-lasting effects of hormones released postprandially from the intestinal mucosa (Cooke, 1987). Cassuto et al (1981) suggested that some of the endocrine cells in the intestinal mucosa could function as receptor cells. Such cells, when stimulated from the luminal side, would release their content of hormones at the basolateral sides and might thereby initiate intestinal secretory reflexes. Finally, it should be recalled that hormones derived from non-intestinal glands may have pronounced effects on intestinal transport. Thus, it has been suggested that the gastrointestinal tract is involved in the regulation of circulatory and extracellular volume (Cooke, 1987; Sj6vall et al, 1987). During acute volume expansion absorption is decreased in the small intestine of rats. Atrial natriuretic peptide could be involved in this regulation (Pettersson and J6nsson, 1989; Semrad et al, 1990; Matsushita et al, 1991). In contrast, during salt depletion and hypovolaemia

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glucocorticoids and angiotensins seem to promote absorption (Cooke, 1987). The action of angiotensins on gut absorption may involve effects on the CNS (Brown and Gillespie, 1988). REFERENCES Adler G, Reinshagen M, Koop I et al (1989) Differential effect of atropine and a cholecystokinin receptor antagonist on pancreatic secretion. Gastroenterology 96: 1158-1164. Adler G, Beglinger C, Braun U et al (1990) Cholecystokinin is a regulator of intestinal phase-stimulated PP release. Regulatory Peptides 30: 105-111. Adler G, Beglinger C, Braun U et al (1991) Interaction of the cholinergic system and cholecystokinin in the regulation of endogenous and exogenous stimulation of pancreatic secretion in humans. Gastroenterology 100: 53%543. Adrian TE, Savage AP, Sagor GR et al (1985) Effect of PYY on gastric, pancreatic and biliary functions in humans. Gastroenterology 89: 494-499. Ainsworth MA, Glad SCrensen H, Svendsen P, Olsen O & Schaffalitzky de Muckadell OB (1992) Relative importance of pancreatic, hepatic and mucosal bicarbonate secretion in duodenal neutralization of acid. Scandinavian Journal of Gastroenterology 27: 343-349. Allescher H-D & Ahmad S (1991) Postulated physiological and pathophysiological roles on motility. In Daniel EE (ed.) Neuropeptide Function in the Gastrointestinal Tract, pp 311400. Boca Raton: CRC Press. Anderson JV & Bloom SR (1986) Neuroendocrine tumours of the gut: long-term therapy with the somatostatin analogue SMS 201-995. Scandinavian Journal of Gastroenterology 21 (supplement 21): 115-130. Andersson S (1974) Bulbogastrone. Gastroenterology 67: 742-744. Armstrong MJ & Leeman SE (1988) Neurotensin and substance P. Advances in Metabolic Disorders 11: 469-492. Baldissera FGA, Nielsen OV & Holst JJ (1985) The intestinal mucosa preferentially releases somatostatin-28 in pigs. Regulatory Peptides 11: 251-262. Bartho L, Holzer P, Leander S & Lembeck F (1989) Evidence for an involvement of substance P, but not cholecystokinin-like peptides in hexamethonium resistant intestinal peristalsis. Neuroscience 28: 211-217. Bayliss WM & Starling EH (1902) The mechanisms of pancreatic secretion. Journal of Physiology 28: 325-353. Binder H J, Lemp GF & Gardner JD (1980) Receptors for vasoactive intestinal polypeptide and secretin on small intestinal epithelial cells. American Journal of Physiology 238: G190G196. Brazer SR, Borislow DS & Liddle RA (1990) Cholecystokinin is not a major hormonal regulator of lower esophageal sphincter pressure. Gastroenterology 99: 641-645. Brown DR & Gillespie MA (1988) Actions of centrally administered neuropeptides on rat intestinal transport: enhancement of ileal absorption by angiotensin II. European Journal of Pharmacology 148: 411-418. Brown JC, Cook MA & Dryburgh JR (1972) Motilin, a gastric motor activity stimulating polypeptide: final purification, amino acid composition and C-terminal residues. Gastroenterology 62: 401-404. Brown JC, Mclntosh CHS & Pederson RA (1988) Gastric inhibitory polypeptide (GIP). Advances in Metabolic Disorders 11: 321-333. Cantor P (1989) Cholecystokinin in plasma. Digestion 42: 181-201. Cantor P, Mortensen PE, Myhre J et al (1992) The effect of the cholecystokinin receptor antagonist MK-329 on meal-stimulated pancreaticobiliary output in humans. Gastroenterology 102: 1742-1751. Caren JF, Eyer JH & Grossman MI (1974) Canine intestinal secretion during and after rapid distension of the small bowel. American Journal of Physiology 227: 183-188. Cassuto J, Jodal M, Tuttle R & Lundggren O (1981) On the role of intramural nerves in the pathogenesis of cholera toxin-induced intestinal secretion. Scandinavian Journal of Gastroenterology 16: 377-384.

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Chey WY, Kim MS, Lee KY & Chang T-M (1979) Effect of rabbit antiserum on postprandial pancreatic secretion in dogs. Gastroenterology 77: 1266-1275. Cooke HJ (1987) Neural and humoral regulation of small intestinal electrolyte transport. In Johnson LR (ed.) Physiology of the Gastrointestinal Tract 2nd edn, pp 1307-1350. New York: Raven Press. Cooke HJ (1989) Role of the 'little brain' in the gut in water and electrolyte homeostasis. FASEB Journal 3: 127-138. Creutzfeldt W & Ebert R (1993) The enteroinsular axis. In Go VLW, Dimagno E, Gardner JD et al (eds) The Pancreas: Biology, Pathobiology, and Disease 2nd edn, pp 769-788. New York: Raven Press. Cuber JC, Corring T, Levenez F, Bernard C & Chayvialle JA (1989) Effects of cholecystokinin octapeptide on the pancreatic exocrine secretion in the pig. Canadian Journal of Physiology and Pharmacology 67: 1391-1397. Cuber JC, Philippe C, Abello J e t al (1990) Plasma neurotensin in the conscious pig: release by individual food components and effects on exocrine pancreas secretion. Pancreas 5: 306-313. Cucchiaro G, Branum GD, Farouk M e t al (1992) The effects of liver denervation on the regulation of hepatic biliary secretion. Transplantation 54: 129-136. Daniel EE (ed.) (1991) Neuropeptide Function in the Gastrointestinal Tract, pp 1-510. Boca Raton: CRC Press. Defize J, Wider MD, Walz D & Hunt R (1988) Isolation and partial characterization of gastrotropin from canine ileum: further studies of the parietal and chief cell response. Endocrinology 123: 2578-2584. Dockray GJ (1987) Physiology of enteric neuropeptides. In Johnson LR (ed.) Physiology of the Gastrointestinal Tract 2nd edn, pp 41-66. New York: Raven Press. Drewe J, Gadient A, Rovati LC & Beglinger C (1992) Role of circulating cholecystokinin in control of fat-induced inhibition of food intake in humans. Gastroenterology 102: 16541659. Ebert R, Unger H & Creutzfeldt W (1983) Preservation of incretin activity after removal of gastric inhibitory polypeptide (GIP) from rat gut extracts by immunoadsorption. Diabetologia 24: 449-454. Eklund S, Jodal M & Lundgren O (1985) The enteric nervous system participates in the secretory response to heat-stable enterotoxins of Escherichia coli in rats and cats. Neuroscience 14: 673-681. Erlinger S (1987) Physiology of bile secretion and enterohepatic circulation. In Johnson LR (ed.) Physiology of the Gastrointestinal Tract 2nd edn, pp 1557-1580. New York: Raven Press. Fahrenkrug J, Schaffalitzky de Muckadell OB & Rune SJ (1978) pH threshold for release of secretin in normal subjects and in patients with duodenal ulcer and in patients with chronic pancreatitis. Scandinavian Journal of Gastroenterology 13: 177-186. Ferris CF, George JK, Eastwood G, Potegal M & Carraway RE (1991) Plasma levels of human neurotensin: methodological and physiological considerations. Peptides 12" 215-220. Feurle GE & Niestroj S (1991) The site of action of neurotensin in the rat pancreas. Pancreas 6: 202-207. Fisher RS, Rock E, Levin G & Malmud L (1987) Effects of somatostatin on gallbladder emptying. Gastroenterology 92: 885-890. Flemstr6m G (1987) Gastric and duodenal mucosal bicarbonate secretion. In Johnson LR (ed.) Physiology of the Gastrointestinal Tract 2nd edn, pp 1011-1030. New York: Raven Press. Florey HW & Harding HE (1935) A humoral control of the secretion of Brunner's glands. Proceedings of the Royal Society of London B 117: 68--77. Fried M, Erlacher U, Schwizer W e t al (1991a) Role of cholecystokinin in the regulation of gastric emptying and pancreatic enzyme secretion in humans. Gastroenterology 101: 503-511. Fried M, Schwizer W, Beglinger C et al (1991b) Physiological role of cholecystokinin on postprandial insulin secretion and gastric meal emptying in man. Studies with the cholecystokinin receptor antagonist, loxiglumide. Diabetologia 34: 721-726. Fukuoka S & Scheele GA (1990) Rapid and selective cloning of monitor peptide, a novel cholecystokinin releasing peptide, using minimal amino acid sequence and the polymerase chain reaction. Pancreas 5: 1-7.

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