Ileal release of glucagon-like peptide-1 (GLP-1)

There is evidence that the distal intestine participates in the regulation of gastric motor and secretory function. It was the aim of this study to examine in greater detail the effects of ileal nutrient exposure on human gastric acid secretion and to investigate potential intermediary mechanisms. Twelve normal subjects were intubated with an oroileal multilumen tube assembly for gastric, duodenal, and ileal perfusion of marker and test solutions, aspiration, and intestinal manometry. We studied ileal effects on gastric acid output in the unstimulated, interdigestive state (during early phase II,N=6), and during endogenous stimulation by intraduodenal essential amino acid perfusion,N=6) and on release of candidate humoral mediators, peptide YY (PYY) and glucagonlike peptide-1 (GLP-1), both known inhibitors of human gastric acid secretion. Compared with ileal saline perfusion, ileal carbohydrate (total caloric load: 60 kcal) decreased interdigestive gastric acid output by 64% (P<0.01), and endogenously stimulated output by 68%, respectively (P<0.005). Under all experimental conditions, ileal carbohydrate increased plasma GLP-1 by 80–100% (allP<0.005). Ileal lipid perfusion had similar inhibitory effects on gastric acid output and stimulatory effects on GLP-1 release as had ileal carbohydrate. By contrast, ileal perfusion with peptone had no or only weak effects on either acid output or plasma GLP-1. Plasma PYY concentrations and suppression of gastric secretion in response to ileal perfusions were not correlated. In humans, both interdigestive and endogenously stimulated gastric acid output are inhibited in response to intraileal carbohydrate or lipids, but not protein, Decreased acid output is associated with release of GLP-1, but not PYY. These findings support the hypothesis that the distal small intestine may participate in the late postprandial inhibitory regulation of gastric secretory function in humans and that GLP-1 may be an intermediary factor.     

Adrenergic pathway in the inhibition of pancreatic secretion by peptide YY in dogs

Peptide YY (PYY) is released by perfusion of an ileocolonic segment with oleate and inhibits exocrine pancreatic secretion. This study was designed to determine the role of the adrenergic pathway in the PYY-induced inhibition of pancreatic secretion. After intravenous administration of PYY, there was a dose-dependent inhibition of pancreatic HCO3 and protein responses to secretin, cholecystokinin, and feeding in conscious dogs and a reduction in pancreatic blood flow in anesthetized animals. These inhibitory effects of PYY on pancreatic secretion and blood flow were abolished in the presence of combined phentolamine and propranolol. Ileal perfusion with oleate caused a rise in plasma PYY levels similar to that observed after intravenous infusion of exogenous PYY. Combined alpha- and beta-adrenergic blockade also antagonized the effects of ileal perfusion with oleate on hormonal and postprandial pancreatic secretion. We conclude that exogenous PYY or endogenous PYY released by ileal oleate inhibits pancreatic secretory responses to exogenous secretin, cholecystokinin, or a meal and causes pancreatic vasoconstriction. Both these effects are mediated, at least in part, by the adrenergic pathway.     

Effects of intraluminal peptide YY on pancreatic function.

Peptide YY (PYY) is released postprandially into both the circulation and the distal intestinal lumen. While circulating PYY inhibits pancreatic secretion and insulin release, the effects of intraluminal PYY on pancreatic function are unknown. The aim of the present study was to evaluate the effect of exogenous, intraileal luminal PYY on pancreatic exocrine function and fasting glucose levels. Chronic pancreatic and ileal fistulae (50 cm from the ileocecal valve) were created in nine mongrel dogs. The animals were given intravenous infusions of secretin (125 ng/kg/h) and cholecystokinin octapeptide (CCK-8, 50 ng/kg/h) for four hours. At the beginning of the second hour, either normal saline or PYY, at low [physiologic (2 ng/min)] or high [supraphysiologic (50 ng/min)] levels, was infused antegrade into the ileal fistula for two hours. Pancreatic juice was collected for PYY and glucose levels. Ileal luminal PYY infusions had no effect on pancreatic bicarbonate or protein output. Fasting serum PYY and glucose concentrations were unaffected by either dose of intraluminal PYY. We conclude that ileal luminal PYY does not influence pancreatic exocrine function or fasting glucose levels.     

Area Postrema Lesion Alters the Effects of Peptide YY on 2-DG-Stimulated Pancreatic Exocrine Secretion

Previously we demonstrated that circulating peptide YY (PYY), which inhibits pancreatic exocrine secretion, binds to specific receptors in the area postrema (AP); therefore we have tested the hypothesis that the removal of the AP (APX) will alter the effects of PYY on pancreatic secretion in awake rats. One-month after AP lesion or sham lesion, rats were implanted with pancreatic, biliary, duodenal, and intravenous catheters. After recovery from the surgery, unanesthetized rats were infused with vehicle or PYY (30 pmol/kg/hr or 100 pmol/kg/hr) under basal or 2-deoxy-d-glucose (2-DG) stimulated (75 mg/kg, intravenous bolus) conditions. PYY at 30 pmol/kg/hr inhibited basal pancreatic fluid secretion in sham-operated rats, but not APX rats. PYY at 100 pmol/kg/hr stimulated basal pancreatic protein secretion in sham-operated rats, and this effect was also lost in APX rats. PYY at 30 and 100pmol/kg/hr inhibited peak 2-DG stimulated protein secretion to a greater extent in APX rats as compared to sham-operated rats (P < 0.05). Since PYY inhibition of basal pancreatic secretion is AP dependent and inhibition of 2-DG stimulated pancreatic secretion is AP independent, we conclude that the 2-DG pathway of pancreatic secretion differs from the pathway responsible for basal secretion, and that APX potentiates the inhibitory effect of PYY on the 2-DG pathway.     

Intestinal regulation of pancreatic enzyme secretion: stimulatory and inhibitory mechanisms]

How exocrine pancreatic secretion is regulated is only partly known. It is assumed that interaction of several neural and hormonal mechanisms is involved. In man, the intestinal component of these control mechanisms is very important while extra-intestinal mechanisms (such as the cephalic and the gastric phase) play lesser roles. Regulation of pancreatic secretion by the intestine is composed of three main mechanisms. 1. The proximal intestinal (duodenal) phase of the secretory response to a meal is elicited by nutrients within the proximal intestinal lumen. It is mediated mainly by interactions between cholinergic reflexes and release of the peptide hormone cholecystokinin (CCK). Recent data suggest that part of the action of CCK is not exerted directly on the acinar cellular level, but rather by modulation of cholinergic inputs. 2. The distal intestinal (ileal) phase is elicited by contact of the distal intestinal mucosa with nutrients that pass through the ileal lumen due to physiological malabsorption. The ileum (in contrast to the duodenum) induces net-inhibition of pancreatic secretion. The mediation is unknown, candidate mediators are PYY and GLP-1. 3. Intestinal feedback-regulation of pancreatic secretion in humans is controlled by intraluminal protease activity; this mechanism is not covered in the present paper.     

The effect of pancreatic polypeptide and peptide YY on pancreatic blood flow and pancreatic exocrine secretion in the anesthetized dog

Pancreatic polypeptide (PP) and peptide YY (PYY) are inhibitors of pancreatic exocrine secretion in vivo but not in vitro, which suggests intermediate mechanisms of action. To examine the role of pancreatic blood flow in these inhibitory effects, xenon-133 gas clearance was used to measure pancreatic blood flow while simultaneously measuring pancreatic exocrine secretion. PP or PYY (400 pmol/kg/h) was administered during the intermediate hour of a 3-h secretin (125 ng/kg/h)/cholecystokinin octapeptide (CCK-8) (50 ng/kg/h) infusion. Exocrine secretion and pancreatic blood flow during the PP or PYY hours were compared with that observed in the first and third hours of the secretin/CCK-8 infusion. PP and PYY significantly inhibited secretin/CCK-8-induced pancreatic exocrine secretion. In addition, PYY (but not PP) significantly reduced pancreatic blood flow during secretin/CCK-8 stimulation. Nevertheless, there was no correlation between pancreatic blood flow and bicarbonate or protein outputs. It is concluded that changes in pancreatic blood flow do not mediate the inhibitory effects of PP or PYY on the exocrine pancreas.     

PYY Potently Inhibits Pancreatic Exocrine Secretion Mediated Through CCK-Secretin-Stimulated Pathways but Not 2-DG-Stimulated Pathways in Awake Rats

Peptide YY (PYY) is an important modulator of stimulated pancreatic exocrine secretion. PYY acts proximal to the acinar cell but the exact site and mechanism of action are unknown. The aim of the present study is to determine the pathway through which PYY exerts its effect on the exocrine pancreas in awake rats under physiological condition. When pancreatic secretion was stimulated by graded doses of cholecystokinin (CCK) (14, 28, 58 pmol/kg/hr) with secretin (1.25, 2.5, 5.0 pmol/kg/hr) or CCK alone at 28 pmol/kg/hr, PYY _1-36 dose-dependently inhibited pancreatic secretory responses. Moreover, PYY_1-36 at 50 pmol/kg/hr almost completely blocked the stimulation by CCK (P < 0.01). Although background infusion of PYY_1-36 or PYY_3-36 at 12.5 pmol/kg/hr inhibited basal pancreatic fluid and protein secretion, but both of them only partly inhibited the subsequent 2-DG stimulated pancreatic fluid and protein secretion. Furthermore, PYY_1-36 at 50 pmol/kg/hr failed to inhibit 2-DG-stimulated pancreatic secretion. These results confirm that PY_1-36 inhibits CCK-stimulated pancreatic secretion under all experimental conditions. However, in the awake, surgically recovered rat, PYY_1-36 at both low and high doses failed to fully inhibit 2-DG-stimulated pancreatic secretion. Therefore, the site of PYY's inhibitory action on pancreatic secretion appears to be primarily on the CCK-stimulated pathway at a site proximal to the convergence of the CCK and 2-DG pathways.     

Trypsin suppression of pancreatic enzyme secretion. Differential effect on cholecystokinin release and the enteropancreatic reflex

We have recently demonstrated that intraduodenal perfusion of trypsin inhibits phenylalanine-stimulated pancreatic enzyme secretion by suppression of release of cholecystokinin (CCK). It is not known whether trypsin in the duodenum inhibits pancreatic secretion stimulated by a cholinergic mechanism. To investigate this question gastrointestinal intubation and perfusion were performed in 12 healthy subjects. Volume and osmoreceptors in the duodenum, which are known to elicit pancreatic secretion through cholinergic pathways, were stimulated by infusing increasing volumes (1.0, 2.5, and 5.0 ml/min) of normal saline or increasing osmolality (300, 400, 500 mosmol) of NaCl solution. Increasing the rates of intraduodenal perfusion of normal saline or increasing the osmolality of the duodenal perfusates caused a dose-related increase in pancreatic trypsin and chymotrypsin outputs without affecting basal plasma CCK levels (0.9 +/- 0.1 pM). The volume- or osmolality-stimulated pancreatic secretions were abolished by atropine, but not by intraduodenal perfusion of trypsin. In contrast, intraduodenal perfusion of phenylalanine (10 mM) produced a significant increase in plasma CCK levels (6.7 +/- 0.8 pM) and a three- to fourfold increase in pancreatic enzyme outputs. Perfusion of the duodenum with bovine trypsin (1 g/L) reduced the plasma CCK levels to basal values and significantly attenuated the phenylalanine-stimulated enzyme secretion to 63% +/- 4% of control. Simultaneous administration of atropine and intraduodenal perfusion of trypsin completely abolished the pancreatic enzyme response to phenylalanine stimulation. These studies indicate that the intestinal phase of human pancreatic enzyme secretion is under both hormonal and neural control. Intraduodenal trypsin inhibits only pancreatic secretion mediated by CCK release, and not that mediated by cholinergic mechanisms. These observations suggest that feedback regulation of pancreatic enzyme secretion is stimulus specific.     

Intracolonic infusion of bile salt stimulates release of peptide YY and inhibits cholecystokinin-stimulated pancreatic exocrine secretion in conscious dogs

The purpose of this study was to examine the effect of transanal (intracolonic) infusion of bile acid on release of peptide YY (PYY) and cholecystokinin (CCK)-stimulated pancreatic exocrine secretion in seven conscious dogs. CCK-8 (50 ng/kg/h) was given intravenously for 120 min and either taurocholic acid (TA, 1 or 2 mmol/h) or saline was infused transanally (150 ml/h) during the 0-60-min period of CCK infusion. Transanal infusion of TA (1 or 2 mmol/h) significantly inhibited output of CCK-8-stimulated pancreatic protein, compared to transanal infusion of saline during the first 60 min. On the average, the magnitude of inhibition was approximately 45%. Plasma concentrations of PYY increased significantly in response to intracolonic infusion of TA or saline. Transanal infusion of TA (1 or 2 mmol/h) significantly increased plasma levels of PYY when compared with transanal infusion of saline during the first 60 min. The magnitude of the increase of plasma PYY levels was approximately 50 pg/ml (p less than 0.05). Plasma levels of pancreatic polypeptide were not altered significantly by transanal infusion of TA. Our results suggest that release of endogenous PYY by TA in the colon plays a role in the inhibition of CCK-stimulated pancreatic exocrine secretion. Bile salts in the hindgut may participate in the physiologic regulation of pancreatic exocrine secretion by stimulation of release of ilealcolonic PYY.     

Cholinergic and adrenergic control of enzyme secretion in isolated rat pancreas

While cholinergic nervous control of pancreatic enzyme secretion is well documented, data concerning adrenergic regulation of the exocrine pancreas are contradictory. In the present study we attempted to elucidate the direct action of adrenergic stimulation on pancreatic enzyme secretion. Rat pancreatic segments were set up in an organ bath and superfused with modified Krebs-Henseleit solution. Electrical field stimulation (EFS) stimulated amylase release from the segments. This stimulation was subject to inhibition with atropine up to 80%. Atropine-resistant enzyme discharge in response to EFS could be blocked by propranolol. Cholinergic agonist urecholine-induced amylase release was completely blocked by atropine. Noradrenaline (NA) exhibited a biphasic effect on amylase release. It inhibited the urecholine-induced amylase release in lower concentrations (10(-8)-10(-7) M), while it stimulated basal enzyme secretion in higher concentrations (10(-5)-10(-4) M). The inhibitory effect was mimicked by phenylephrine and completely prevented by prazosin. Isoprenaline concentration dependently enhanced, while clonidine and guanfacine did not affect amylase discharge. In conclusion, in rat pancreatic acinar tissue it seems likely that acetylcholine is the main neurotransmitter. Adrenergic action can be dual, inhibitory via alpha 1-adrenoceptors or stimulatory via beta-adrenoceptors on amylase secretion.     

Role of gastrin-releasing peptide in neural control of pancreatic exocrine secretion

We studied the effect of electrical stimulation of the vagus nerves on the exocrine secretion of isolated perfused porcine pancreas before and after procedures that almost completely blocked the effects elicited by infusions of gastrin-releasing peptide (GRP): desensitization of the pancreas for GRP (by perfusion with high concentrations of GRP); administration of an antagonist of GRP action [D-Arg1, D-Pro2, D-Trp7,9, Leu11)-substance P]; and perfusion with Fab fragments of antibodies against GRP. Both desensitization and antagonist administration significantly (p less than 0.01) inhibited the effect of vagus stimulation on pancreatic protein secretion (by 42.1 and 33%). The inhibitory effect of anti-GRP perfusion was less pronounced (22% inhibition, 0.05 greater than p less than 0.1). The results support the notion that pancreatic, GRP-producing nerve fibers are involved in the neural control of pancreatic enzyme secretion.     

Oxyntomodulin inhibits pancreatic secretion through the nervous system in rats

Glicentin (GLIC), oxyntomodulin (OXM), and peptide YY (PYY) released in blood by ileocolonic L-cells after meals may inhibit pancreatic secretion. Whereas OXM interacts with glucagon and tGLP-1 receptors, OXM 19-37, a biologically active fragment, does not. The purpose of this study was to measure the effect of OXM, OXM 19-37, GLIC, tGLP-1, and PYY on pancreatic secretion stimulated by 2 deoxyglucose (2DG), electrical stimulation of the vagus nerves (VES), acetylcholine and cholecystokinin octapeptide (CCK8) in anesthetized rats. The effect of OXM was also studied in dispersed pancreatic acini. Plasma oxyntomodulin-like immunoreactivity (OLI) was measured by radioimmunoassay after the exogenous infusion of OXM and after an intraduodenal meal. OXM 19-37, infused at doses mimicking postprandial plasma levels of OLI, decreased pancreatic secretion stimulated by 2DG, VES, or CCK8. Similar effects were found with OXM and GLIC. OXM 19-37 did not change the pancreatic stimulation induced by acetylcholine in vivo, or CCK-induced amylase release in isolated acini. Vagotomy completely suppressed the inhibitory effect of OXM 19-37 on CCK8-stimulated pancreatic secretion. PYY inhibited the effect of 2DG, but not that of CCK8, whereas tGLP-1, even in pharmacologic doses, had no effect on stimulated pancreatic secretion. OXM, OXM 19-37, but not tGLP-1, inhibit pancreatic secretion at physiologic doses, through a vagal neural indirect mechanism, different from that used by PYY, and probably through a GLIC-related peptide-specific receptor.     

Regulation of gastrointestinal functions by the ileocecal area]

The importance of the distal small intestine and the ileocecal region for the regulation of gastrointestinal functions in humans has not been investigated in depth until recently. A regulatory role is postulated because even in healthy subjects, undigested nutrients pass across the ileocecal junction after most meals (physiologic malabsorption). Nutrient exposure of the ileocecal region causes slowing of gastric emptying and small intestinal transit, and decrease in small intestinal motor activity; under certain experimental conditions, ileal nutrients induce conversion of intestinal motility from digestive to interdigestive patterns. In addition, the secretory activity of the proximal gastrointestinal tract is inhibited by the ileocecal region. Inhibition of gastric secretion and exocrine pancreatic secretion are well established responses to ileal nutrient exposure; inhibition of bile secretion likely occurs, but is not proven. The intermediary mechanisms of these effects have not been clarified; the most likely candidates include endorphins, peptide YY (PYY), and glucagon-like-peptide-1 (GLP-1). Overall, the available data support the concept that the ileocecal region participates in the physiologic control of gastrointestinal motor and secretory functions. Whether disturbances of these regulatory mechanisms participate in the pathophysiology of gastrointestinal disease has not been investigated.     

A Review: Acute and Chronic Effects of Ethanol and Alcoholic Beverages on the Pancreatic Exocrine Secretion In Vivo and In Vitro

Whereas oral or intraduodenal ethanol causes a moderate stimulation of pancreatic bicahonate and enzyme output, intravenous ethanol inhibits basal and hormonally stimulated pancreatic exocrine secretion in humans, dogs, cats, pigs, rabbits, and rats. This inhibition could be mediated by inhibitory cholinergic mechanisms or be the result of a direct cellular effect of ethanol. In vitro investigations have specified several signaling molecules that may be involved in the action of ethanol on stimulus-secretion coupling in the exocrine pancreas, including cyclic adenosine monophosphate, intracellular calcium, and cholecystokinin and somatostatin receptors. In difference to pure ethanol solutions and distilled spirits, beer strongly stimulates pancreatic enzyme output, probably by nonalcoholic fermentation products. During chronic alcoholism, the ethanol-induced inhibition is replaced by an enhanced enzyme output that causes intraductal protein precipitation. In vitro investigations suggest that this increase is reversible after alcohol withdrawal. The occurrence of protein precipitates is considered to be a crucial step in the development of chronic alcoholic pancreatitis in humans. Other ethanol-induced secretory alterations that may contribute to the development of alcoholic pancreatitis are a decreased secretion of trypsin inhibitor, an increased cholinergic tone, and changes in the concentration of lithostathine.     

Regulation of pancreatic enzyme secretion in conscious rats by intraluminal somatostatin: mechanism of action

These studies were undertaken to characterize 1) the immunoreactive somatostatin (SS) forms found in the gastrointestinal lumen and 2) to assess the possible role of luminal SS on pancreatic exocrine function. Results indicate that different forms of SS are secreted into the rat gastric and duodenal lumen in proportions corresponding to their gastric and duodenal contents. Inhibition of diversion-stimulated pancreatic exocrine secretion by intraduodenal infusion of SS (SS-ID) is dose dependent with a maximal effective dose of 24 micrograms/kg-1h-1 for volume and 48 micrograms/kg-1h-1 for protein output. Infusion of supramaximal doses result in a loss of the inhibitory effect of SS-ID on both volume and protein outputs. Comparison between inhibition of pancreatic secretion by iv SS (SS-IV) and SS-ID indicates that SS-ID is about 20 times less potent than SS-IV in its inhibition of stimulated pancreatic exocrine secretion. Intraileal (SS-IL) infusion of SS at 48 micrograms/kg-1h-1 did not inhibit stimulated pancreatic secretion but was rather stimulatory possibly through the inhibition of putative ileal inhibitors. Likewise, passive immunization against circulating SS did not affect the inhibitory effects of SS-ID on pancreatic secretion. These data indicate that SS is secreted into the rat gastrointestinal lumen and that its infusion into the duodenal lumen inhibits stimulated pancreatic secretion in a dose-dependent fashion. The observation that SS-IL did not inhibit pancreatic secretion and that passive immunization against circulating SS did not affect the inhibitory effect of SS-ID suggest that the action of SS-ID on stimulated exocrine pancreatic secretion is probably indirect and may involve a duodenal signal, possibly an inhibition of endogenous release of cholecystokinin and/or secretin.     

Mechanism of galanin's inhibitory action on pancreatic enzyme secretion: modulation of cholinergic transmission--studies in vivo and in vitro.

This study examined the inhibitory mechanism of galanin, a 29 amino acid polypeptide on pancreatic enzyme secretion in anaesthetised rats, isolated pancreatic acini, and lobules. Urethane anaesthetised rats with pancreatic fistulas pretreated with 3-0-methyl-glucopyranose (500 mg/kg/h) were stimulated with an intravenous bolus of 2-deoxyglucose (2-DG) (75 mg/kg). Maximal amylase secretion was mean (SEM) 274 (19)% of basal secretion. Atropine (150 micrograms/kg/h) and galanin (10 nmol/kg/h) almost completely inhibited 2-DG stimulated amylase secretion suggesting an inhibition of cholinergic transmission. To further test this possibility this study investigated the effect of galanin on carbachol and cholecystokinin stimulated amylase release from isolated pancreatic acini. Galanin did not suppress carbachol or cholecystokinin stimulated amylase release, indicating that galanin inhibits exocrine secretion by indirect mechanisms. The cholinergic pathway was assessed by using pancreatic lobules containing intrapancreatic neurons. Veratridine, a sodium channel activator, dose dependently stimulated amylase release. Veratridine (100 microM) stimulated amylase release by 411 (10)% of basal secretion. Atropine (1 microM) or tetrodotoxin (1 microM) almost completely blocked veratridine stimulated amylase release. Galanin (1 microM) significantly inhibited veratridine stimulated amylase release with a maximal inhibition of 50% (p < 0.05). In addition, when lobules were incubated with [3H]-choline, galanin significantly (p < 0.05) inhibited veratridine stimulated release of newly synthesised [3H]-acetylcholine. Thus galanin inhibits pancreatic secretion by inhibiting cholinergic transmission. These studies show that galanin inhibits rat pancreatic enzyme secretion by an indirect mechanism by reducing cholinergic transmission.     

Peptide YY inhibits nutrient-, hormonal-, and vagally-stimulated pancreatic exocrine secretion

Peptide YY (PYY) is a recently isolated gut peptide that is found primarily in the mucosal endocrine cells of the terminal ileum, colon, and rectum of several mammalian species, including humans. The purpose of this study was to characterize the effect of PYY on pancreatic exocrine secretion in six conscious dogs prepared with pancreatic and gastric fistulas. In control experiments, pancreatic exocrine secretion was stimulated by either intravenous (i.v.) administration of secretin (100 ng/kg/h), cholecystokinin-8 (50 ng/kg/h), neurotensin (5 micrograms/kg/h), or 2-deoxy-D-glucose (75 mg/kg); or by the intraduodenal infusion of hydrochloric acid (4 mEq/h), a mixture of amino acids (phenylalanine + tryptophan at 5 mmol/h), sodium oleate (9 mmol/h), or a liquid meal. On separate days, PYY (12.5, 25, 50, 100, 200, or 400 pmol/kg/h) was given intravenously in combination with one of the above pancreatic secretagogues. Intravenous PYY at 200 and 400 pmol/kg/h inhibited secretin-stimulated pancreatic bicarbonate output significantly (p less than 0.05). Pancreatic bicarbonate and protein responses to all pancreatic secretagogues were reduced significantly (p less than 0.05) by PYY at 400 pmol/kg/h. Intravenous administration of atropine (0.6 mg bolus, followed by 0.02 mg/kg/h) did not abolish the ability of PYY to inhibit secretin-stimulated pancreatic bicarbonate secretion. This study demonstrates that PYY can inhibit nutrient-, hormonal-, and vagally-stimulated pancreatic exocrine secretion in the dog; its mechanism of action appears to be independent of cholinergic innervation.     

Glucagon-Like Peptide-1 7-36 Amide and Peptide YY Have Additive Inhibitory Effect on Gastric Acid Secretion in Man

Background: Glucagon-like peptide-1 7-36 amide (GLP-1) and peptide YY (PYY) are colocalized in the L-cell of the ileal mucosa, and both peptides may function as enterogastrone hormones. However, it is not known whether they interact with regard to the effect on acid secretion. Methods: The effect of intravenous infusion of GLP-1 and PYY, either alone or in combination, on pentagastrin-induced acid secretion in eight healthy volunteers was examined. The peptides were infused at two different rates: 0.25 pmol/kg/min (low rate) and 0.5 pmol/kg/min (high rate). Results: Given alone, GLP-1 and PYY inhibited acid secretion by 26 ± 5% and 18 ± 5% (low rate) and 45 ± 8% and 38 ± 7% (high rate), respectively. Combined infusion resulted in an inhibition of 32 ± 5% (low rate) and 62 ± 7% (high rate). Both infusion rates resulted in GLP-1 and PYY plasma concentrations below or similar to postprandial levels. Conclusion: The present study suggests that the interaction between GLP-1 and PYY in man is of the additive type. The results indicate that GLP-1 and PYY have an important role in the physiologic control of gastric acid secretion.     

Stimulatory effect of beta-adrenergic agonists on ileal L cell secretion and modulation by alpha-adrenergic activation.

Postprandial release of peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) from L cells results from both nutrient transit in the ileal lumen and neural drive of endocrine cells. The adrenosympathetic system and its effectors have been shown to induce secretion of L cells in vivo or in vitro. Because these transmitters act through three receptors, beta, alpha1, alpha2, coupled to different intracellular pathways, we evaluated the responses of L cells to specific agonists, using the model of isolated vascularly perfused rat ileum. General stimulation of adrenergic receptors with epinephrine (10(-7) M) induced significant GLP-1 and PYY secretions (94+/-38 and 257+/-59 fmol/8 min respectively) which were abolished upon propranolol (10(-7) M) pretreatment and strongly decreased upon infusion with 10(-8) M prazosin. Blockade of alpha2-receptors with idazoxan (10(-8) M) did not alter epinephrine-induced peptide secretion. The beta-adrenergic agonist isoproterenol (10(-6) M) infused for 30 min induced a transient release of GLP-1 and PYY (integrated release over the 8 min of the peak secretion: 38+/-16 and 214+/-69 fmol for GLP-1 and PYY respectively, P<0.05). Because terbutaline but not dobutamine or BRL 37,344 (10(-5) M) induced significant GLP-1 and PYY secretions (135+/-30 and 305+/-39 fmol/8 min respectively), isoproterenol-induced secretions are suggested to result mainly from stimulation of the beta2-isoreceptor type. In contrast, the alpha1-agonist phenylephrine (10(-7) M) did not stimulate peptide release. When co-infused with 10(-6) M or 10(-7) M isoproterenol, 10(-7) M phenylephrine raised GLP-1 release to 174+/-53 and 108+/-28 fmol/8 min respectively (vs 38+/-16 and 35+/-10 fmol/8 min for isoproterenol alone, P<0.05) whereas PYY secretion was not significantly increased. Clonidine (10(-7) M), an alpha2-agonist, induced a moderate and delayed increase of GLP-1 and PYY but abolished the isoproterenol-induced peptide secretion. Our results showed that general stimulation of adrenergic receptors stimulates the secretory activity of ileal endocrine L cells. The net peptide secretion results from the activation of the beta2-isoreceptor type. Additionally, GLP-1 and PYY secretions are positively modulated by alpha1-receptor stimulation and inhibited by alpha2-receptor activation upon beta-receptor occupation.     

Pancreatic exocrine function in severe human chronic renal failure.

Patients with chronic renal failure have an abnormal immunoreactive gastrointestinal hormone profile, which is characterised by raised fasting serum concentrations of hormones that have antagonistic effects on exocrine pancreatic function. In addition, in this present study we have found that in renal insufficiency cholecystokinin disappears slowly from the plasma after a constant intravenous infusion of the hormone (p = 0.05 compared with healthy subjects). To evaluate whether the stimulatory or inhibitory hormones have a predominant effect, pancreatic exocrine function under conditions of mannitol perfusion of the duodenum and continuous intravenous cholecystokinin stimulation was studied in eight patients who had severe chronic renal failure and eight age-matched and sex-matched control subjects. Compared with healthy subjects, patients with renal insufficiency had hypersecretion of trypsin in response both to mannitol perfusion of the duodenum and to cholecystokinin stimulation (p less than 0.05). No significant differences in lipase secretion were noted between the patients with renal insufficiency and control subjects. These findings are consistent with the hypothesis that, of the abnormally raised fasting serum concentrations of gastrointestinal hormones found in renal insufficiency, hormones that stimulate rather than inhibit pancreatic exocrine function predominate. Secondly, the dissociation between trypsin and lipase outputs in chronic renal failure may suggest a differential trophic influence of stimulatory hormones -- that is, hypercholecystokininaemia -- on pancreatic exocrine enzyme secretion.