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Endocrinology Vol. 139, No. 1 189-194
Copyright © 1998 by The Endocrine Society

ARTICLES

Glucagon-Like Peptide-1-(7–36) Amide and Peptide YY Mediate Intraduodenal Fat-Induced Inhibition of Acid Secretion in Dogs1

Leslie C. Fung, Connie Chisholm and Gordon R. Greenberg

Departments of Medicine and Physiology, University of Toronto, Toronto, Ontario, Canada

Address all correspondence and requests for reprints to: Dr. G. R. Greenberg, Room 6356, Medical Sciences Building, University of Toronto, Toronto, Ontario, Canada M5S 1A8.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Intraduodenal fat inhibits gastric acid secretion via the release of one or more hormonal enterogastrones thought to arise from ileo-colonic mucosa. This study determined whether glucagon-like peptide-1 (GLP-1)-(7–36) amide and peptide YY (PYY), colocalized in L cells found in the ileum, mediate intraduodenal fat-induced inhibition of stimulated gastric acid, and evaluated the influence of cholecystokinin-A (CCK-A) receptor activation. Gastric acid secretion in response to duodenal perfusions of 8% peptone was measured in conscious dogs with gastric and duodenal cannulas. Intraduodenal administration of a 10% fat emulsion suppressed gastric acid secretion by 72 ± 4% (P < 0.001) and increased plasma levels of GLP-1 and PYY by 44 ± 5 and 46 ± 4 fmol/ml, respectively (both P < 0.01). Pretreatment with the CCK-A receptor antagonist MK-329 completely reversed the inhibition of gastric acid by fat, suppressed rises of plasma GLP-1 (maximum change, 23 ± 4 fmol/ml), and reduced plasma PYY responses to baseline. Intravenous infusions of 50 pmol/kg·h GLP-1 or PYY, which reproduced plasma elevations after intraduodenal fat, inhibited gastric acid secretion by 66 ± 5% and 51 ± 6%, respectively (both P < 0.01); coinfusions of GLP-1 and PYY abolished gastric acid secretion (P < 0.001) without influencing plasma gastrin or somatostatin. Pretreatment with 1500 pmol/kg·h of the GLP-1 antagonist exendin-(9–39) amide did not alter the magnitude of inhibition of gastric acid caused by exogenous GLP-1. These results indicate that GLP-1 and PYY released by intraduodenal fat, in part through CCK-dependent pathways, are major enterogastrones in dogs. This inhibitory action occurs independent of circulating concentrations of somatostatin and gastrin and appears to involve a GLP-1 receptor distinct from that mediating incretin effects.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
PERFUSION of the duodenum with fat causes potent inhibition of gastric acid secretion (1, 2). Although hormonal factors or enterogastrones released from the ileum are proposed to mediate this response to fat, the mechanisms have not been fully established. Infusions of the cholecystokinin-A (CCK-A) receptor antagonist, MK-329, reverse intestinal fat-induced inhibition of gastric acid secretion, implicating a role for CCK as an enterogastrone (3, 4). However, studies in vitro have shown that CCK is equipotent to gastrin in the stimulation of acid secretion (5), suggesting that the enterogastrone action by CCK is indirect and mediated through the release of other peptides that inhibit acid secretion. One candidate hormone, peptide YY (PYY), is released into the circulation after duodenal fat via CCK-A receptor activation (6), but the magnitude of the response accounts for only about half of the inhibitory effect by duodenal fat on stimulated acid secretion (4, 7). Glucagon-like peptide-1 (GLP-1)-(7–36) amide is colocalized with PYY in L cells found in the ileum (8) and has been shown to inhibit vagal and pentagastrin- and nutrient-stimulated acid secretion (9, 10, 11). However, it has not been established whether circulating levels of GLP-1 and PYY observed after intraduodenal fat act in concert to mediate inhibition of gastric acid secretion or whether GLP-1 secretion is regulated via activation of CCK receptors.

The aim of the present study was to examine the enterogastrone roles of PYY and GLP-1 as the principal mediators of intestinal fat-induced inhibition of stimulated gastric acid and to determine whether the mechanism of action is through activation of CCK-A receptors in conscious dogs. The influence of endogenous CCK release in duodenal fat-induced inhibition of gastric acid secretion and PYY and GLP-1 secretion was studied by iv administration of the CCK-A receptor antagonist, MK-329. The circulating GLP-1 and PYY responses to intraduodenal fat were compared with responses to exogenous infusions of CCK octapeptide (CCK-OP), as the actions of CCK-A receptors could be direct on L cells or indirect via activation of CCK receptors located within vagus nerves (12, 13). The effects on stimulated acid secretion of iv infusions of exogenous PYY and GLP-1-(7–36) amide to achieve plasma increments comparable to those observed after intestinal fat were studied singularly and in combination to ascertain the magnitude of acid inhibition. The results were compared with administration of the putative GLP-1 antagonist, exendin-(9–39) amide (14), to examine the individual role of GLP-1 in the mediation of fat-induced suppression of acid secretion. Plasma somatostatin responses to GLP-1 infusions were also undertaken, as GLP-1 is reported to stimulate this counterregulatory peptide in rats (15, 16) and somatostatin is known to inhibit acid secretion (17, 18).


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animal preparation
The studies were performed on four conscious mongrel dogs, weighing 25–32 kg, with surgically placed chronic gastric and duodenal cannulas. Food, but not water, was withheld for 24 h before each study. The dogs were placed in a Pavlov harness, and two indwelling catheters were introduced into leg veins. One catheter was used for blood sampling, and the second catheter was used for the infusion of test agents. The care and use of these animals were approved by the University of Toronto animal care committee.

Experimental protocols
In the first series of experiments, after a 20-min basal period nutrient-stimulated gastric acid secretion was investigated by perfusing the duodenum with 8% protein (Bacto Peptone, Difco Laboratories, Detroit, MI) at a rate of 2.4 ml/min for 180 min through an indwelling catheter placed 10 cm distally into the duodenal cannula that had been located opposite the entrance of the main pancreatic duct. In the second series of experiments, intraduodenal protein perfusions (as in experimental series 1) were studied with 10% Intralipid (Kabi Vitrium, Baxter Pharmaceutical, Newmarket, Canada) perfused from 90–150 min at a rate of 1.7 ml/min via a second indwelling catheter placed through the duodenal cannula. In the third series of experiments, the CCK receptor antagonist MK-329 (a gift from Dr. D. Veber, Merck, Sharpe, and Dohme, West Point, PA) at a dose of 75 µg/kg or its vehicle (2.0 ml 100% dimethylsulfoxide in 20 ml 0.9% saline containing 0.1% BSA) was administered by bolus iv injection 10 min before the start of the fat perfusion (as in experimental series 2). In the fourth series of experiments, intraduodenal protein-stimulated acid secretion was studied on separate occasions with iv infusions from 90–150 min of synthetic GLP-1-(7–36) amide (Bachem, Torrance, CA) at doses of 50 and 150 pmol/kg·h alone, synthetic PYY (Bachem) at a dose of 50 pmol/kg·h alone, GLP-1-(7–36) amide in combination with PYY at 50 pmol/kg·h, and GLP-1-(7–36) amide at doses of 50 and 150 pmol/kg·h with synthetic exendin-(9–39) amide (Bachem) at a dose of 1500 pmol/kg·h beginning 10 min before the start of the GLP-1-(7–36) infusions. In the fifth series of experiments, CCK-stimulated release of GLP-1 and PYY was studied in the basal state by examining iv infusions of sulfated CCK-OP (Peninsula Laboratories, Belmont, CA) at a dose of 250 pmol/kg·h for 90 min. Gastric acid secretion was collected continuously for 180 min and divided into 15-min aliquots, and the volume and hydrogen ion concentration of each aliquot were measured. Blood samples were obtained at 20 and 10 min before, at 0 min (immediately before the start of the infusions), and at 10-min intervals thereafter.

Laboratory methods
RIAs. Blood for GLP-1 determinations was collected in tubes containing 1000 kallikrein inhibitor units (KIU) aprotinin (Trasylol, Bayer, Germany) and 1.2 mg EDTA Na/ml blood. Samples were rapidly centrifuged, and the plasma was stored at -20 C until assayed. Plasma GLP-1 concentrations were measured by RIA using antiserum RA7168 (Peninsula). The reactivity of the antiserum was 100% for GLP-1-(7–36) amide, 42% for GLP-1-(1–36) amide, 0.4% for GLP-1-(7–37), and less than 0.2% for GLP-1-(1–37), GLP-2, and other members of the glucagon-secretin group of peptides. Synthetic GLP-1-(7–36) amide (Peninsula) was used for standards and for preparation of [125I]GLP-1 labeled by the chloramine-T method and purified as previously described (19). Before RIA, GLP-1 was extracted from plasma with ethanol (2.5 ml 95% ethanol and 1 ml plasma). Extracted samples of 200 µl were assayed at 4 C in duplicate by adding 700 µl 0.05 M barbitone Na (pH 8.0) containing 0.25% (wt/vol) BSA, and 1000 KIU aprotinin and antiserum at a final dilution of 1:24,000. The addition of 100 µl radioactive label was delayed 24 h, and the mixture was incubated for an additional 96 h. Bound from free GLP-1 was separated by dextran-coated charcoal. The limit of detection of the assay was 0.4 fmol/tube or 2 fmol/ml plasma, and the sensitivity of the assay (IC50) was 10.0 fmol/tube or 50.0 fmol/ml plasma. The mean intraassay variation was 4.6%, and the mean interassay variation was 7.8%. Plasma concentrations of gastrin (20), PYY (21), and somatostatin (22) were determined by RIA techniques using methods described in detail previously.

Chromatography. Gel chromatography studies for GLP-1 were undertaken on plasma samples of 2 ml each obtained 30 min after initiating the lipid perfusion. Plasma samples were collected and extracted as described above, air-dried, and reconstituted in 2.0 ml of a column buffer consisting of 0.05 M barbitone Na (pH 8.0) containing 0.25% (wt/vol) BSA and 1000 KIU aprotinin and applied to a 9 x 1000-mm Sephadex G-50 (superfine) column calibrated with synthetic GLP-1-(7–36) amide, GLP-1-(1–36) amide (both from Peninsula), dextran blue (void volume), cytochrome-c (mol wt, 12,384), and Na125I (total volume) at 4 C. Fractions were collected at a flow rate of 6 ml/h and then assayed for GLP-1 directly in the elution buffer. Elution positions are expressed as the coefficient of distribution (Kav), where Kav = (Ve - Vo)/(Vt - Vo), with Ve corresponding to the elution volume, Vo to the void volume, and Vt to the total column volume. Under these experimental conditions, the Kav for synthetic GLP-1-(1–36) amide was 0.56, and that for synthetic GLP-1-(7–36) amide was 0.63.

Hydrogen ion concentrations. The hydrogen ion concentration was determined by titration (autoburette titrator and pH meter; Radiometer, Copenhagen, Denmark) of 2-ml samples from each 15-min aliquot to pH 7.0 using 0.025 N NaOH. Gastric acid output was calculated by multiplying the hydrogen ion concentration by the volume of each 15-min aliquot.

Statistical analysis
Results are expressed as the mean ± SEM or the mean incremental hormone response in plasma as calculated by subtracting the mean basal concentration for each dog from the concentration during each time period. Individual differences in concentrations of hormones and gastric acid secretion at specific time points within a group were detected by one-way ANOVA, and when a significant interaction was indicated, comparisons for all given time points were made using Student’s paired t test. Repeated measures ANOVA was used to detect differences between groups, followed by a multiple comparisons test. Data analysis was carried out using Sigma-Stat (Jandel Scientific, San Rafael, CA). P < 0.05 or less was considered significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Effect of MK-329 on gastric acid secretion and plasma GLP-1 and PYY
Acid secretion. Intraduodenal perfusions of 8% peptone increased gastric acid output to a mean plateau of 4.7 ± 0.7 mmol/15 min from 90–180 min over the basal acid output of 0.1 ± 0.1 mmol/15 min (P < 0.001; Fig. 1Go). After intraduodenal administration of the 10% fat emulsion, acid output rapidly declined to a sustained nadir of 1.3 ± 0.2 mmol/15 min (P < 0.001 compared with controls) or by 72 ± 4% and then progressively returned to control values. Pretreatment with MK-329 (75 µg/kg) completely reversed this inhibition of acid output induced by intraduodenal fat to 5.0 ± 0.6 mmol/15 min (P < 0.01), which was not different from the control value.



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  		Figure 1. Gastric acid secretion in the basal state and during stimulation by intraduodenal perfusions of 8% peptone to intraduodenal (ID) saline (•), intraduodenal fat emulsion with MK-329 ({circ}), or its vehicle ({blacksquare}). Values are the mean ± SE.

 
Plasma GLP-1 and PYY responses. Basal plasma concentrations of GLP-1 (6 ± 2 fmol/ml) were not influenced by intraduodenal perfusions of peptone (7 ± 2 fmol/ml), but in response to intraduodenal fat, plasma GLP-1 increased to 51 ± 8 fmol/ml (P < 0.01; Fig. 2AGo). Gel permeation chromatography of plasma samples obtained after the administration of intraduodenal lipid showed the presence of a single peak (Kav = 0.63) corresponding to the position of synthetic GLP-1-(7–36) amide (Fig. 3Go). Pretreatment with MK-329 decreased the mean plasma GLP-1 response after fat to 29 ± 4 fmol/ml (P < 0.05), a value that remained (P < 0.05) above baseline (Fig. 2AGo). Basal plasma concentrations of PYY (24 ± 3 fmol/ml) were not altered by intraduodenal protein (25 ± 4 fmol/ml), but after coadministration of intraduodenal fat, plasma PYY increased to 71 ± 9 fmol/ml (P < 0.01; Fig. 2BGo). MK-329 abolished increases in plasma PYY after fat administration (P < 0.01) to values that were not different from baseline (Fig. 2BGo).



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  		Figure 2. Plasma GLP-1 (upper) and plasma PYY (lower) in the basal state and during stimulation by intraduodenal perfusions of 8% peptone to intraduodenal (ID) fat emulsion with MK-329 ({circ}) or its vehicle ({blacksquare}). Values are the mean ± SE.

 


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  		Figure 3. Characterization by gel chromatography of 2-ml plasma samples obtained 30 min after intraduodenal lipid for GLP-1 undertaken on a 9 x 1000-mm Sephadex G-50 (superfine) column eluted with 0.05 M barbitone sodium buffer, pH 8.0, and calibrated with dextran blue (Vo), cytochrome-c (CC), GLP-1-(1–36) amide (I), GLP-1-(7–36) amide (II), and Na125I as a total volume marker. Entire fractions (0.6 ml each) were assayed for GLP-1 content. Points represent the mean ± SE from two experiments.

 
Effect of exogenous CCK-OP on plasma GLP-1 and PYY
Intravenous infusions of CCK-8 (250 pmol/kg·h) increased plasma PYY by 39 ± 4 fmol/ml (P < 0.01) at 50 min, and similar levels were thereafter sustained (Fig. 4Go). CCK-8 infusions also caused a modest plasma GLP-1 elevation of 9 ± 2 fmol/ml (P < 0.05 compared with baseline; Fig. 4Go).



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  		Figure 4. Plasma GLP-1 ({circ}) and PYY (•) responses to iv infusions of 250 pmol/kg·h CCK-OP. Values are the mean ± SE.

 
Effect of exogenous GLP-1-(7–36) amide and PYY on gastric acid secretion
Intravenous infusions of GLP-1-(7–36) amide at 50 and 150 pmol/kg·h decreased gastric acid output by 66 ± 5% (P < 0.01) and 96 ± 3% (P < 0.001), respectively, compared with control values (Fig. 5Go). Pretreatment with iv infusions of exendin-(9–39) amide at 1500 pmol/kg·h did not alter the magnitude of the gastric acid inhibitory response to GLP-1 (Fig. 5Go). Intravenous infusions of PYY at 50 pmol/kg·h alone also decreased gastric acid output by 51 ± 6% (P < 0.01 compared with controls; Fig. 6Go). However, coinfusions at 50 pmol/kg·h PYY and GLP-1-(7–36) amide inhibited gastric acid secretion to baseline values (P < 0.001 compared with controls; Fig. 6Go). The peak incremental plasma PYY and GLP-1 levels at 50 pmol/kg·h were 59 ± 4 and 71 ± 5 fmol/ml, respectively. Compared with the control values, no differences were observed during infusions of PYY and GLP-1 in the peak plasma concentrations of gastrin (15 ± 2 vs. 17 ± 3 fmol/ml) and somatostatin (12 ± 2 vs. 14 ± 3 fmol/ml).



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  		Figure 5. Gastric acid secretion in the basal state and during stimulation by intraduodenal perfusions of 8% peptone to iv infusions of GLP-1-(7–36) amide at 50 pmol/kg·h ({blacksquare}), 150 pmol/kg·h ({square}), and 150 pmol/kg·h with iv infusions of 1500 pmol/kg·h exendin-(9–30) ({circ}) or vehicle (•). Values are the mean ± SE.

 


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  		Figure 6. Gastric acid secretion in the basal state and during stimulation by intraduodenal perfusion of 8% peptone after iv infusions of PYY at 50 pmol/kg·h ({circ}), GLP-1 at 50 pmol/kg·h ({blacksquare}), and coadministration of 50 pmol/kg·h GLP-1 and PYY ({square}) or vehicle (•). Values are the mean ± SE.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The present study shows that intraduodenal fat-induced inhibition of gastric acid is mediated by the composite release of GLP-1-(7–36) amide and PYY into the circulation, and this effect requires, in part, activation of CCK-A-type receptors. Administration of the CCK-A receptor antagonist, MK-329, completely reversed the inhibitory effect of intraduodenal fat on peptone-stimulated acid secretion and suppressed the plasma elevations of GLP-1 and PYY associated with duodenal fat perfusions. Plasma rises in GLP-1 and PYY in response to intraduodenal fat, when reproduced by exogenous coinfusion of the two peptides, reversibly abolished acid secretion.

Although GLP-1 and PYY are colocalized in open-type endocrine L cells found in the ileum (8), circulating levels of both hormones increased rapidly after initiation of intraduodenal fat, and similar results have been reported in rats (23, 24). In accord with previous findings in humans (25), chromatographic studies showed that the predominant molecular form circulating after fat administration corresponded to GLP-1-(7–36) amide, the biologically active peptide. Moreover, previous studies have shown that diversion of nutrients from the ileum does not influence PYY release, whereas ileocolectomy abolishes PYY responses to intraduodenal fat (25). Together, these findings suggest that mechanisms regulating L cell secretion include either neural or hormonal pathways arising from the duodenum. Our results confirm observations that PYY responses to intraduodenal fat occur via CCK-A receptor activation (6, 26) and also indicate that the same mechanism mediates, in part, GLP-1 secretion. Further, as shown in humans (27), exogenous CCK-8 caused modest, but significant, elevations in plasma GLP-1 concentrations. However, this CCK-dependent component of L cell regulation probably occurs principally via neural, rather than hormonal, pathways because studies in vitro indicate that CCK does not stimulate either GLP-1 or PYY secretion from the isolated perfused rat ileum (28) or from intestinal cell cultures (21). Moreover, although plasma levels of CCK were not measured in the present study, the exogenous CCK-8 dose (250 pmol/kg·h) employed to maximally inhibit acid secretion (3) probably caused circulating CCK levels above values elicited by the administration of intraduodenal lipid (29). CCK receptor-binding sites have, however, been localized on vagus nerves (12, 13), and CCK stimulates the discharge of vagal afferents in the proximal duodenum (30). It, therefore, seems more likely that L cell regulation via the duodenum occurs through CCK activation of a local vago-vagal reflex, as has been reported for other digestive functions, including lower esophageal sphincter relaxation (31), exocrine pancreatic secretion (32), and gastric emptying (30).

Intravenous infusions of GLP-1 at a dose that reproduced circulating levels of GLP-1 after intraduodenal fat accounted for about 66% of the total inhibition of stimulated acid secretion. This acid inhibitory response to GLP-1 parallels results in humans (9), where infusions of GLP-1 to postprandial elevations caused about 43% inhibition of pentagastrin-stimulated acid secretion. Thus, GLP-1 mediates, in part, enterogastrone activity, but it is not the sole hormone causing the inhibitory effect by fat on acid secretion. PYY is known to suppress cephalic (33) and gastric (7, 34) phases of acid secretion, and in accord with previous studies (4), fat-mediated plasma PYY responses when simulated by exogenous infusions caused a 51% inhibition of acid secretion. Our findings further show that the inhibition achieved after coadministration of PYY and GLP-1 was additive and abolished acid secretion. Similar findings regarding the additive effect of GLP-1 and PYY on the inhibition of acid secretion have also recently been reported in humans (35). Although other hormonal inhibitors, including secretin (36) and somatostatin (4), may participate in the modulation of the acid inhibitory responses to intraduodenal fat, our results are consistent with the idea that GLP-1 and PYY, coreleased from L cells, play major roles as physiological enterogastrones.

The present findings regarding regulation of the secretion and actions of GLP-1 and PYY implicate a modulatory role on gastric acid secretion by the duodenum through a feedforward CCK-dependent neural mechanism and a feedback inhibitory hormonal pathway to parietal cells, analogous to the negative feedback loop previously proposed for the effects of GLP-1 and PYY on intestinal motor activity (37). However, the precise mechanisms by which GLP-1 and PYY inhibit acid secretion are unknown. The inhibitory response to GLP-1 was substantially more rapid, but less sustained, than that to PYY, yet the inhibitory effects of GLP-1 and PYY were additive, perhaps suggesting independent mechanisms of action. When studied in vitro, GLP-1 stimulates acid production from parietal cells (38), whereas PYY is without effect (39), indicating that the inhibitory actions of both peptides are indirect. Although GLP-1 stimulates somatostatin release in rats (15, 16), we found that GLP-1 in dogs did not alter somatostatin secretion, and similar negative responses have been reported in pigs (40) and humans (11). Further, as in previous reports (11), GLP-1 did not alter gastrin release. Putative actions by which PYY influences acid secretion include inhibition of acetylcholine release from vagus nerves innervating the stomach (41) and inhibition of gastrin-induced histamine release from ECL cells (42). Whether GLP-1 acts as a cofactor in the mediation of these effects by PYY requires further study.

Confirmation of the role of GLP-1 as a major hormonal mediator of duodenal fat inhibition of acid secretion would be facilitated by the availability of a selective antagonist. Exendin-(9–39) amide has been shown to interact specifically with the GLP-1 receptor on rat endocrine cells in vitro (43) and causes inhibition of GLP-1-mediated insulin secretion (44). This effect by exendin requires a dose 10-fold in excess of that of GLP-1 (43). Notwithstanding administration of this dose ratio of exendin to GLP-1, we found that exendin-(9–39) amide had no effect on GLP-1 inhibition of acid secretion. This finding may reflect species differences in the response to exendin or, alternatively, the GLP-1 receptor subtype mediating inhibition of acid secretion may differ from that mediating the incretin effect on ß-cells.

In summary, the present study indicates that the composite release of GLP-1 and PYY into the circulation plays a major role in the inhibition of gastric acid caused by intraduodenal fat. GLP-1 and PYY released by intraduodenal fat occurs, in part, through activation of CCK-A receptors, probably via neural rather than hormonal pathways. Mechanisms by which GLP-1 and PYY inhibit acid secretion appear to be different, but are independent of circulating concentrations of somatostatin and gastrin. The inability to show a reversal of the effects of GLP-1 after exendin implicates a distinct GLP-1 receptor subtype mediating the inhibition of acid secretion.


   Footnotes
 
1 This work was supported by a grant from the Medical Research Council of Canada (MA6763). Back

Received July 7, 1997.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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