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Inhibition of Sham Feeding-Stimulated Human Gastric Acid Secretion by Glucagon-Like Peptide-2

Departments of Surgery (M.W., A.W.) and Clinical Biochemistry (L.H.), Rigshospitalet, DK-2100; Medical Physiology (B.H., J.J.H.), The Panum Institute DK-2200, University of Copenhagen, Copenhagen, Denmark

Address all correspondence and requests for reprints to: Jens J. Holst, Department of Medical Physiology, The Panum Institute, Blegdamsvej 3C, DK-2200 Copenhagen, Denmark. E-mail: holst{at}mfi.ku.dk

	Abstract

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Glucagon-like peptide (GLP)-2 is formed from proglucagon in the intestinal L cells and is secreted postprandially in parallel with the insulinotropic hormone GLP-1, the latter of which, in addition, acts to inhibit gastric secretion and motility by inhibiting central parasympathetic outflow. We now studied the effect of GLP-2 on gastric secretion stimulated by sham feeding to test the hypothesis that also GLP-2 acts as an enterogastrone. Eight healthy volunteers were studied twice on separate days. They were sham fed with and without GLP-2 infused iv at a rate of 0.8 pmol/kg·min. Gastric contents were aspirated continuously by a nasogastric tube for determination of acid secretion, volume, and osmolarity. Sham feeding increased gastric acid secretion nearly 5-fold. Infusion of GLP-2 reduced incremental acid secretion by 65 ± 6%, compared with saline infusion (8.75 ± 0.37 vs. 3.04 ± 0.47 mmol x 60 min; P < 0.01). Plasma concentrations of GLP-2 rose from a basal mean of 3.3 ± 0.9 to a mean of 115 ± 8 pmol/L (range, 57–149 pmol/L) during infusion of GLP-2 and remained at basal level during saline infusion. Plasma concentrations of GLP-1, gastrin, cholecystokinin, and secretin remained low and unchanged on both study days. We conclude that GLP-2 is a powerful inhibitor of gastric acid secretion in man. Further investigations will show to what extent GLP-2 contributes to the inhibitory effects on gastric secretion exerted by hormones from the distal small intestine, under physiological circumstances.

	Introduction

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GLUCAGON-LIKE peptide (GLP)-2 is one of the proglucagon-derived peptides produced in the L cells of the small intestine (1). The GLP-2 sequence was discovered in 1983, when Bell et al. (1, 2) deduced the amino acid sequences of hamster and human proglucagon, in which a second glucagon-like sequence occupies positions 126–159 of its 160 amino acids. The structure of naturally occurring porcine GLP-2 was determined in 1988 (3) and (based on chromatography and immunochemistry and sequencing human GLP-2) was subsequently found to correspond to residues 126–158 of human proglucagon (3, 4). A similar peptide is found in the human circulation (4). It was soon apparent that synthetic replicas of human proglucagon 126–159 had no measurable effect on pancreatic islet and liver function (5, 6); and, until recently, the possible biological functions of GLP-2 remained enigmatic. In a preliminary study, GLP-2 was reported to inhibit proliferation of a culture of intestinal mucosal cells (7). It was, therefore, a surprise, when Drucker and co-workers, in a series of studies (8, 9, 10), showed that GLP-2 is capable of stimulating cell proliferation in the intestinal mucosa of rodents. Thus, GLP-2 may be the elusive growth factor secreted during intestinal adaption in the many studies (11) showing correlation between intestinal growth and secretion of the N-terminal fragment of intestinal proglucagon [glicentin (proglucagon 1–69)], the biological activity of which is controversial (12). On the other hand, GLP-2 was recently demonstrated to have powerful, dose-related inhibitory effects on vagally induced antral motility in pigs (13). This led us to further examine the effect of GLP-2 on vagally induced gastric secretion (sham feeding) in humans, employing iv infusion of GLP-2 in a dose intended to mimic postprandial concentrations.

	Subjects and Methods

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Subjects

Eight healthy subjects (five men and three women; age, 20–29 yr) volunteered for the study. The study was approved by the regional ethical committee of Copenhagen (reference no. KF 01–162/95), and written informed consent was obtained from all subjects. They all had negative Helicobacter Pylori serology, as shown by an enzyme-linked immunosorbent assay technique measuring IgG, IgA, and IgM (14).

Experimental design

In random order, volunteers were subjected to sham feeding, with or without GLP-2 infusion, on two separate occasions within 3 weeks. In all, a double-lumen nasogastric tube (AN 10, Anderson Samplers Inc., New York, NY) was passed into the stomach, in the morning, after an overnight fast. The position was controlled by fluoroscopy. A radioactive marker, ⁵⁷Co-cobalamin (Amersham, Rainham, UK), dissolved in 1000 mL 0.9% saline containing 1.25 mg cobolamin and 1% human serum albumin, was infused at a rate of 60 mL/h (approximately 22 kBq/h) to allow determination of recovery and correction of secretory rates. The volume of gastric aspirates was noted, and the concentration of H⁺ was determined by titration, to pH 7.0, with an autotitrator (Radiometer, Copenhagen, Denmark). After 75 min, GLP-2 (or saline) was administered as a continuous iv infusion of 0.8 pmol/kg·min for 150 min, preceded by a basal period of 30 min. For these studies, we employed synthetic human GLP-2, corresponding to human proglucagon 126–158 (WHERL GmbH, Wolfenbüttel, Germany). The purity of the peptide was more than 98%, and only a single peak was noted on analytical high-performance liquid chromatography analysis. The correctness of structure was ascertained by mass and sequence analysis. The peptide was dissolved in 0.9% saline containing 1% human serum albumin (albumin, Novo Nordisk, Bagsvaerd, Denmark), subjected to sterile filtration, checked for sterility and pyrogens, and kept at -20 C until use. All experiments were performed using the same peptide batch. After 120 min, subjects were sham fed for 15 min. Sham feeding was performed as so-called chew and spit, allowing the subjects to see, smell, chew, and taste the food before spitting it out, as described by Stenquist and Olbe (15). The test meal consisted of 200 g sirloin steak, 20 g green beans, a slice of bread, and 200 mL water. All meals were cooked in a separate area so that the subjects could neither see nor smell the food until the time of sham feeding. Gastric aspirates were collected on ice, for each 15-min period, by intermittent mechanical suction, producing a subatmospheric pressure of 150 mm Hg.

Venous blood was sampled from the opposite cubital vein every 15 min. The samples were immediately placed in crushed ice and centrifuged at 4 C at the end of each 45-min period. The tubes contained either 450 kallikrein inhibiting units (KIU) aprotinin and 12.5 KIU heparin per milliliter of blood or, for GLP-2 assay, aprotinin (500 KIU/mL), EDTA (3.9 mmol/L), and the DPP-IV inhibitor diprotin A (0.1 mmol/L) (Bachem Feinchemikalen, Bubendorf, Switzerland). Plasma was stored at -20 C until measurements of GLP-2, GLP-1, gastrin, cholecystokinin (CCK), and secretin concentrations could be carried out.

Hormone analyses

Plasma GLP-1 concentrations were measured as previously described, using GLP-1 7–36 amide for standards (Peninsula Laboratories, Merseyside, St. Helens, UK), ¹²⁵I-labeled GLP-1 7–36 amide, and antiserum 89390. The antibody has an absolute requirement for the amidated C-terminus of the molecule for binding and therefore measures the sum of GLP-1 7–36 amide and its first metabolite, GLP-1 9–36 amide (16). GLP-2 immunoreactivity was measured using antibody 92160. The antibody has an absolute requirement for the free N-terminus of the molecule for binding and therefore measures only fully processed, intact intestinal GLP-2 (4, 13). The experimental detection limit was 5 pmol/L, and the intraassay coefficient of variation was 2.3% at a concentration of 40 pmol/L.

Gastrin concentrations in plasma were measured as previously described, using antiserum 2604 (17, 18), which binds gastrin-34 and gastrin-17 (sulfated or nonsulfated) with equimolar potency without binding of CCK peptides. The detection limit of the assay is 0.5 pmol/L.

Plasma secretin concentrations were measured after extraction of plasma with ethanol, as described previously (19, 20), using the secretin specific antiserum 5595–3. The detection limit of the assay was 0.8 pmol/L.

Plasma CCK concentrations were measured using a new antiserum, 92128, which specifically binds the bioactive form of CCK (i.e. tyrosyl-sulfated and carboxyamidated CCK) in plasma without significant binding of gastrin peptides. The detection limit of the assay was 0.1 pmol/L. (21).

Volume secretion, pH, recovery, and osmolarity

The volume of gastric secretion was noted, and the concentration of H⁺ was determined by titration to pH 7.0 using an autotitrator (Radiometer). The radioactivity of ⁵⁷Cobalt in each of the gastric samples was measured in a spectrometer and used for calculation of the recovery of the gastric juice volume. Subsequently, secretory rates were corrected for this recovery. Osmolarity was determined by freezing-point reduction (22) and used as an index of duodenogastric reflux. Validation studies have shown that the reduction in gastric juice osmolarity correlates well with the degree of reflux, calculated in accordance with Faber et al. (23).

Calculations and statistical analysis

Data from the basal period (-15 to +15 min), the two last 15-min periods before sham feeding (30–60 min), during sham feeding (60–75 min), and after sham feeding (135–150 min) were pooled. These data were analyzed by Friedman’s nonparametric repeated-measures test, followed by Dunn’s multiple-comparison test at specific time-intervals, and differences between periods were evaluated by the Wilcoxon signed-rank test (i.e. the GLP-2- or saline-infusion) using Graph Pad Software (PRISM, San Diego, CA). Results are given as the mean ± SEM. P-values less than 0.05 were considered significant.

	Results

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Sham feeding and gastric acid secretion

Gastric acid secretion increased immediately from 0.9 ± 0.1 to 4.3 ± 0.4 mmol H⁺/15 min, in response to sham feeding during saline infusion (Fig. 1, upper panel; P < 0.01), but the response was suppressed during GLP-2 infusion (from 1.4 ± 0.3 to 2.5 ± 0.4 mmol H⁺/15 min; Fig. 1, upper panel). Overall, the incremental secretion of gastric acid, in response to stimulation by sham feeding during saline infusion (basal 6.69 ± 0.32 mmol H⁺ x 60 min_{0–60 min} and 13.6 ± 2.46 mmol H⁺ x 60 min_{75–135 min}), was reduced by 65 ± 6% during sham feeding and GLP-2 infusion (basal 7.35 ± 0.47 mmol H⁺ x 60 min_{0–60 min} and 10.39 ± 1.05 mmol H⁺ x 60 min_{75–135 min}) (8.75 ± 0.37 vs. 3.04 ± 0.47 mmol H⁺ x 60 min; P < 0.02; Fig. 1, upper panel). GLP-2 infusion had no impact on gastric acid secretion at basal level (0–60 min), compared with infusion of saline (P = 0.22; Fig. 1, upper panel). The infusion of synthetic human GLP-2, 126–158, was well tolerated and without any side effects in all subjects. Blood pressure and heart rate were measured before, during, and after the experiment and showed no variations (data not shown).

View larger version (16K): [in this window] [in a new window]   Figure 1. Gastric acid (upper panel) and volume (lower panel) secretion, in response to sham feeding in healthy volunteers, during concomitant iv infusion of either saline (open squares) or glp-2 (closed triangles). Asterisk, Significant increase above basal level; cross, significant difference between study days (n = 8, mean ± SEM, P < 0.01).

Sham feeding increased gastric vol output significantly, from 38 ± 4 to 80 ± 13 mL/15 min (Fig. 1, lower panel; P < 0.01); and the output decreased to prestimulatory values, at the end of the study, during saline infusion. Sham feeding during concomitant infusion of GLP-2 increased gastric vol output significantly, from 34 ± 3 to 68 ± 10 mL/15 min (Fig. 1, lower panel; P < 0.01); and the output decreased to prestimulatory amounts, at the end of the experiment, with no statistically significant differences between study days (Fig. 1; lower panel).

The recovery of the gastric marker showed no differences between study days (94 ± 5% vs. 91 ± 7% during saline and GLP-2, respectively). Osmolarity increased slightly in all subjects, in response to sham feeding, but there were no differences between the study days or after the GLP-2 infusion (data not shown). Glucose concentrations were stable throughout the study with no effect of either sham feeding or GLP-2 (data not shown).

Hormones

iv infusion of 0.8 pmol/kg·min GLP-2 resulted in a mean plasma concentration from basal level of 3.3 ± 0.9 to a mean of 115 ± 8 pmol/L (range, 57–149 pmol/L), whereas infusion of saline per se or sham feeding had no effect on GLP-2 plasma concentrations (Table 1.) Plasma concentrations of GLP-1 remained low and unchanged by sham feeding and infusion of GLP-2 (Table 1.). Likewise, plasma concentrations of gastrin, CCK, and secretin remained low and unchanged by sham feeding and infusion of GLP-2 (Table 1.).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

Plasma concentrations of GLP-2 are not well examined; but in humans, ingestion of mixed meals increases the plasma concentration of GLP-2 from 15 ± 2 to a peak value of 61 ± 9 pmol/L (range, 30–82.5 pmol/L) (14), elevations somewhat lower than those obtained by infusion in the present study, where plateau values ranged from 57–149 pmol/L. Thus, the values overlap; but in some subjects, the selected dose of 0.8 pmol/kg·min of GLP-2 in this study must be considered as slightly supraphysiological. Therefore, it will be important to investigate lower doses of GLP-2 in future studies. It should be noted, however, that the chosen infusion rate corresponds to infusion rates of GLP-1 that elicit plasma concentrations in the high physiological range and that are equally inhibitory, with respect to gastric acid secretion. The higher plasma levels obtained with an identical rate of infusion of GLP-2 indicate that GLP-2 is metabolized at a slower rate than GLP-1, an issue that also warrants further investigation.

Our observations indicate that GLP-1 and GLP-2 share the inhibitory effects on upper gastrointestinal function. As noted above, all of the inhibitory effects of GLP-1 involve the vagal innervation of the stomach; and because sham feeding represents a purely vagally mediated stimulation of acid secretion, GLP-2 seems to share its mechanism of action. Further studies, however, should be directed at elucidating the effects of GLP-2 on hormonally or histamine-stimulated acid secretion.

In the present study, we measured the plasma concentrations of the hormones gastrin, CCK, secretin, and GLP-1, because all of these hormones powerfully influence gastric acid secretion (33). If GLP-2 affected the secretion of these hormones, this might explain its actions on acid secretion. Sham feeding had no effect on their plasma concentrations, in agreement with earlier observations (15). The plasma concentrations of GLP-2 also remained unchanged during sham feeding in the saline infusion experiment, suggesting that vagal efferent activity has little effect on GLP-2 secretion. The latter is in agreement with previous observations regarding GLP-1 secretion (28).

In conclusion, we propose that GLP-2 may have two major effects: acute effects as an enterogastrone hormone, augmenting the effects of the two other ileal-brake hormones, GLP-1 and PYY (34); and perhaps more chronic effects as a growth factor for the intestinal epithelium (because these effects require weeks of continuous GLP-2 administration) (35). The mechanism of action of GLP-2, with respect to its trophic and gastrointestinal actions, is unknown. However, a GLP-2 receptor has recently been cloned (36), which will undoubtedly facilitate further investigations. Interestingly, this receptor is expressed in a number of hypothalamic nuclei in analogy with the expression of the GLP-1 receptor, a localization which seems compatible with the effects of GLP-2 on cephalically stimulated acid secretion.

	Acknowledgments

 
We thank A. H. Johnsen (Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Denmark) for high-performance liquid chromatography, mass, and sequence analysis of GLP-2.

Received January 8, 1999.

Revised March 24, 1999.

Accepted March 30, 1999.

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