Effect of GLP-1 on gastric volume, emptying, maximum volume ingested, and postprandial symptoms in humans

Silvia Delgado-Aros1, Doe-Young Kim1, Duane D. Burton1, George M. Thomforde1, Debra Stephens1, Benjamin H. Brinkmann1, Adrian Vella2, and Michael Camilleri1

1 Enteric Neuroscience Program, Gastroenterology Research Unit, and 2 Endocrine Research Unit, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Glucagon-like peptide-1 (GLP-1) relaxes the stomach during fasting but decreases hunger and food consumption and retards gastric emptying. The interrelationships between volume, emptying, and postprandial symptoms in response to GLP-1 are unclear. We performed, in healthy human volunteers, a placebo-controlled study of the effects of intravenous GLP-1 on gastric volume using 99mTc-single photon emission computed tomography imaging, gastric emptying of a nutrient liquid meal (Ensure) using scintigraphy, maximum tolerated volume (MTV) of Ensure, and postprandial symptoms 30 min after MTV. The role of vagal cholinergic function in the effects of GLP-1 was assessed by human pancreatic polypeptide (HPP) response to the Ensure meal. GLP-1 increased fasting and postprandial gastric volumes and retarded gastric emptying; MTV and postprandial symptoms were not different compared with controls. Effects on postprandial gastric function were associated with reduced postprandial HPP levels. GLP-1 does not induce postprandial symptoms despite significant inhibition of gastric emptying and vagal function; this may be partly explained by the increase in postprandial gastric volume.

accommodation; single photon emission computed tomography; vagus; satiation; diabetes


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

GLUCAGON-LIKE peptide-1(7-36)amide (GLP-1) is produced by the processing of proglucagon in enteroendocrine L cells of the intestinal mucosa. It is released in response to meal ingestion (6, 27), exerting a glucose-dependent effect on beta  cells of the pancreas and enhancing insulin release. GLP-1 also has an inhibitory effect on the pancreatic alpha  cells, reducing glucagon release (12, 30). These properties provide the rationale for reducing glycemia and for its use in diabetes mellitus (7, 29, 40).

However, GLP-1 also exerts several effects on the upper digestive tract: inhibition of gastric acid and pancreatic exocrine secretions (42-44) and delay in gastric emptying for liquids and solids in health (28) and diabetes (29). The latter may result from enhanced pyloric tone or diminished antroduodenal motility during the interdigestive and fed states in health (26). Preliminary data also indicate relaxation of the proximal stomach in response to intravenous GLP-1 during fasting (41). GLP-1 has also been reported to reduce the amount of food and fluid consumed and to reduce hunger and enhance the feeling of fullness in health (8) and diabetes (35); however, its effects on postprandial symptoms are unclear.

Previous studies showed dose-related, reversible inhibition of human pancreatic polypeptide (HPP) release in response to a meal after subcutaneous or intravenous infusion of GLP-1. GLP-1 also inhibits centrally induced pancreatic and gastric acid secretions (42), and these effects are lost after abdominal vagotomy in humans (45) and pigs (44), suggesting an inhibition of efferent vagal-cholinergic function.

Postprandial gastric accommodation is a vagally mediated reflex (31, 34). Impaired gastric accommodation is an important cause of postprandial symptoms (5, 22-24). We hypothesized that GLP-1 diminishes the postprandial gastric accommodation response by inhibition of vagal function, reducing maximum volume ingested and increasing postprandial symptoms. The aims of this study were to compare the effects of GLP-1 on postprandial gastric volumes, gastric emptying, maximum tolerated volume (MTV) of a nutrient liquid meal, postprandial symptoms, and vagal function in healthy volunteers.


    METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Study Population

Healthy volunteers over 18 yr of age were recruited from the local community by public advertisement. Exclusion criteria included pregnant or breast-feeding women, prior abdominal surgery other than appendectomy or tubal ligation; positive symptoms on an abridged bowel disease questionnaire; present or previous chronic gastrointestinal illness; and systemic disease or use of medications that may alter gastrointestinal motility.

Study Design

This study was approved by the Mayo Institutional Review Board. Eligible volunteers gave their written informed consent and were randomized to receive either GLP-1 (Bachem, San Diego, CA) as an infusion of 1.2 pmol · kg-1 · min-1 over 60 min or saline infusion (placebo) in a double-blind design.

The study was performed on two consecutive days. On the first day (protocol 1), subjects underwent assessment of gastric volumes and measurements of fasting and postprandial glucose and HPP. On the second day (protocol 2), MTV, scintigraphic gastric emptying, and postprandial symptoms were assessed. GLP-1 or saline (placebo) was infused for 60 min on both occasions.

GLP-1. GLP-1 was infused at a rate of 1.2 pmol · kg-1 · min-1. Previous studies have demonstrated that steady-state levels are achieved within ~30 min from the onset of the infusion (40). Therefore, the physiological measurements of gastric accommodation, emptying, and satiety, as well as the plasma levels of glucose and HPP, were taken under steady levels for a total of at least 30 min.

We used an infusion rate of GLP-1 of 1.2 pmol · kg-1 · min-1 since it has been previously shown to affect gastrointestinal function and satiety in humans (26, 40, 41, 43). Higher rates of GLP-1 infusion may cause gastrointestinal distress (36).

99mTc-SPECT method to measure gastric volume. We have used a recently developed method to measure the gastric volume using single photon emission computed tomography (SPECT) (13) (Fig. 1). Intravenous 99mTc-sodium pertechnetate is taken up by the gastric mucosa (16, 20); 10 min after intravenous injection of 99mTc-sodium pertechnetate, dynamic tomographic acquisition of the gastric wall was performed using a dual-head gamma camera (Helix SPECT System, Elscint, Haifa, Israel) in a multiorbit mode system. In this mode, the system performs orbits of 360° at 10 min/orbit. A three-dimensional rendering of the stomach and its volume was obtained using the AVW 3.0 image processing libraries (Biomedical Imaging Resource, Mayo Foundation, Rochester, MN). This was accomplished by identifying the stomach in the transaxial SPECT images and separating it from the background noise using a semiautomated segmentation algorithm.


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Fig. 1.   99mTc-SPECT technique to measure gastric volume. Ten minutes after intravenous injection of 99mTc-sodium pertechnetate to allow gastric mucosal uptake of the isotope, dynamic tomographic acquisition was performed with the single photon emission computed tomography (SPECT) camera. Tomographic images were processed to obtain a 3-dimensional stomach and its volume.

A customized algorithm was developed to estimate the volume of the proximal stomach; this algorithm estimates the longest axis of the reconstructed stomach and divides it into a proximal two-thirds and distal one-third. The volume corresponding to the length of the proximal two-thirds was then also obtained.

The accuracy and reliability of the SPECT method to measure gastric volume change have been demonstrated (1, 3) by simultaneous measurement of postprandial volume change by SPECT and by means of a barostatically controlled balloon. The latter is currently considered the gold standard for the measurement of gastric accommodation.

Protocol 1: measurement of gastric volumes, plasma levels of glucose, and HPP. After an 8-h period of fasting, patients lay down on the SPECT camera and the 10 mCi 99mTc-sodium pertechnetate was injected intravenously. Ten minutes later, a first orbit (360° over 10 min) was performed for baseline (preinfusion) tomographic images (Fig. 2).


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Fig. 2.   Protocol 1. Gastric volumes and plasma levels of glucose and human pancreatic polypeptide (HPP) were obtained at baseline, before glucagon-like peptide-1 (GLP-1) or placebo infusion, and during fasting and the postprandial period, while GLP-1 or placebo infusion was ongoing.

Infusion of 1.2 pmol · kg-1 · min-1 GLP-1 or saline placebo was started. After 30 min of infusion (time to achieve steady levels), a second image was obtained over 10 min to assess effects of the GLP-1 on fasting gastric volumes.

A nutrient liquid meal (Ensure, 237 ml, 250 kcal, 6 g fat, 40 g carbohydrate, and 9 g protein) was ingested over 3 min, and two further 10-min images were obtained to measure postprandial gastric volumes.

Blood samples were taken at baseline (preinfusion), after 30 and 40 min of infusion (fasting period), and at 10 and 20 min postprandially for measurement of glucose and HPP. Plasma glucose concentrations were measured using a glucose oxidase method (using a glucose analyzer). Plasma levels of HPP were analyzed using a radioimmunoassay kit (11, 25).

Protocol 2: measurement of MTV, gastric emptying, and postprandial symptoms. To compare the effects of GLP-1 and placebo on MTV (that is, the volume ingested until maximum satiety is reached), we adapted the method used by Tack et al. (33), appending a scintigraphic evaluation of gastric emptying by radiolabeling Ensure ingested during the test (Fig. 3).


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Fig. 3.   Protocol 2. Measurement of maximum tolerable volume (MTV), gastric emptying, and postprandial symptoms. Participants drank Ensure at a constant rate until maximum satiety was reached (i.e., MTV). The second glass of Ensure ingested was radiolabeled with 111In-diethylenetriaminepentaacetic acid (DTPA) to measure gastric emptying. Thirty minutes after the drink test was finished, postprandial symptoms were assessed using a visual analog scale (VAS).

After 30 min of GLP-1 or saline placebo infusion to achieve steady state, subjects were asked to ingest Ensure at a constant rate (30 ml/min) by refilling a glass with a perfusion pump and drinking at the filling rate. Participants scored their level of satiety during the drink test by using a graphic rating scale graded 0-5 (0 = no symptoms; 5 = maximum or unbearable satiety). Participants were told to stop meal intake when a score of 5 was reached. The total volume ingested was the MTV.

To assess gastric emptying, the second glass of Ensure was radiolabeled with 50 µCi of 111In-diethylenetriaminepentaacetic acid, and 1-min-duration scans of the abdomen were obtained at 10-min intervals for the first 30 min and then at 15-min intervals until at least 50% of the meal was emptied or for a maximum of 3 h after the meal.

Thirty minutes after completing ingestion of the Ensure, participants were requested to score their postprandial symptoms (nausea, bloating, fullness, pain) using a 10-cm visual analog scale anchored with the words "unnoticeable" and "unbearable" at the left and right ends of the lines, respectively. This symptom assessment is consistent with previous studies in the literature (38).

Data and Statistical Analysis

Gastric volumes. Total and proximal gastric volume at baseline (preinfusion), fasting, and during two postprandial periods (0-10 min and 10-20 min) were measured; the postprandial gastric volume was calculated from the average of the two postprandial volumes. Volume change from baseline (preinfusion) to fasting and postprandial periods were assessed as differences and as ratios over baseline volumes (fasting difference = fasting volume - baseline volume; fasting ratio = fasting volume/baseline volume; postprandial difference = postprandial volume - baseline volume; postprandial ratio = postprandial volume/baseline volume).

MTV and postprandial symptoms. The total volume ingested (MTV) was recorded. The aggregate postprandial symptoms score (30 min after ingestion of Ensure was completed) was calculated as the sum of visual analog scale scores for each postprandial symptom (maximum 400).

Gastric emptying. Gastric emptying during the drink test was measured by scintigraphy by radiolabeling the second glass of Ensure for all participants and as described above. The primary end point for assessment of effects on gastric emptying was the proportion emptied at 30 min, which corresponded with the time when the GLP-1 or placebo infusion was completed. This time was selected in view of the very short half-life of infused GLP-1, estimated as ~5 min (17). At this time point, all of the participants had ingested approximately the same volume since the rate of ingestion of the nutrient liquid meal was standardized and all of the participants, except one, were still drinking at 30 min. Four of the participants who reached full satiety at that point did not completely drink the last glass of Ensure (200 ml) and had slightly less volume and caloric intake: three were in the GLP-1 group (875, 822, and 772 ml), and one was in the placebo group (882 ml). Thus the volumes and caloric intakes were identical for 19 of the participants. The secondary end point was the proportion emptied at 90 min (1 h after the infusion ended); this was intended to determine whether there were longer-lasting effects of the infused hormone.

Plasma glucose and HPP. Fasting and postprandial plasma levels of glucose and HPP were calculated from the average of the two fasting measurements and the two postprandial measurements, respectively. Changes in the levels of glucose and HPP from baseline to fasting and to postprandial periods were assessed by subtracting baseline (preinfusion) values from fasting and postprandial levels.

Unpaired t-test was used to compare absolute gastric volumes as well as the volume differences and ratios between GLP-1 and placebo groups. The Wilcoxon rank sum test was used to compare the variables that were not normally distributed: MTV, the aggregate postprandial symptoms score, the gastric emptying at 30 and 90 min, and change in plasma levels of glucose and HPP. Before the study, the estimated sample size for 80% power to detect a 25% difference in the primary end point (postprandial gastric volume) in response to GLP-1 compared with placebo was 12 per group (á = 0.05). All of the tests were two-tailed, and results are presented as medians and interquartile ranges (IQR).


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Study Conduct and Participants

Twenty-four healthy volunteers were studied (13 in the GLP-1 group and 11 in the placebo group). We were not able to obtain peripheral blood samples from two participants; accurate assessment of gastric emptying was not possible for technical reasons in one participant. Missing data excluded these individuals from specific comparisons; however, data for all 24 participants were used when available, that is, in all comparisons except those indicated above. There were no statistically significant differences among demographic and baseline variables between the two study groups (Table 1).

                              
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Table 1.   Demographic and baseline variables

Total Gastric Volumes

Figure 4 shows examples of the stomach reconstructions at baseline (preinfusion), fasting, and postprandially in the GLP-1 and placebo groups. Table 2 shows the data for total gastric volumes, differences in volumes, and ratios. The fasting volume was significantly greater in the group that received GLP-1 (312 ml; IQR 253-365) compared with the placebo group (225 ml; IQR 185-239; P = 0.002).


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Fig. 4.   Examples of gastric volumes obtained at baseline, during fasting, and during postprandial periods from 2 participants in the study, 1 treated with placebo and the other with GLP-1. Note the visibly larger volume of the stomach with GLP-1 infusion.


                              
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Table 2.   Total gastric volumes and ratios

The difference between fasting and baseline volume was 80 ml (IQR 61-128) for the participants who received GLP-1 and 17 ml (IQR -21 to 25) for those who received placebo (P = 0.005). The ratio of fasting over baseline volume was also greater for the GLP-1 group (1.48; IQR 1.26-1.60) than for the placebo group (1.08; IQR 0.90-1.12; P = 0.003).

Postprandial volumes were also greater in the GLP-1 group (848 ml; IQR 789-899) compared with the placebo group (651 ml; IQR 602-801; P = 0.004). The difference between postprandial and baseline volume was 608 ml (IQR 532-671) for the GLP-1 group and 435 ml (IQR 401-549) for the placebo group (P = 0.008). No significant differences were found between groups when comparing total gastric volume ratios postprandially [3.53 (IQR 3.19-4.39) for the GLP-1 group and 3.14 (IQR 2.79-3.61) for the placebo group; P = 0.15].

Proximal Gastric Volumes

Table 3 shows gastric volumes, differences, and ratios for the proximal stomach in the two groups. No significant differences were found when comparing fasting absolute volumes, differences between fasting and baseline volumes, or the fasting/baseline ratios.

                              
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Table 3.   Proximal gastric volumes and ratios

In contrast, the postprandial proximal volumes were significantly greater in the GLP-1 group (629 ml; IQR 581-647) than in the placebo group (455 ml; IQR 338-618; P < 0.0001). The absolute difference between postprandial and baseline volume was also significantly greater in the GLP-1 group (461 ml; IQR 400-553) compared with the placebo group (302 ml; IQR 223-389; P = 0.0003). There was a trend toward a greater postprandial ratio in the GLP-1 group (5.77; IQR 3.41-7.45) compared with the placebo group (3.72; IQR 2.84-4.81; P = 0.08).

MTV and Postprandial Symptoms

As shown in Table 4, the median volume ingested to reach full satiety was 1,119 ml (IQR 874-1,546) for the GLP-1 group and 1,350 ml (IQR 1,082-1,606) for the placebo group (P = 0.16). The individual values are shown in Fig. 5.

                              
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Table 4.   Maximum tolerable volume and postprandial symptoms



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Fig. 5.   Individual values for the MTV ingested in each of the 2 groups.

The aggregate postprandial symptom score was 185 (IQR 121-250) in the GLP-1 group and 169 (IQR 121-199) in the placebo group (P = 0.54). No differences were found when comparing each of the symptoms separately (nausea, bloating, fullness, and abdominal pain; see Table 4).

Gastric Emptying of Nutrient Liquid

One volunteer, subsequently shown to be in the GLP-1 group, vomited after the satiety test was completed. These data were excluded from the analysis of gastric emptying.

Figure 6 shows the gastric emptying of the radiolabeled liquid nutrient meal. The proportion emptied was significantly lower for the GLP-1 group than for the placebo group at the point that the infusion ended at 30 min [7% (IQR 3.5-19) vs. 23% (IQR 14-23), respectively; P = 0.008]. However, this effect was transient; 1 h after the infusion ended, the proportion emptied was not different for the two groups, being 21% (IQR 14.5-38) for the GLP-1 group vs. 35% (IQR 21.75-38.25) for the placebo group (P = 0.28).


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Fig. 6.   Gastric emptying of a nutrient liquid meal. Gastric emptying curves observed following radiolabeled Ensure ingestion are shown. The primary end point for assessing the gastric emptying effects of GLP-1 and placebo was the proportion emptied at the time the infusion ended, at 30 min. Median proportion emptied in the GLP-1 group was 7% and in the placebo group was 23%. Data shown are median and interquartile ranges. *P < 0.05.

Plasma Levels of Glucose and HPP

During fasting, the glucose change relative to baseline (preinfusion) was -12.3 mg/dl (IQR -19.1 to -8) for the GLP-1 group and 0.5 mg/dl (IQR -2.3 to 3.3) for the placebo group (P = 0.0002). The postprandial increase in glucose levels was -9.3 mg/dl (IQR -18.5 to -6.4) for the GLP-1 group and 19.3 mg/dl (IQR 15.9-26.6) for the placebo group (P < 0.0001; Fig. 7).


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Fig. 7.   Plasma levels of glucose (A) and HPP (B). GLP-1 decreased plasma levels of glucose and inhibited the normal postprandial increase in HPP. Bars are medians; error bars show interquartile ranges. *P < 0.05.

The fasting HPP change relative to baseline was similar in the two groups: -12.0 pg/ml (IQR -22.5 to -2.0) for GLP-1 and -0.25 pg/ml (IQR: -14.4 to 31.4) for placebo (P = 0.12). However, GLP-1 significantly reduced the postprandial increase in HPP levels to 6.5 pg/ml (IQR -22.4 to 6.9) for GLP-1 compared with 119.8 pg/ml (IQR 60.1-357.0) for placebo (P = 0.0001).


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

The results of the present study suggest that GLP-1 increases gastric volume during fasting and in the postprandial period and retards gastric emptying. These effects are not associated with changes in maximum volume of Ensure tolerated or in postprandial symptoms.

Wank et al. (41) showed that slightly lower infusion rates of 0.3 and 0.9 pmol · kg-1 · min-1 of GLP-1 diminished fasting gastric tone recorded with an electronic barostat device. We confirmed this finding in our study using SPECT and expanded the knowledge base by showing that the effect is observed in both proximal and whole stomach. Before our study, the effects of GLP-1 on postprandial gastric volumes or accommodation had not been reported. In our study, greater postprandial gastric volumes (proximal and whole stomach) with GLP-1 were demonstrated compared with placebo, using a validated method that images the gastric wall rather than the intragastric content. Hence this method is independent of the volume and the rate of emptying of the meal. Our method does not measure tone and therefore cannot measure relaxation of the stomach. However, since the intragastric pressure is subject to the positive intra-abdominal pressure and to equilibration with atmospheric pressure via the belching reflex, and since these conditions were not altered before and after the meal, the postprandial increase in volume, measured by SPECT, constitutes a measure of the gastric accommodation, which is enhanced by intravenous infusion of GLP-1.

The mechanisms by which GLP-1 increases gastric volume are unclear. It is known that, during fasting, gastric tone is maintained via vagal cholinergic input and that alpha 2-adrenergic and nitrergic pathways induce gastric relaxation (34, 37). During the fed state, gastrointestinal motility is partly controlled by nonadrenergic, noncholinergic vagal pathways (21) and nitric oxide modulates the postprandial accommodation response (31). Our study starts to explore the mechanism for the enhanced postprandial gastric volume in response to GLP-1. Thus we have shown that the effect of GLP-1 on postprandial gastric volume is accompanied by a marked inhibition of the normal postprandial increase of HPP. The latter is a hormone of the endocrine pancreas that is under cholinergic control (32). The effect of GLP-1 on the postprandial HPP response has been previously shown to be independent of gastric emptying (26, 29). This suggests that the delay in gastric emptying by GLP-1 is not the cause of the inhibition of pancreatic polypeptide release. Moreover, we focused on the change in HPP levels in the first 20 min after the meal to appraise the cephalic, rather than the enteral, phases of hormone release. Therefore, our data are consistent with GLP-1 inhibition of efferent vagal-cholinergic function.

The increased gastric volume observed with GLP-1 may result from inhibition of cholinergic innervation during fasting and postprandially. An alternative hypothesis is that GLP-1 enhances gastric volumes by activation of vagal nitrergic pathways, which mediate the normal postprandial accommodation response.

In this study, we confirmed the delay of gastric emptying for liquid meals during intravenous infusion of GLP-1 in healthy subjects. Schirra et al. (28) had previously reported that an isolated subcutaneous injection of either 125 or 250 pmol/kg of GLP-1 delays the emptying of a 300 kcal mixed liquid meal. The retarding effect of GLP-1 on gastric emptying is transient, and the postinfusion emptying of the liquid meal (as assessed by the proportion emptied at 90 min, that is, 1 h after the infusion ended) was not different in the two groups. This observation is consistent with the short biological activity of the hormone (~5 min). The mechanism by which GLP-1 delays gastric emptying of liquids is unclear. The reported inhibition of antroduodenal motility during the postprandial state (26, 28) and the increase in isolated pyloric pressure waves may contribute to delayed emptying of solids. However, gastric emptying of liquids is thought to depend on fundic pressure (46) and to be less influenced by antral motility (10, 18). An alternative mechanism for delayed gastric emptying of liquids is that the GLP-1-induced increase in postprandial gastric volume was associated with a decrease in fundic tone. Previous studies on GLP-1 have shown decreased fasting fundus tone (41).

GLP-1 decreases the feeling of hunger before meals and reduces food and fluid intake in healthy subjects (4, 8) and in diabetic (35) and nondiabetic (14) obese patients. However, no effects of GLP-1 on postprandial symptoms have been reported. In this study, we observed no differences in the MTV and aggregate postprandial symptoms scores or in individual symptoms of nausea, bloating, fullness, or pain. It might be expected that increased gastric volume could allow the ingestion of a larger volume before reaching satiation and possibly reduce the likelihood of developing postprandial symptoms. Failure to observe this could be explained by the marked inhibition of gastric emptying by GLP-1. Another possible explanation is that GLP-1 might regulate food intake independently of its motor effects. Data from animal studies suggest a central site of action of the effect of GLP-1 on reduced food consumption, unrelated to a change in gastric functions (9, 39). Thus we postulate that GLP-1 sensory effects might also be centrally mediated in humans.

In conclusion, we have shown that GLP-1, a novel agent in the treatment of diabetes and obesity, increases the fasting and postprandial volume of the stomach, transiently retarding gastric emptying without increasing postprandial symptoms in healthy subjects. The present study suggests that GLP-1 inhibits vagal cholinergic function; further studies are needed to clarify the mechanism of the increased postprandial volume of the stomach in response to GLP-1.


    ACKNOWLEDGEMENTS

We thank Cindy Stanislav for secretarial support.


    FOOTNOTES

This study was supported in part by General Clinical Research Center Grant RR-00585 (Physiology Core and Immunochemistry Core Laboratories) from the National Institutes of Health. M. Camilleri is supported by Grants R01-DK-54681 and K24-DK-02638 from the National Institute of Diabetes and Digestive and Kidney Diseases.

Address for reprint requests and other correspondence: M. Camilleri, Mayo Clinic, Charlton 7-154, 200 First St. S.W., Rochester, MN 55905.

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 1 June 2001; accepted in final form 25 September 2001.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

1.   Bouras, EP, Camilleri M, Burton DD, Thomforde GM, and Brinkmann B. SPECT test to measure gastric accommodation validated with simultaneous barostat measurement (Abstract). Gastroenterology 120: A97, 2001[ISI].

2.   Coulie, B, Tack J, Sifrim D, Andrioli A, and Janssens J. Role of nitric oxide in fasting gastric fundus tone and in 5-HT1 receptor-mediated relaxation of gastric fundus. Am J Physiol Gastrointest Liver Physiol 276: G373-G377, 1999[Abstract/Free Full Text].

3.   Delgado-Aros, S, Burton DD, Brinkmann BH, and Camilleri M. Reliability of a semi-automated analysis to measure gastric accommodation using SPECT in humans (Abstract). Gastroenterology 120: A287, 2001.

4.   Flint, A, Raben A, Astrup A, and Holst JJ. Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans. J Clin Invest 101: 515-520, 1998[Abstract/Free Full Text].

5.   Gilja, OH, Hausken T, Wilhelmsen I, and Berstad A. Impaired accommodation of proximal stomach to a meal in functional dyspepsia. Dig Dis Sci 41: 689-696, 1996[ISI][Medline].

6.   Goke, R, Fehmann HC, and Goke B. Glucagon-like peptide-1(7-36) amide is a new incretin/enterogastrone candidate. Eur J Clin Invest 21: 135-144, 1991[ISI][Medline].

7.   Gutniak, M, Orskov C, Holst JJ, Ahren B, and Efendic S. Antidiabetogenic effect of glucagon-like peptide-1(7-36) amide in normal subjects and patients with diabetes mellitus. N Engl J Med 326: 1316-1322, 1992[Abstract].

8.   Gutzwiller, JP, Goke B, Drewe J, Hildebrand P, Ketterer S, Handschin D, Winterhalder R, Conen D, and Beglinger C. Glucagon-like peptide-1: a potent regulator of food intake in humans. Gut 44: 81-86, 1999[Abstract/Free Full Text].

9.   Imeryuz, N, Yegen BC, Bozkurt A, Coskun T, Villanueva-Penacarrillo ML, and Ulusoy NB. Glucagon-like peptide-1 inhibits gastric emptying via vagal afferent-mediated central mechanisms. Am J Physiol Gastrointest Liver Physiol 273: G920-G927, 1997[Abstract/Free Full Text].

10.   Kelly, KA. Gastric emptying of liquids and solids: roles of proximal and distal stomach. Am J Physiol Gastrointest Liver Physiol 239: G71-G76, 1980[Abstract/Free Full Text].

11.   Koch, MB, Go VL, and DiMagno EP. Can plasma human pancreatic polypeptide be used to detect diseases of the exocrine pancreas? Mayo Clin Proc 60: 259-265, 1985[ISI][Medline].

12.   Kreymann, B, Williams G, Ghatei MA, and Bloom SR. Glucagon-like peptide-1 7-36: a physiological incretin in man. Lancet 2: 1300-1304, 1987[ISI][Medline].

13.   Kuiken, SD, Samsom M, Camilleri M, Mullan BP, Burton DD, Kost LJ, Hardyman TJ, Brinkmann BH, and O'Connor MK. Development of a test to measure gastric accommodation in humans. Am J Physiol Gastrointest Liver Physiol 277: G1217-G1221, 1999[Abstract/Free Full Text].

14.   Naslund, E, Barkeling B, King N, Gutniak M, Blundell JE, Holst JJ, Rossner S, and Hellstrom PM. Energy intake and appetite are suppressed by glucagon-like peptide-1 (GLP-1) in obese men. Int J Obes Relat Metab Disord 23: 304-311, 1999[Medline].

15.   Naslund, E, Bogefors J, Skogar S, Gryback P, Jacobsson H, Holst JJ, and Hellstrom PM. GLP-1 slows solid gastric emptying and inhibits insulin, glucagon, and PYY release in humans. Am J Physiol Regulatory Integrative Comp Physiol 277: R910-R916, 1999[Abstract/Free Full Text].

16.   O'Connor, MK, O'Connell R, Keane FB, Byrne PJ, and Hennessy TP. The relationship between technetium-99m pertechnetate gastric scanning and gastric contents. Br J Radiol 56: 817-822, 1983[Abstract].

17.   Orskov, C, Wettergren A, and Holst JJ. Biological effects and metabolic rates of glucagonlike peptide-1 7-36 amide and glucagonlike peptide-1 7-37 in healthy subjects are indistinguishable. Diabetes 42: 658-661, 1993[Abstract].

18.   Rees, WD, Go VL, and Malagelada JR. Antroduodenal motor response to solid, liquid and homogenized meals. Gastroenterology 76: 1438-1442, 1979[ISI][Medline].

19.   Rodriquez de Fonseca, F, Navarro M, Alvarez E, Roncero I, Chowen JA, Maestre O, Gomez R, Munoz RM, Eng J, and Blazquez E. Peripheral vs. central effects of glucagonlike peptide-1 receptor agonists on satiety and body weight loss in Zucker obese rats. Metabolism 49: 709-717, 2000[ISI][Medline].

20.   Rossi, P, Gourtsoyiannis N, Bezzi M, Raptopoulos V, Massa R, Capanna G, Pedicini V, and Coe M. Meckel's diverticulum: imaging diagnosis. AJR Am J Roentgenol 166: 567-573, 1996[Abstract].

21.   Russo, A, Fraser R, Adachi K, Horowitz M, and Boeckxstaens G. Evidence that nitric oxide mechanisms regulate small intestinal motility in humans. Gut 44: 72-76, 1999[Abstract/Free Full Text].

22.   Salet, GA, Samsom M, Roelofs JM, van Berge Henegouwen GP, Smout AJ, and Akkermans LM. Responses to gastric distension in functional dyspepsia. Gut 42: 823-829, 1998[Abstract/Free Full Text].

23.   Samsom, M, Roelofs JM, Akkermans LM, van Berge Henegouwen GP, and Smout AJ. Proximal gastric motor activity in response to a liquid meal in type I diabetes mellitus with autonomic neuropathy. Dig Dis Sci 43: 491-496, 1998[ISI][Medline].

24.   Samsom, M, Salet GA, Roelofs JM, Akkermans LM, van Berge Henegouwen GP, and Smout AJ. Compliance of the proximal stomach and dyspeptic symptoms in patients with type I diabetes mellitus. Dig Dis Sci 40: 2037-2042, 1995[ISI][Medline].

25.   Samsom, M, Szarka LA, Camilleri M, Vella A, Zinsmeister AR, and Rizza RA. Pramlintide, an amylin analog, selectively delays gastric emptying: potential role of vagal inhibition. Am J Physiol Gastrointest Liver Physiol 278: G946-G951, 2000[Abstract/Free Full Text].

26.   Schirra, J, Houck P, Wank U, Arnold R, Goke B, and Katschinski M. Effects of glucagon-like peptide-1(7-36)amide on antropyloro-duodenal motility in the interdigestive state and with duodenal lipid perfusion in humans. Gut 46: 622-631, 2000[Abstract/Free Full Text].

27.   Schirra, J, Katschinski M, Weidmann C, Schafer T, Wank U, Arnold R, and Goke B. Gastric emptying and release of incretin hormones after glucose ingestion in humans. J Clin Invest 97: 92-103, 1996[Abstract/Free Full Text].

28.   Schirra, J, Kuwert P, Wank U, Leicht P, Arnold R, Goke B, and Katschinski M. Differential effects of subcutaneous GLP-1 on gastric emptying, antroduodenal motility, and pancreatic function in men. Proc Assoc Am Physicians 109: 84-97, 1997[ISI][Medline].

29.   Schirra, J, Leicht P, Hildebrand P, Beglinger C, Arnold R, Goke B, and Katschinski M. Mechanisms of the antidiabetic action of subcutaneous glucagon-like peptide-1(7-36)amide in non-insulin dependent diabetes mellitus. J Endocrinol 156: 177-186, 1998[Abstract/Free Full Text].

30.   Schirra, J, Sturm K, Leicht P, Arnold R, Goke B, and Katschinski M. Exendin(9-39)amide is an antagonist of glucagon-like peptide-1(7-36)amide in humans. J Clin Invest 101: 1421-1430, 1998[Abstract/Free Full Text].

31.   Schuurkes, JA, and Meulemans AL. Nitric oxide and gastric relaxation. Dig Dis Sci 39: 79S-81S, 1994[Medline].

32.   Schwartz, TW. Pancreatic polypeptide: a hormone under vagal control. Gastroenterology 85: 1411-1425, 1983[ISI][Medline].

33.   Tack, J, Piessevaux H, Coulie B, Caenepeel P, and Janssens J. Role of impaired gastric accommodation to a meal in functional dyspepsia. Gastroenterology 115: 1346-1352, 1998[ISI][Medline].

34.   Thumshirn, M, Camilleri M, Choi MG, and Zinsmeister AR. Modulation of gastric sensory and motor functions by nitrergic and alpha2-adrenergic agents in humans. Gastroenterology 116: 573-585, 1999[ISI][Medline].

35.   Toft-Nielsen, MB, Madsbad S, and Holst JJ. Continuous subcutaneous infusion of glucagon-like peptide 1 lowers plasma glucose and reduces appetite in type 2 diabetic patients. Diabetes Care 22: 1137-1143, 1999[Abstract].

36.   Toft-Nielson, M, Madsbad S, and Holst JJ. The effect of glucagon-like peptide I (GLP-I) on glucose elimination in healthy subjects depends on the pancreatic glucoregulatory hormones. Diabetes 45: 552-556, 1996[Abstract].

37.   Toma, TP, Thompson DG, Troncon L, and Ahuwalia NK. Effect of glyceryl trinitrate on proximal stomach musculature in normal volunteers. Rev Med Chir Soc Med Nat Iasi 96: 5-9, 1992[Medline].

38.   Tosetti, C, Salvioli B, Stanghellini V, Cogliandro L, Cogliandro R, Marra MG, DeGiorgio R, Mazzotta E, Zamboni P, and Corinaldesi R. Reproducibility of a water load test in healthy subjects and symptom profile compared to patients with functional dyspepsia (Abstract). Gastroenterology 116: A336, 1999.

39.   Turton, MD, O'Shea D, Gunn I, Beak SA, Edwards CM, Meeran K, Choi SJ, Taylor GM, Heath MM, Lambert PD, Wilding JP, Smith DM, Ghatei MA, Herbert J, and Bloom SR. A role for glucagon-like peptide-1 in the central regulation of feeding. Nature 379: 69-72, 1996[ISI][Medline].

40.   Vella, A, Shah P, Basu R, Basu A, Holst JJ, and Rizza RA. Effect of glucagon-like peptide 1(7-36) amide on glucose effectiveness and insulin action in people with type 2 diabetes. Diabetes 49: 611-617, 2000[Abstract].

41.   Wank, U, Schirra J, Arnold R, Goke B, and Katschinki M. Effects of GLP-1 on proximal gastric motor and sensory function in human (Abstract). Gastroenterology 114: A1190, 1998[ISI].

42.   Wettergren, A, Petersen H, Orskov C, Christiansen J, Sheikh SP, and Holst JJ. Glucagon-like peptide-1 7-36 amide and peptide YY from the L-cell of the ileal mucosa are potent inhibitors of vagally induced gastric acid secretion in man. Scand J Gastroenterol 29: 501-505, 1994[ISI][Medline].

43.   Wettergren, A, Schjoldager B, Mortensen PE, Myhre J, Christiansen J, and Holst JJ. Truncated GLP-1 (proglucagon 78-107-amide) inhibits gastric and pancreatic functions in man. Dig Dis Sci 38: 665-673, 1993[ISI][Medline].

44.   Wettergren, A, Wojdemann M, and Holst JJ. Glucagon-like peptide-1 inhibits gastropancreatic function by inhibiting central parasympathetic outflow. Am J Physiol Gastrointest Liver Physiol 275: G984-G992, 1998[Abstract/Free Full Text].

45.   Wettergren, A, Wojdemann M, Meisner S, Stadil F, and Holst JJ. The inhibitory effect of glucagon-like peptide-1 (GLP-1) 7-36 amide on gastric acid secretion in humans depends on an intact vagal innervation. Gut 40: 597-601, 1997[Abstract].

46.   Wilbur, BG, and Kelly KA. Effect of proximal gastric, complete gastric, and truncal vagotomy on canine gastric electric activity, motility, and emptying. Ann Surg 178: 295-303, 1973[ISI][Medline].


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