1 Enteric Neuroscience Program, Gastroenterology Research Unit, and 2 Endocrine Research Unit, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905
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ABSTRACT |
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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
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INTRODUCTION |
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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 cells of the
pancreas and enhancing insulin release. GLP-1 also has an inhibitory
effect on the pancreatic
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.
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METHODS |
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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 · kgThe 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 · kg1 · 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.
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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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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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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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 |
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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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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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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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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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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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Plasma Levels of Glucose and HPP
During fasting, the glucose change relative to baseline (preinfusion) was
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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).
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DISCUSSION |
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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 · kg1 · 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 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.
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ACKNOWLEDGEMENTS |
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We thank Cindy Stanislav for secretarial support.
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FOOTNOTES |
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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.
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