Dr. J. Tack, Department of Internal Medicine, Division of Gastroenterology, University Hospital Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium. E-mail: Jan.Tack@med.kuleuven.ac.be
Background : Intraduodenal administration of lipids, through lipid digestion and release of cholecystokinin (CCK), induces viscero-visceral reflexes that affect gastric tone and sensitivity. It is unclear whether the same mechanisms control gastric function after an orally ingested meal.
Aim : To evaluate the effect of orlistat, a selective lipase inhibitor, on gastric response to an orally administered meal.
Methods : Eighteen healthy volunteers participated in this study. They were treated for 5 days with orlistat (120 mg) or placebo t.d.s. in a double-blind randomized crossover design. During treatment, all subjects underwent a gastric barostat study, measurement of plasma CCK levels and a satiety drinking test.
Results : Although CCK plasma levels were significantly decreased, pre-treatment with orlistat failed to affect gastric compliance (72 ± 6 mL/mm Hg and 64 ± 6 mL/mm Hg, NS), gastric sensitivity (discomfort threshold 12.2 ± 0.6 mm Hg vs. 10.9 ± 0.6 mm Hg above minimal distending pressure, NS) or gastric accommodation (172 ± 41 mL vs. 206 ± 49 mL, NS) to an orally ingested meal. Furthermore, orlistat pre-treatment had no significant effect on the amount of calories ingested during a satiety drinking test (1329 ± 88 kcal vs. 1217 ± 115 kcal, NS).
Conclusion : Administration of a lipase inhibitor does not affect gastric compliance, sensitivity to distension and accommodation to an orally ingested meal, and does not influence meal-induced satiety.
During fasting, muscle fibres of the proximal stomach maintain a vagally mediated tonic contractile activity, which generates gastric fundus tone.1, 2 During and after ingestion of a meal, a relaxation of the proximal stomach occurs, which provides the meal with a reservoir and enables a gastric volume increase without a rise in pressure.1 Studies in animals and in man have established that this accommodation reflex is mediated via a vago-vagal reflex pathway, which activates nitrergic neurones in the gastric wall.3–7 Recent studies have established that impaired accommodation to a meal is a major pathophysiological mechanism in functional dyspepsia, associated with early satiety and weight loss,8, 9 and restoration of accommodation is considered a valid therapeutic target.8, 10, 11 However, the control of the accommodation reflex in man is incompletely understood.
Recently, we demonstrated that, during oral intake of a meal, triggering of the accommodation reflex occurs from the oropharynx, the stomach and especially from the duodenum.12 Duodenal lipid infusion is able to induce a relaxation of the proximal stomach, thereby mimicking meal-induced gastric relaxation.13–21 The gastric relaxation induced by duodenal lipid infusion requires lipid digestion and subsequent release of cholecystokinin (CCK),13, 15, 18, 19 which can be blocked by administration of a lipase inhibitor.21 However, it is unclear whether the same pathway is also controlling gastric accommodation to an orally ingested meal.
Furthermore, duodenal lipid infusion was found to sensitize the stomach to distention, again through lipid digestion and subsequent release of CCK which can be blocked by administration of a lipase inhibitor.21 The findings are potentially relevant as hypersensitivity to gastric distention is a putative mechanism in functional dyspepsia,22–24 and many dyspeptic patients experience aggravation of symptoms after a fatty meal.14, 25–27 Duodenal lipid infusion in healthy subjects is also able to elicit dyspeptic symptoms. Decreasing lipid-induced sensitization might have therapeutic potential in functional dyspepsia, provided that the same pathway is also controlling gastric sensitivity to an orally ingested meal.
The aim of this study was to investigate the effect of a selective lipase inhibitor (1) on gastric accommodation to an orally ingested meal, (2) on fasting and postprandial sensory–motor changes during gastric distensions, (3) on sensory responses during a satiety drinking test and (4) on meal-induced release of CCK.
Materials and methods
Eighteen healthy volunteers (nine males, mean age 24 ± 1118–32) participated in the study. None of them was taking any medications nor had symptoms or a history of gastrointestinal disease, drug allergies or major abdominal surgery. The local Ethics Committee approved the study and all subjects gave written informed consent before participation.
The subjects participated in a double-blind, randomized, crossover study. Two test periods of 5 days each were separated by a washout period of approximately 3 weeks. During the test period, volunteers received one tablet of orlistat (120 mg) or placebo three times a day. In the first 3 days of each test period, the volunteers were allowed to eat ad libitum. On the morning of day 4, volunteers underwent a gastric barostat and on the morning of day 5 they performed a satiety drinking test.
Sensitivity to gastric distension and gastric accommodation to a meal was studied using a gastric barostat. Following an overnight fast of at least 12 h, a double lumen polyvinyl tube (Salem sump tube Ch, Sherwood Medical, petit Rechain, Belgium) with an adherent plastic bag (1000 mL capacity, 17 cm maximal diameter) finely folded was introduced through the mouth and secured to the subject's chin with adhesive tape. The position of the bag in the gastric fundus was checked fluoroscopically.
The polyvinyl tube was then connected to a programmable barostat device (Synectics Visceral Stimulator, Stockholm, Sweden). To unfold the bag, it was inflated with a fixed volume of 300 mL of air for 2 min with the subject in a recumbent position, and again deflated completely. The subjects were then positioned in a comfortable sitting position with the knees bent (80°) and the trunk upright in a specifically designed bed.
After a 30-min adaptation period, minimal distending pressure (MDP) was first determined by increasing intrabag pressure by 1 mm Hg every 3 min until a volume of 30 mL or more was reached. This pressure level equilibrates the intra-abdominal pressure. Subsequently, isobaric distensions were performed in stepwise increments of 2 mm Hg starting from MDP, each lasting for 2 min, while the corresponding intragastric volume was recorded. Subjects were instructed to score their perception of upper abdominal sensations at the end of every distending step, using a graphic rating scale that combined verbal descriptors on a scale graded 0–6.8, 24 The end point of each sequence of distensions was established at an intrabag volume of 1000 mL or when the subjects reported discomfort or pain (score 5 or 6) (Figure 1).
After a 30-min adaptation period with the bag completely deflated, the pressure level was set at MDP + 2 mm Hg for 90 min. After 30 min, a liquid meal (200 mL, 300 kcal, 16% proteins (6.0 g), 49% carbohydrates (18.4 g) and 35% lipids (5.8 g), Nutridrink, Nutricia, Bornem, Belgium) was administered. Immediately before the meal, placebo or orlistat 120 mg was orally administered. Gastric tone measurement was continued for 60 min after the meal. At that time, a second series of stepwise gastric distentions was performed.
Plasma CCK analyses
To assess changes in plasma levels of CCK, 16 mL of venous blood samples were taken 15, 10 and 5 min before the meal, at meal ingestion time, and 2, 5, 10, 20, 30 and 60 min after the meal. Plasma CCK concentrations were determined by a sensitive and specific radioimmunoassay using antiserum Dino-7 as previously described.28
Subjects underwent a test to quantify the occurrence of meal-induced satiety. A peristaltic pump (Minipuls 2; Gilson, Villiers-Le-Bel, France) filled one of two beakers at a fixed rate of 15 mL/min with a liquid meal (Nutridrink; Nutricia). The subjects were requested to maintain intake at the filling rate, thereby alternating the beakers as they were filled and emptied. At 5-min intervals, they were asked to score their satiety using a graphic rating scale that combined verbal descriptors on a scale graded of 0–5 (1, threshold; 5, maximum satiety). Participants were instructed to stop meal intake when a score of 5 was reached. All patients underwent the satiety test twice with an interval of 5–43 days. Immediately before starting the test, placebo or orlistat 120 mg was administered orally.
Assessment of sensations during distensions and satiety test
The subjects rated gastrointestinal sensations of fullness, bloating, nausea, heartburn, belching, epigastric burning, discomfort and satiety on a visual analogue scale (VAS). The VAS consisted of a 10-cm long line with 0 cm meaning ‘no sensation’ and 10 cm meaning ‘the strongest sensation ever felt’. During distentions, the subjects rated the sensations during the last 20 s of each pressure step. During the satiety test, volunteers scored the sensations every 5 min.
Perception threshold was defined as the first level of pressure and the corresponding volume that evoked a perception score of 1 or more. Discomfort threshold was defined as the first level of pressure and the corresponding volume that evoked a score of 5 or more. Pressure thresholds were expressed as pressures above the MDP. Intragastric volumes during consecutive pressure steps were calculated by averaging the volume readings for each pressure step. All data obtained were used to construct pressure–volume curves. Gastric compliance was calculated as the slope of the pressure–volume curve.
Visual analogue scale scores, obtained during distentions, were compared to investigate the effect of the drug. To investigate the sensations during distention, only the values comprised between the MDP and the pressure level tolerated by at least 75% of the subjects (third quartile) were compared. The third quartile corresponded to a pressure of MDP + 12 mm Hg. VAS scores were used to construct pressure–symptom profiles for each individual symptom, from which we obtained the maximal score reached at the end of distention, the slope of the curve and the areas under the pressure–perception curve (AUCs).
The end point of these studies was the gastric accommodation to a meal. Gastric tone before and after administration of the meal was measured by calculation of the mean balloon volume for consecutive 5-min intervals. The meal-induced gastric relaxation was quantified as the difference between the average volumes during 30 min before and 60 min after the administration of the meal.
Sensory responses during satiety test.
The duration of the satiety test and the amount of calories ingested to reach maximum satiety were quantified. Subjects scored each sensation at time 0 and every 5 min. VAS scores were used to construct time–symptom profiles for each individual symptom. AUCs, maximal symptom score and the slope of the scores/time curves were derived from these data.
Student's t-test was used to compare pressures and volumes during distentions, volumes during accommodation testing, AUCs and maximal scores reached during gastric distentions and during the satiety test. The pressure–volume and symptom–pressure curves obtained during distentions and symptom–time curves obtained during satiety drinking test were analysed by analysis of variance (anova). Symptom scores and gastric accommodation during satiety test were correlated using Pearson's test. Based on previous studies, the study was estimated to have at least 85% power to detect 30% changes in accommodation and in sensitivity at a 0.05 significance level.
Data are presented as mean ± S.E.M. Probability values of P < 0.05 were considered statistically significant. Bonferroni's correction for multiple comparisons was applied.
Conduct of the study
All participants completed the trial as planned. Side effects of orlistat (fatty stools and flatus) were always mild and expected given the pharmacological profile of the drug.
Fasting gastric distentions
The slopes of the pressure–volume curve did not differ significantly between the two treatment groups (72 ± 6 and 64 ± 6 mL/mm Hg, NS) (Figure 2a). During placebo treatment, fasting perception and discomfort threshold were reached at distending pressures of 4.0 ± 0.6 and 12.3 ± 0.9 mm Hg, respectively, above the MDP. The corresponding intragastric balloon volumes were 277 ± 46 and 752 ± 41 mL. During orlistat treatment, first perception and discomfort thresholds during fasting distentions (3.6 ± 0.4 and 10.9 ± 0.6 mm Hg, respectively, above MDP) did not differ significantly from placebo treatment values (Figure 2b). The corresponding intragastric volumes were also not significantly altered (240 ± 31 and 675 ± 48 mL, NS compared with placebo).
During fasting distentions, the AUC for dyspeptic symptoms did not differ significantly between both groups (Table 1).
Table 1. Area under the curve (AUC) of perception scores (score*min) during fasting isobaric gastric distentions, with placebo and orlistat pre-treatment (no significant differences were observed)
70 ± 11
80 ± 9
81 ± 12
78 ± 10
76 ± 16
75 ± 10
78 ± 10
77 ± 11
44 ± 12
28 ± 7
35 ± 13
23 ± 8
66 ± 11
64 ± 10
42 ± 13
31 ± 10
Minimal distending pressure did not differ after placebo and after orlistat (7.3 ± 0.3 mm Hg vs. 6.9 ±0.5 mm Hg, NS). Preprandial intra-balloon volumes did not differ between placebo and orlistat treatment (137 ± 19 mL vs. 192 ± 18 mL, NS). In both groups, administration of the meal caused an immediate relaxation of the proximal stomach, reflected by an increase in intra-balloon volume (Figure 3). Five minutes after the meal, the intra-balloon volume was significantly greater than the average preprandial volume and it remained significantly elevated until 60 min postprandially. Postprandial intra-balloon volumes (380 ± 53 mL vs. 398 ± 39 mL, NS) and gastric accommodation to a meal (172 ± 41 mL vs. 206 ± 49 mL, NS) did not differ between both treatments.
Postprandial gastric distentions
During postprandial distentions, 60 min after ingestion of the meal, the slopes of the postprandial pressure–volume curves did not differ between both treatment groups (63 ± 5 and 74 ± 6 mL/mm Hg; NS compared with fasting distentions as well; Figure 4). After placebo, postprandial thresholds for first perception and for discomfort were 3.7 ± 0.6 and 10.9 ± 0.7 mm Hg above the MDP, respectively (NS compared with fasting). The corresponding intragastric balloon volumes were 449 ± 88 and 793 ± 50 mL, respectively (P = 0.03 compared with fasting distentions, NS with Bonferroni's correction). During orlistat treatment first perception and discomfort thresholds were not significantly altered (pressures of 2.7 ± 0.4 and 10.3 ± 0.9 mm Hg, respectively; NS compared with placebo). The corresponding intragastric volumes also were not significantly altered (331 ± 50 and 782 ±34 mL, respectively, NS compared with placebo).
Area under the curves of symptom severities during postprandial distentions did not differ significantly between both groups (Table 2).
Table 2. Area under the curve (AUC) of perception scores (score*min) during postprandial isobaric gastric distentions, with placebo and orlistat pre-treatment (no significant differences were observed)
94 ± 13
91 ± 11
95 ± 13
95 ± 11
98 ± 14
89 ± 13
97 ± 13
87 ± 11
47 ± 18
34 ± 10
54 ± 16
31 ± 13
63 ± 13
57 ± 12
37 ± 13
36 ± 12
After orlistat pre-treatment, preprandial mean CCK levels (4.0 ± 0.5 pg/mL vs. 3.0 ± 0.4 pg/mL, P = 0.09) and preprandial AUC (60.6 ± 7.9 min pg/mL vs. 46.2 ± 6.9 min pg/mL, P = 0.06) tended to be lower, compared with placebo. Ingestion of the meal induced a rapid increase in CCK levels. Five minutes after the meal, mean plasma CCK levels were significantly higher than the average preprandial level and levels remained significantly elevated until 60 min postprandially. The mean postprandial CCK levels (14.0 ± 1.5 pg/mL vs. 9.8 ± 1.0 pg/mL, P < 0.01), the postprandial AUC (959.0 ± 143.4 min pg/mL vs. 652.8 ± 85.8 min pg/mL, P = 0.03) and the maximal postprandial value (26.5 ± 4.1 pg/mL vs. 17.1 ± 1.5 pg/mL, P = 0.02) were all significantly lower after orlistat pre-treatment.
Both after placebo and after orlistat treatments, a highly significant correlation existed between satiety scores and amount of calories ingested (R > 0.95, P < 0.0001). During placebo treatment the amount of calories ingested until the occurrence of maximum satiety was 1329 ± 88 kcal. Pre-treatment with orlistat do not significantly alter the amount of calories ingested until maximum satiety (1217 ± 115, NS compared with placebo). The AUCs for symptoms during the satiety drinking test did not differ significantly between the two treatment groups (Table 3).
Table 3. Area under the curve (AUC) of perception scores (score*min) during the satiety drink test, with placebo and orlistat pre-treatment (no significant differences were observed)
207 ± 15
190 ± 13
160 ± 21
149 ± 17
148 ± 11
135 ± 10
119 ± 24
140 ± 19
76 ± 14
87 ± 17
61 ± 11
55 ± 16
40 ± 10
59 ± 15
27 ± 8
34 ± 10
The control of gastric sensitivity and gastric accommodation to a meal is incompletely understood. Several studies have shown that, when lipids are delivered directly into the duodenum, they induce a relaxation of the stomach and modulate dyspeptic symptoms, especially nausea.13–21 Lipid digestion and subsequent release of CCK and activation of CCK B receptors are key factors in these events.15–21
From these observations, a number of potential pathways to interfere with meal-induced relaxation and sensitization can be derived, including inhibition of lipase activity, antagonism of CCK B receptors or modification of the lipid composition of a meal. Such interventions could potentially have therapeutic implications in functional dyspepsia, provided that the same mechanisms govern gastric sensitivity and accommodation to an orally ingested meal. In this study, however, we observed that pre-treatment with the lipase inhibitor orlistat failed to influence gastric sensitivity and gastric accommodation to an orally ingested meal. Orlistat pre-treatment had no significant effect on the amount of calories ingested during a satiety drinking test, and failed to have a major influence on symptoms elicited during fasting and postprandial gastric distentions and during the satiety drinking test.
The lipase inhibitor, the treatment duration and treatment dose used in this study are identical to those used in previous studies where lipid was infused in the duodenum.21 Moreover, measurements of CCK levels confirmed that significant inhibition of lipase activity and subsequent release of CCK were achieved during orlistat treatment in the present studies. The main difference between the present studies and previous studies is the mode of nutrient administration. It seems that the pathways that become activated during duodenal lipid infusion are less important in the control of gastric relaxation and gastric sensitivity to distention after an orally ingested meal. A previous study already established that the CCK1 receptor antagonist loxiglumide inhibited the relaxation of the proximal during duodenal lipid infusion, but not the relaxation of the proximal stomach in response to an orally administered meal.29 These findings are in keeping with previous observations on the site of triggering of the accommodation reflex, where we demonstrated that not only exposure of the duodenum to food, but also of the oropharynx and the stomach contribute to the gastric accommodation reflex.12 Furthermore, in a preliminary study using orally administered radio-labelled lipid-containing liquid meal in healthy controls, emptying of liquid to the duodenum occurred only in the earliest phase.30 Exposure of the duodenum to nutrients, especially lipids, will cause enhanced contractile activity of the pylorus and inhibited antral contractile activity, thereby effectively inhibiting additional emptying of nutrients from the stomach.31 During duodenal lipid infusion, these feedback mechanisms do not succeed in inhibiting the further delivery of lipid nutrients.
Several studies have used duodenal lipid infusion as a stimulus to study the relaxation of the proximal stomach, assuming that this allowed to study meal-induced gastric accommodation.7, 32, 33 The results of the present and previous studies suggest that different control mechanisms underlie gastric relaxation after an orally ingested meal and gastric relaxation during duodenaly lipid infusion. It is conceivable that the gastric responses to duodenal lipid infusion mainly reflect a negative feedback pathway, aiming to prevent further delivery of nutrients from the stomach to the duodenum, rather than mimicking the accommodation reflex which provides the proximal stomach with storage capacity for the meal.
Several studies have demonstrated that CCK is involved in the sensation of meal-induced satiety.34, 35 In this study, we observed lowered CCK levels in the orlistat group, and this was accompanied by lower satiety scores during the satiety drinking test. However, the end point of the test (amount of calories ingested to reach maximum satiety) was not significantly altered by orlistat pre-treatment. This observation is in keeping with recent observations that the end point of the satiety drinking test is determined by gastric accommodation,36 which was not altered by orlistat pre-treatment.
Our observations do not necessarily exclude a potential role for lipase inhibition or CCK B-receptor antagonism in the therapeutic approach to functional dyspepsia. It is conceivable that the effects of duodenal lipid exposure and subsequent release of CCK and sensitization of the stomach are exaggerated in patients with functional dyspepsia. In fact, specific sensitivity to lipids has been suggested in patients with functional dyspepsia.14, 25–27 Establishing this potential will require additional studies on the effect of lipase inhibition in patients with functional dyspepsia and hypersensitivity to gastric distention.
In summary, we could not demonstrate a major influence of a lipase inhibitor on gastric accommodation and gastric sensitivity after an orally ingested meal. Orlistat pre-treatment also failed to influence the amount of calories ingested to reach maximum satiety. These observations differ from the influence of a lipase inhibitor on the gastric sensory–motor changes after intra-duodenal lipid administration. This implies that other chemical or mechanical stimuli are involved in the process of gastric accommodation to a meal and postprandial sensations.