The effect of gastric secretion on gastric physiology and emptying in the fasted and fed state assessed by magnetic resonance imaging

Abstract Conventional measurement of gastric secretion is invasive and cannot assess the intra‐gastric distribution of gastric contents or the effects of secretion on gastric function. This study assessed the effect of gastric secretion on gastric volume responses and emptying (GE) using a validated fast T₁ mapping magnetic resonance imaging (MRI) technique. Twelve healthy participants were studied in the fasted state and after 200 kcal Gadolinium‐DOTA labelled glucose meal during intravenous infusion of pentagastrin or placebo in double‐blind, randomized order. Total gastric volume (TGV) and gastric content volume (GCV) was assessed by MRI volume scans and secretion by fast T₁ mapping. Data was described by the κ‐coefficient (volume change after meal ingestion), by GE half time (T₅₀) and maximal GE rate (GER_max) derived all from a GE model. Pentagastrin increased GCV and TGV compared to placebo [κ(GCV):1.6 ± 0.1 vs 0.6 ± 0.1; κ(TGV): 1.6 ± 0.1 vs 0.7 ± 0.1; P < 0.001]. T₁ maps revealed a secretion layer above the meal, the volume of which was associated with κ (R² = 83%, P < 0.001). TGV and GCV change were similar in both conditions (κ; P = ns). T₅₀ was higher for pentagastrin than for placebo (84 ± 7 vs 56 ± 4min, P < 0.001); however, GER_max was similar (5.9 ± 0.6 vs 4.9 ± 0.4 mL min^?1, P = ns). This study shows volume and distribution of gastric secretion can be quantified in‐vivo by non‐invasive MRI T₁ mapping. Increased GCV drove TGV accommodation without evidence of a direct effect of pentagastrin or excess acid on gastric function. Secretion increases GCV thus prolongs GE as assessed by T₅₀; however, GE rate is unchanged.     

Performance characteristics of scintigraphic measurement of gastric emptying of solids in healthy participants

Background Gastric emptying (GE) is measured in pharmacodynamic and diagnostic studies. Our aim was to assess inter‐ and intra‐subject coefficients of variation (COV) of scintigraphic GE measurements in healthy subjects, and associations of GE with gender and body mass index (BMI). Methods Data from participants with scintigraphic measurements of gastric emptying of solids were analyzed. Primary endpoints were gastric emptying T_1/2 (GE T_1/2) and GE at 1, 2, 3, and 4 h. Key Results The patient cohort consisted of 105 males and 214 females; at least two studies were performed in 47 subjects [16 males (M), 32 females (F)]. Inter‐subject COV (COV_inter) for GE T_1/2 were similar in M and F: overall 24.5% (M 26.0%, F 22.5%); COV are predictably lowest for GE at 4 h (COV_inter 9.6%). COV_intra for T_1/2 and GE at 4 h were overall 23.8% and 12.6%, and were similar to COV_inter values. Gender (but not age or BMI) was significantly associated with GE T1/2 [P < 0.001, F 127.6 ± 28.7 (SD) min; M 109.9 ± 28.6 min] and with GE at 1 h and 2 h. Repeat GE T_1/2 values in 47 participants were significantly correlated (r = 0.459, P < 0.001) with median difference of ?6 min (mean ?1.6, range ?56 to 72 min). Bland–Altman plots showed Δ GE T_1/2 similarly distributed across mean GE T_1/2 100–155 min, and across studies conducted 90–600 days apart. Conclusions & Inferences Inter‐subject variations in scintigraphic GE results are only slightly higher than the intra‐subject measurements, which are also reproducible over time in healthy volunteers. Gender, but not BMI, is significantly associated with GE results.     

Comparison of calculations to estimate gastric emptying half‐time of solids in humans

Background Measuring solid gastric emptying (GE) at 4 h is used to identify gastroparesis. GE half‐time (GE T_1/2) is useful to assess overall and early GE. Aim To examine the validity of hourly imaging as a measurement of GE T_1/2 compared with estimates from more detailed imaging. Methods 155 human subjects (99 female, 56 male) underwent scintigraphic GE of a solid–liquid meal. We calculated the GE T_1/2 using linear interpolation based on a full set of abdominal images obtained over 4 h, and the GE T_1/2 based on images at 1, 2, 3, and 4 h after the meal with interpolation of data. Key Results Differences in GE T_1/2 values (entire set of scan times compared with just the hourly scans) were small [overall median (5th, 95th percentiles) = ?0.2[?7.5, 4.6] min] with slightly greater differences in males compared with females. The agreement between the two methods was very high [concordance correlation coefficient (CCC) (95% CI) = 0.993 (0.990, 0.995)] and a Bland–Altman plot indicated the variation in the results between the two methods did not change appreciably across the range of GE studied (within ±10 min for all but four subjects). Calculated GE T_1/2 values, omitting the 3‐h data from the hourly measurements, were associated with similar high accuracy overall and for fast GE, but were less accurate with slow GE. Conclusions & Inferences Results of GE T_1/2 solids, using hourly imaging over 4 h, are accurate in the range 75–235 min which reflects the typical range of GE of solids in health and disease.     

Characterization of gastric volume responses and liquid emptying in functional dyspepsia and health by MRI or barostat and simultaneous 13C-acetate breath test

Abstract The assessment of gastric accommodation and emptying by different methodologies provides inconsistent results. We aimed to compare magnetic resonance imaging (MRI), barostat and ¹³C‐acetate breath test (BT) for the assessment of gastric volume responses and emptying in healthy controls (HC) and patients with functional dyspepsia (FD). Eight HC and eight FD patients underwent: (i) continuous BT with simultaneous MRI in the upright position after ingestion of isocaloric, 300 kcal, 200 and 800 mL meals, both labelled with 100 mg of ¹³C‐acetate; and (ii) BT with gastric barostat after ingestion of the 200 mL meal. MRI measured total gastric volume and gastric content volume (GCV) at baseline, after filling and during emptying. Meal emptying half‐times (T½) for MRI and BT were calculated (mean ± SD). We found: (i) Initial GCV was lower in FD than in HC (762 ± 22 vs 810 ± 52 mL, P < 0.04) after the 800 mL meal but not the 200 mL meal. T½_MRI was shorter for the 800 mL than the 200 mL meal (P < 0.001), but similar in HC and FD (200 mL: HC 117 ± 30 min vs FD 138 ± 42 min, ns; 800 mL: HC 71 ± 16 min vs FD 78 ± 27 min, ns). In contrast, T½_BT was similar between meals and groups (200 mL: HC 111 ± 11 min vs FD 116 ± 19 min; 800 mL: HC 114 ± 14 min vs FD: 113 ± 17 min). (ii) Barostat measurements showed similar postprandial volume increases between groups. We conclude that direct measurements by MRI provide a sensitive, non‐invasive assessment of gastric accommodation and emptying after a meal. In contrast to MRI, BT did not detect faster emptying of high‐volume compared to low‐volume liquid nutrient meals in HC or FD.     

Duodenal ulcer disease,gastroduodenal motor function and reflux esophagitis – a cross‐sectional survey in a subset of Taiwanese patients

Background To investigate the association between the gastric emptying rate and the presence of erosive esophagitis in duodenal ulcer (DU) patients among a population with high prevalence of Helicobacter pylori infection. Methods Cross‐sectional survey was performed in a cohort of 60 male patients with either active or healed DU, with or without the presence of erosive esophagitis. Clinical and social‐demographic data, blood level of fasting gastrin, pepsinogen I & I/II ratio, and scintigraphic measurement of half emptying time (t_1/2) of the solid phase gastric emptying were evaluated. Key Results Patients with active DU and erosive esophagitis tended to have higher plasma level of fasting gastrin than those without erosive esophagitis (75.11 ± 13.74 vs 45.81 ± 5.06 pg mL^?1, P = 0.059). In the absence of H. pylori infection, patients with healed DU and erosive esophagitis had a trend to have longer half‐emptying time (t_1/2: 96.5 ± 6.4 vs 69.1 ± 11.3 min, P = 0.0572) than those without erosive esophagitis, and statistically significant longer after excluding those diagnosed with hiatal hernia (t_1/2: 100.8 ± 7.9 min vs 69.1 ± 11.3 min, P < 0.05) from the former group. Among the healed DU patients, those with negative H. pylori infection, hiatal hernia and overweight (body mass index ≥24) had significantly increased risk of severe esophagitis. Conclusions & Inferences Presence of erosive esophagitis in a subset of Taiwanese patients with healed DU and negative H. pylori status was associated with slower solid phase gastric emptying.     

Measurement of gastric emptying of a high‐nutrient liquid by 3D ultrasonography in diabetic gastroparesis

Background Gastric emptying (GE) is delayed in 30–50% of patients with longstanding diabetes. Scintigraphy represents the ‘gold standard’ for measurement of GE, but is associated with a radiation burden. Three‐dimensional (3D) ultrasonography has recently been demonstrated to provide a valid measure of liquid GE in healthy subjects; however, the technique has not been validated in patients with gastroparesis. The primary aim of this study was to compare measurements of GE of a high‐nutrient glucose drink by 3D ultrasonography and scintigraphy in diabetic gastroparesis. Methods Ten patients (eight type 1, two type 2, 6M, 4F, aged 46.1 ± 4.5 years, BMI 29.1 ± 1.6 kg m^?2, duration 19.6 ± 3.3 years) with diabetic gastroparesis [defined as retention at 100 min of solid (100 g minced beef) ≥61% and/or 50% emptying time (T50) of liquid (150 mL 10% dextrose) ≥31 min], were studied. Concurrent measurements of GE by scintigraphy and 3D ultrasonography were performed following ingestion of 75 g glucose in 300 mL water labeled with 20 MBq ^99mTc‐sulfur colloid. Key Results There was no significant difference in GE between the two techniques (T50s: scintigraphy – 103.3 ± 10.0 min VS 3D ultrasonography – 98.8 ± 10.4 min; P = 0.60). There was a significant correlation between scintigraphic and ultrasonographic T50s (r = 0.67, P = 0.03). The limits of agreement for the T50s were ?57.22 min and +48.22 min (mean difference ?4.5 min). Blood glucose after the drink was greater when GE was relatively more rapid (e.g. at t = 60 min; scintigraphy: r = ?0.65, P = 0.04; 3D ultrasonography: r = ?0.78, P = 0.008). Conclusions & Inferences Three‐dimensional ultrasonography appears to provide a valid, and non‐invasive, measure of GE of high‐nutrient liquids in diabetic gastroparesis.     

Central administration of pan‐somatostatin agonist ODT8‐SST prevents abdominal surgery‐induced inhibition of circulating ghrelin,food intake and gastric emptying in rats

Background Activation of brain somatostatin receptors (sst_1–5) with the stable pan‐sst_1–5 somatostatin agonist, ODT8‐SST blocks acute stress and central corticotropin‐releasing factor (CRF)‐mediated activation of endocrine and adrenal sympathetic responses. Brain CRF signaling is involved in delaying gastric emptying (GE) immediately post surgery. We investigated whether activation of brain sst signaling pathways modulates surgical stress‐induced inhibition of gastric emptying and food intake. Methods Fasted rats were injected intracisternally (i.c.) with somatostatin agonists and underwent laparotomy and 1‐min cecal palpation. Gastric emptying of a non‐nutrient solution and circulating acyl and desacyl ghrelin levels were assessed 50 min post surgery. Food intake was monitored for 24 h. Key Results The abdominal surgery‐induced inhibition of GE (65%), food intake (73% at 2 h) and plasma acyl ghrelin levels (67%) was completely prevented by ODT8‐SST (1 μg per rat, i.c.). The selective sst₅ agonist, BIM‐23052 prevented surgery‐induced delayed GE, whereas selective sst₁, sst₂, or sst₄ agonists had no effect. However, the selective sst₂ agonist, S‐346‐011 (1 μg per rat, i.c.) counteracted the abdominal surgery‐induced inhibition of acyl ghrelin and food intake but not the delayed GE. The ghrelin receptor antagonist, [D‐Lys³]‐GHRP‐6 (0.93 mg kg^?1, intraperitoneal, i.p.) blocked i.p. ghrelin‐induced increased GE, while not influencing i.c. ODT8‐SST‐induced prevention of delayed GE and reduced food intake after surgery. Conclusions & Inferences ODT8‐SST acts in the brain to prevent surgery‐induced delayed GE likely via activating sst₅. ODT8‐SST and the sst₂ agonist prevent the abdominal surgery‐induced decrease in food intake and plasma acyl ghrelin indicating dissociation between brain somatostatin signaling involved in preventing surgery‐induced suppression of GE and feeding response.     

Effects of clonidine and sumatriptan on postprandial gastric volume response, antral contraction waves and emptying: an MRI study

Abstract Gastric emptying (GE) may be driven by tonic contraction of the stomach (‘pressure pump’) or antral contraction waves (ACW) (‘peristaltic pump’). The mechanism underlying GE was studied by contrasting the effects of clonidine (α₂‐adrenergic agonist) and sumatriptan (5‐HT₁ agonist) on gastric function. Magnetic resonance imaging provided non‐invasive assessment of gastric volume responses, ACW and GE in nine healthy volunteers. Investigations were performed in the right decubitus position after ingestion of 500 mL of 10% glucose (200 kcal) under placebo [0.9% NaCl intravenous (IV) and subcutaneous (SC)], clonidine [0.01 mg min^?1 IV, max 0.1 mg (placebo SC)] or sumatriptan [6 mg SC (placebo IV)]. Total gastric volume (TGV) and gastric content volume (GCV) were assessed every 5 min for 90 min, interspersed with dynamic scan sequences to measure ACW activity. During gastric filling, TGV increased with GCV indicating that meal volume dictates initial relaxation. Gastric contents volume continued to increase over the early postprandial period due to gastric secretion surpassing initial gastric emptying. Clonidine diminished this early increase in GCV, reduced gastric relaxation, decreased ACW frequency compared with placebo. Gastric emptying (GE) rate increased. Sumatriptan had no effect on initial GCV, but prolonged gastric relaxation and disrupted ACW activity. Gastric emptying was delayed. There was a negative correlation between gastric relaxation and GE rate (r² = 49%, P < 0.001), whereas the association between ACW frequency and GE rate was inconsistent and weak (r² = 15%, P = 0.05). These findings support the hypothesis that nutrient liquid emptying is primarily driven by the ‘pressure pump’ mechanism.     

Effect of mianserin on gastric sensorimotor function and gastric emptying: a randomized,placebo‐controlled,double‐blind,crossover study in healthy volunteers

Background Antidepressants such as mianserin can improve symptoms in some functional dyspeptic patients but their mechanism of action remains unclear. We aimed to assess the effects of mianserin on gastric sensorimotor function in man. Methods In this randomized, placebo‐controlled, double‐blind, crossover study 12 healthy subjects (six men) underwent a gastric barostat study and a gastric emptying breath test after 7 days pretreatment with placebo or mianserin (20 mg; p.o.). Graded isobaric and isovolumetric distentions were performed to determine gastric compliance and sensitivity. Subsequently, intrabag pressure was held constant and the volume increase after administration of a liquid meal (200 mL; 300 kcal) was studied. Breath was sampled before and after ingestion of a test meal and half‐emptying times for solids and liquids were determined from the breath samples. Mianserin was compared to placebo using t‐tests and mixed model analysis (mean ± SD). Key Results Mianserin did not affect pressures or volumes needed to induce first perception or discomfort. During isovolumetric distensions compliance was decreased after mianserin treatment (1.8 ± 0.4 vs 2.0 ± 0.3 mmHg 100 mL^?1; P < 0.05). Premeal volumes were comparable in both treatment arms (221 ± 99 vs 220 ± 88 mL), but meal‐induced relaxation during the first 30 min was significantly inhibited after mianserin treatment (F_6,40 = 2.58, P < 0.05). Mianserin did not affect either solid or liquid gastric emptying. Conclusions & Inferences Mianserin does not alter gastric emptying rate or sensitivity to gastric distension, but inhibits gastric accommodation to a meal in its early phase. These observations provide no explanation for the effects of mianserin in functional dyspeptic patients.     

Tissue ghrelin level and gastric emptying rate in adult patients with celiac disease

Abstract Celiac disease (CD) patients show a number of gastrointestinal motor abnormalities. Ghrelin, a gastric peptide implicated in short‐term feeding control and long‐term body weight regulation, has been recently considered a key regulator of gastric motility. The aim of this study was to evaluate the gastric emptying rate of solids and the density of ghrelin‐immunopositive cells in adult CD patients before and at least 1 year after starting a gluten‐free diet. Twenty CD patients (M 8/F 12; mean age 36 years) and 10 controls underwent endoscopy with gastric and duodenal biopsies and ¹³C‐octanoic acid breath test to measure gastric emptying of solids. Celiac disease patients repeated the protocol at least 1 year after starting gluten‐free diet. Ghrelin tissue levels were evaluated by immunohistochemistry on gastric mucosa specimens. Gastric emptying time was normal in all control subjects (t_1/2 = 89 ± 16 min) while it was delayed in CD patients prior to gluten‐free diet (t_1/2 = 252 ± 101 min; P < 0.005). The mean number of ghrelin‐positive cells/field (×400) was 14.4 ± 2.7 in controls and 25.3 ± 5.7 in CD patients respectively (P < 0.0001). Gluten withdrawal was effective in normalizing gastric emptying time in all CD patients (97 ± 14 min; P < 0.0001) and resulted in a significant reduction of the density of ghrelin‐immunopositive cells (19.8 ± 5.4; P < 0.0001). The density of ghrelin‐positive cells correlated directly with the degree of duodenal damage (P < 0.001) and inversely with the body mass index of CD patients (P < 0.0001). However, in neither CD patients nor controls, a correlation between tissue ghrelin levels and gastric emptying rate was detected. In conclusion, tissue ghrelin level does not correlate with gastric emptying rate in adult CD patients and in controls.     

The nitric oxide synthase inhibitor, Ng-nitro-l-arginine-methyl-ester, attenuates the delay in gastric emptying induced by hyperglycaemia in healthy humans

Abstract The aim of this study was to determine whether the nitric oxide (NO) synthase inhibitor, N^g‐nitro‐l ‐arginine‐methyl‐ester (l ‐NAME), reverses the effects of acute hyperglycaemia on gastric emptying and antropyloroduodenal (APD) motility. The study had a four‐way randomized crossover (hyperglycaemia vs euglycaemia; l ‐NAME vs placebo) design in a clinical laboratory setting. Seven healthy volunteers [four males; age 30.3 ± 3.8 years; body mass index (BMI) 23.6 ± 1.2 kg m^?2] were the study subjects. After positioning a transnasal manometry catheter across the pylorus, the blood glucose concentration was maintained at either 15 or 5 mmol L^?1 using a glucose/insulin clamp. An intravenous infusion of l ‐NAME (180 μg kg^?1 h^?1) or placebo (0.9% saline) was commenced (T = ?30 min) and continued for 150 min. At T = ?2 min, subjects ingested a drink containing 50 g of glucose made up to 300 mL with water. Gastric emptying was measured using 3D ultrasound, and APD motility using manometry. Hyperglycaemia slowed gastric emptying (P < 0.05), and this effect was abolished by l ‐NAME. l ‐NAME had no effect on gastric emptying during euglycaemia. Hyperglycaemia suppressed fasting antral motility [motility index: 3.9 ± 0.8 (hyperglycaemia) vs 6.5 ± 0.6 (euglycaemia); P < 0.01]; l ‐NAME suppressed postprandial antral motility [motility index: 3.6 ± 0.2 (l ‐NAME) vs 5.1 ± 0.2 (placebo); P < 0.001]. Postprandial basal pyloric pressure was higher during hyperglycaemia (P < 0.001), and lower after administration of l ‐NAME (P < 0.001). Slowing of gastric emptying induced by hyperglycaemia is mediated by NO, and may involve the modulation of tonic pyloric activity.     

Indirect vs direct assessment of gastric emptying: A randomized crossover trial comparing C‐isotope breath analysis and MRI

Background

Indirect methods to assess gastric emptying (GE), such as ¹³C breath tests (BT), are commonly used. However, BT usually use a sampling time of 4+ hours. The current study aims to assess the validity of BT for four liquid meals differing in physicochemical properties. To this aim, we compared them to MRI GE‐measurements.

Methods

Fifteen healthy males (age 22.6 ± 2.4 years, BMI 22.6 ± 1.8 kg/m²) participated in a randomized 2 × 2 crossover experiment. Test foods were liquid meals, which were either thin/thick and 100/500 kcal, labeled with 100 mg of ¹³C‐octanoate. GE was measured with MRI and assessed by ¹³C recovery from breath. Participants were scanned every 10 minutes and at six time points breath samples were collected up to t = 90 minutes. Two curves were fitted to the data to estimate emptying halftime (t_{50 Ghoos} and t_{50 Bluck}). T₅₀ times were ranked per participant and compared between methods.

Key Results

On average, MRI and BT showed similar t₅₀ rankings for the four liquid meals. In comparison to MRI, t_{50 Ghoos} overestimated, while t_{50 Bluck} underestimated GE time_. Moreover, more viscous foods were overestimated. In most participants individual t₅₀ time rankings differed significantly between methods.

Conclusions & Inferences

BT can assess relative emptying differences on group level and collecting breath data for 90 minutes constitutes a lower burden for participants and the research facility. However, BT has severe shortcomings compared to MRI for individual GE assessment. Notably, food matrix effects should be considered when interpreting the results of BT.     

The effects of fasting duration on gastric emptying in man,an exploration of the role of the endocannabinoid system and inter‐individual responsiveness

Background In animal studies, gut vagal afferent neurons express cannabinoid (CB1) receptors, whose expression is increased by fasting. We aimed to explore the possibility that similar effects might be relevant in man in controlling gastric emptying. Methods Fourteen healthy volunteers underwent measurements of gastric emptying using the ¹³C acetate breath test, after either a nutrient (skimmed milk) or non‐nutrient (water) meal following both a 12 and 24 h fast. Further gastric emptying studies were performed with and without the CB1 receptor antagonist Rimonabant (20 mg or 80 mg). Because of the inter‐individual variations observed, two subjects underwent additional studies with and without Rimonabant to determine intra‐individual consistency. Gastric emptying was evaluated as cumulative C13 : C12 ratio values, measured at 5 min intervals for 30 min. Key Results In the group as a whole, fasting duration slowed gastric emptying for both the nutrient [120 ± 30 (mean ± SD) vs 101 ± 34, P < 0.05] and non‐nutrient [226 ± 62 vs 177 ± 47, P < 0.05] meals, but there was no effect of Rimonabant. However, there was consistent inter individual variation; thus while 12 subjects showed a slowing, two (14%) exhibited accelerated gastric emptying for both the nutrient and the non‐nutrient meal after 24 h fasting and in one of whom, Rimonabant consistently reversed the fasting effect on the non‐nutrient meal. Conclusions & Inferences Extended fasting alters the gastric emptying of liquid meals but there are consistent differences between individuals. Where there is an accelerated response to fasting, Rimonabant appears to reverse the effect.     

The 13C-octanoic acid breath test: validation of a new noninvasive method of measuring gastric emptying in rats

Abstract Currently available rat models for measuring gastric emptying are hampered by the necessity to kill the animals at the end of each experiment, which makes repetitive testing impossible. We have developed and validated a noninvasive test model, adapted from the¹³C‐octanoic breath test in humans, for repetitive measurements of gastric emptying in rats. Male Wistar rats were trained on a fixed protocol to eat a piece of pancake doped with 1 μg¹³C‐octanoic acid after 12 h fasting, and to stay thereafter in cylindrical glass cages. Breath tests were performed by a fully automated system of computer‐guided switching valves, which collected consecutive breath samples. All breath samples were analysed by gas chromatography and isotope mass spectrometry. The area under the curve (AUC) from the cumulative¹³CO₂excretion from 0 to 6 h was determined by the trapezium method to calculate the gastric half‐emptying times (t½). Inter‐day variability was determined. The effect of subcutaneous or intraperitoneal injection of saline was studied. The test was further validated for pharmacological interventions by oral administration of cisapride and parenteral administration of atropine, to induce, respectively. acceleration and delay of gastric emptying. Mean gastric emptying times ± SD of 24 rats were 119.3 ± 28.2 min, 138.7 ± 26.0 min, and 124.5 ± 30.9 min on three different test days. The mean coefficient of variation of three repeated measurements in the same 24 rats was 17.5%. No significant differences were observed after subcutaneous or intraperitoneal injection of saline. In a second test series of eight rats, cisapride significantly accelerated gastric emptying (mean t½ 112.7 ± 33.1 min, P < 0.05), while atropine caused a significant delay (mean t½ 205.9 ± 24.9 min, P < 0.05) when compared to control test results (mean t½ 140.7 ± 16.7 min) in the same rats. We validated the¹³C‐octanoic breath test to study gastric emptying in rats. This test method obviates the necessity to kill laboratory animals and allows repetitive measurements of gastric emptying to study its physiology or pathophysiology as well as the effect of pharmacological agents.     

Effect of itopride on gastric emptying in longstanding diabetes mellitus

Abstract Delayed gastric emptying (GE) occurs in 30–50% of patients with longstanding type 1 or 2 diabetes, and represents a major cause of morbidity. Current therapeutic options are limited. We aimed at evaluating the effects of itopride on GE in patients with longstanding diabetes. Twenty‐five patients (20 type 1, 5 type 2; 10 males, 15 females; mean age 45.2 ± 2.7 years; body mass index 27.5 ± 0.9 kg m^?2; duration of diabetes 20.2 ± 2.4 years) were enrolled in a double‐blind, placebo‐controlled, randomized, crossover trial. Subjects received both itopride (200 mg) and placebo t.i.d. for 7 days, with a washout of 7–14 days. GE (scintigraphy), blood glucose (glucometer) and upper gastrointestinal (GI) symptoms (questionnaire) were measured following each treatment period. The test meal comprised 100 g ground beef (^99mTc‐sulphur colloid) and 150 mL of 10% dextrose [⁶⁷Ga‐ethylenediaminetetraacetic acid (EDTA)]. There was a slight trend for itopride to accelerate both solid (P = 0.09) and liquid (P = 0.09) GE. With itopride treatment, the emptying of both solids and liquids tended to be more accelerated, as the emptying with placebo was slower (solids: r = 0.39, P = 0.057; liquids: r = 0.44, P < 0.03). Twelve (48%) patients had delayed solid and/or liquid GE on placebo and in this group, itopride modestly accelerated liquid (P < 0.05), but not solid (P = 0.39), emptying. Itopride had no effect on mean blood glucose during the GE measurement (placebo: 9.8 ± 0.6 mmol L^?1vs itopride: 9.6 ±0.6 mmol L^?1), or GI symptoms (placebo: 1.4 ± 0.4 vs itopride: 1.8 ± 0.5). Itopride, in a dose of 200 mg t.i.d. for 7 days, tends to accelerate GE of liquids and solids in longstanding diabetes. The magnitude of this effect appears to be modest and possibly dependent on the rate of GE without itopride.     

Gastric tone,volume and emptying after implantation of an intragastric balloon for weight control

Background The intragastric balloon, filled with air or liquid is used before elective bariatric surgery because its efficacy is limited. This might be the consequence of altered gastric functions. Therefore, we aimed to investigate, in an animal model, the changes in gastric motility and emptying induced by long‐term insertion of a balloon used for weight reduction. Methods Ten Göttingen mini‐pigs were allocated into two groups with and without an intragastric balloon for 5 months. Balloons were inserted under endoscopy during general anesthesia and were filled with 350 mL of air. Gastric emptying was evaluated by scintigraphy. Gastric volume was measured by single photon emission computed tomography and proximal gastric compliance obtained using an electronic barostat. Changes in vagal tone were assessed by heart rate variability (HRV). Key Results After balloon insertion, gastric volume was significantly increased (2047 ± 114.8 cm³ after vs 1674 ± 142.5 cm³ before insertion, P < 0.05). Gastric compliance was also larger in balloon group (219 ± 23.4 mL mmHg^?1 in balloon vs 168 ± 7.7 mL mmHg^?1 in control group). Gastric emptying was reduced after insertion of the balloon (T_1/2 = 204 ± 28.8 min vs 159 ± 25.4 before vs after insertion). High frequency components of the spectral analysis of HRV, representing vagal tone, were increased in balloon group. Conclusions & Inferences The proximal stomach was enlarged after the insertion of a balloon in the stomach as a consequence of an increased gastric compliance. This change in compliance was probably causative for a reduction in gastric emptying rate of solids. These alterations were associated with increased vagal tone.     

Gastric secretion does not affect the reliability of the 13C‐acetate breath test: A validation of the 13C‐acetate breath test by magnetic resonance imaging

Background ¹³C‐Acetate labeled meals are widely used to determine meal emptying by means of analyzing resulting ¹³CO₂ exhalation dynamics. In contrast to the underlying metabolic processes, only few ¹³C breath test meal emptying studies have focused on intragastric processes that may alter ¹³CO₂ exhalation. This work assessed the effect of enhanced gastric secretion on the reliability of half emptying time (t50) measurements by ¹³C‐acetate breath test. Methods ¹³CO₂ exhalation data were acquired in a double‐blind, randomized, cross‐over gastric emptying study in 12 healthy volunteers receiving either pentagastrin or placebo intravenously. The standard method proposed by Ghoos et al. was applied to calculate t50 (t50_Ghoos) from ¹³CO₂ exhalation data, which were compared and tested for agreement to meal half emptying times (t50_MV) from concurrent recorded MRI (magnetic resonance imaging) volume data. In addition, the accumulated gastric secretion volumes during infusion as detected by MRI (AUC_SV₆₀) were correlated with the corresponding cumulative percent ¹³C doses recovered (cPDR₆₀). Key Results t50_Ghoos and t50_MV showed a linear correlation with a slope of 1.1 ± 0.3 (r² = 0.67), however, a positive offset of 136 min for t50_Ghoos. No correlation was detected between AUC_SV₆₀ and cPDR₆₀ (r² = 0.11). Both, breath test and MRI, revealed a prolonged t50 under pentagastrin infusion with median differences in t50_Ghoos of 45[28–84] min (P = 0.002) and t50_MV of 39[28–52] min (P = 0.002). Conclusions & Inferences This study suggests that ¹³CO₂ exhalation after ingestion of a ¹³C‐labeled liquid test meal is not affected by stimulated gastric secretion, but is rather reflecting the dynamics of meal or caloric emptying from the stomach.     

Evaluation of (‐)‐[18F]Flubatine‐specific binding: Implications for reference region approaches

We aimed to characterize changes in binding of (‐)‐[¹⁸F]Flubatine to α₄β₂*‐nicotinic acetylcholine receptors (α₄β₂*‐nAChRs) during a tobacco cigarette smoking challenge. Displacement of (‐)‐[¹⁸F]Flubatine throughout the brain was quantified as change in (‐)‐[¹⁸F]Flubatine distribution volume (V_T), with particular emphasis on regions with low V_T. Three tobacco smokers were imaged with positron emission tomography (PET) during a 210 min bolus‐plus‐constant infusion of (‐)‐[¹⁸F]Flubatine. A tobacco cigarette was smoked in the PET scanner ～125 min after the start of (‐)‐[¹⁸F]Flubatine injection. Equilibrium analysis was used to estimate V_T at baseline (90‐120 min) and after cigarette challenge (180‐210 min), at the time of greatest receptor occupancy by nicotine. Smoking reduced V_T by 21 ± 9% (average ±SD) in corpus callosum, 17 ± 9% in frontal cortex, 36 ± 11% in cerebellum, and 22 ± 10% in putamen. The finding of displaceable (‐)‐[¹⁸F]Flubatine binding throughout the brain is an important consideration for reference region‐based quantification approaches with this tracer. We observed displacement of (‐)‐[¹⁸F]Flubatine binding to α₄β₂*‐nicotinic acetylcholine receptors in corpus callosum by a tobacco cigarette challenge. We conclude that reference region approaches utilizing corpus callosum should first perform careful characterization of displaceable (‐)‐[¹⁸F]Flubatine binding and nondisplaceable kinetics in this putative reference region.     

Influence of tegaserod on proximal gastric tone and on the perception of gastric distention in functional dyspepsia

Background Abnormalities in gastric sensorimotor function (hypersensitivity to distention and impaired meal accommodation) have been implicated in the pathophysiology of functional dyspepsia (FD). To study the effect of the 5‐HT₄ agonist tegaserod on sensitivity to gastric distention and gastric accommodation in FD. Methods Thirty FD patients (7 males, mean age 42 ± 2 years) underwent a gastric barostat study on two separate occasions, 2 weeks apart, after 5 days of pretreatment with placebo or tegaserod 6 mg b.i.d. in a double‐blind randomized order. After introduction of the barostat bag, graded isobaric distentions (2 mmHg increments/2 min) were performed to determine gastric compliance and sensitivity to distention. Subsequently, the pressure level was set at intra‐abdominal pressure [minimal distending pressure (MDP)] + 2 mmHg for 90 min, with administration of a liquid meal (200 mL; 300 kcal) after 30 min. Key Results Tegaserod had no influence on MDP (7.9 ± 0.4 vs 7.4 ± 0.4 mmHg) or fasting gastric compliance (44 ± 10 vs 61 ± 6 mL mmHg^?1) and on fasting thresholds for first perception (3.6 ± 0.4 vs 4.2 ± 0.2 mmHg above MDP) or discomfort (9.9 ± 0.7 vs 10.5 ± 0.5 mmHg above MDP). Tegaserod did not alter intra‐balloon volumes before and after the meal [respectively 146 ± 14 vs 120 ± 11 and 297 ± 28 vs 283 ± 29 mL, not significant (NS)], or the amplitude of the meal‐induced gastric relaxation (151 ± 23 vs 162 ± 23 mL, NS). In the subgroup with normal gastric emptying (n = 22), tegaserod significantly enhanced meal‐induced accommodation (126 ± 23 vs 175 ± 29 mL, anova P < 0.001). Conclusions & Inferences Tegaserod does not alter gastric sensorimotor function in FD patients as a group. In the subgroup with normal gastric emptying, tegaserod 6 mg b.i.d enhanced gastric accommodation.     

9The TANTALUSTM System for obesity: effect on gastric emptying of solids

Background: Gastric electrical stimulation (GES) is currently investigated for the treatment of obesity. The TANTALUS System delivers gastric contractility modulation (GCM) signals in synchrony with gastric slow waves, resulting in significant augmentation of gastric contractions during food intake. We hypothesized that such modulation of contractile activity may affect gastric emptying and plasma ghrelin levels. Aim: To test the effect of GCM of the gastric antrum on gastric emptying of solids and ghrelin levels. Methods: 12 obese subjects were implanted with 2 pairs of antral electrodes and an implantable pulse generator (IPG, TANTALUS ^TM) Gastric emptying test (GE) for solids was performed twice, on separate days, in each subject, starting few weeks after implantation: 1) control, before the start of stimulation, and 2) with stimulation, after device was turned on. Blood samples for ghrelin, were taken at baseline, and at 15, 30, 60 and 120 min after the test meal. Results as mean + SD, analysis by t‐test and p < 0.05. Results: 11 females, 1 male, age: 39.1 ± 8.9 years, BMI: 41.6 ± 3.4, 3 subjects with type 2 diabetes. One diabetic patient did not complete GE test because of technical issues. GCM significantly accelerated gastric emptying: retention at 2 hours 18.7 ± 12.2% vs. 31.9 ± 16.4%, stimulation vs. control respectively, p = 0.008. T ^1/2 78.3 ± 23.5 vs. 95 ± 31.7 min, stimulation vs. control respectively, p = 0.04. Mean results for gastric emptying were within normal at both baseline and stimulation. Meal ingestion induced only minimal, insignificant reduction in ghrelin levels. There was no significant difference in AUC of ghrelin between control and stimulation. Conclusions: After GCM stimulation, there is significant acceleration of gastric emptying of solids in obese patients, without affect on ghrelin levels. The obese subjects did not exhibit the significant, meal‐induced reduction in ghrelin.