Burton, Duane D.

AbstractBackgroundRapid gastric emptying, increased food intake, and alterations in gastrointestinal hormones are associated with obesity. The effect of regular physical activity (PA) on food intake, gastric emptying (GE), gastric accommodation, and gastrointestinal (GI) hormones in adults with obesity remains unclear. Our aim was to compare, at time of presentation, weight trends, eating behavior, GE, and GI hormone levels among individuals with obesity who engage in regular PA compared to those who do not.MethodsIn 270 participants with obesity, we performed validated measurements of GI phenotypes: GE of solids and liquids, gastric volume (GV) during fasting and after consumption of 200 mL Ensure®, satiety by kcal intake (T‐kcal) during a buffet meal, satiation (volume to fullness [VTF] and maximal tolerated volume [MTV]) of a liquid nutrient, and plasma levels of fasting and postprandial GLP‐1, PYY, CCK, and ghrelin. Physical Activity Stages of Change Questionnaire was used to assess whether participants were regularly PA or not.Key resultsPA was associated with lower BMI (Δ 2.01 kg/m2, P = .001) and body weight (Δ 4.42 kg, P = .0278). GE of solids (T‐50% Δ 7.54 min, P = .021) and liquids (T‐50% Δ 2.99 min, P = .029%) was significantly more rapid in physically active participants. PA was also associated with relatively higher postprandial ghrelin AUC (Δ 10.4 pg/mL, P = .015). There was no significant difference in postprandial satiation, satiety, GV, or other GI hormones (CCK, PYY, or GLP‐1) between groups.Conclusions & InferencesPhysical activity is associated with lower BMI, but faster GE and higher postprandial ghrelin levels, two factors that are also associated with obesity.

Abnormal gastric accommodation (GA) and gastric emptying contribute to pathophysiology in functional dyspepsia (FD). Secretin is a key regulator of GA in animal studies. Our aim was to study the effects of secretin on gastric motility, satiation, postprandial symptoms, and key hormones. We performed two double-blind, randomized, saline-controlled crossover trials in 10 healthy volunteers and 10 patients with FD by Rome IV criteria. We used measured GA (by validated SPECT method) after a 111In radiolabeled Ensure 300-mL meal and quantified gastric emptying for 30 min by scintigraphy. Satiation was measured by volume to fullness (VTF) and maximum tolerated volume (MTV) on an Ensure nutrient drink test and postprandial symptoms 30 min post-MTV. Fasting and postprandial GLP-1, GIP, and HPP were measured. The ages and sex distribution of healthy controls and patients with FD were similar. Compared with placebo, secretin delayed gastric emptying at 30 min in both health [−11% (−16, −4), P = 0.004]; and FD [−8% (−9, 0), P = 0.03]. Satiation (VTF and MTV), GA, and plasma levels of GLP-1, GIP, and HPP did not differ between treatment arms in health or FD. On ANCOVA analysis (adjusting for age and sex), secretin did not consistently increase postprandial symptoms in health or FD. Secretin delayed gastric emptying in both health and FD without significantly altering GA, VTF, or MTV or selected hormones. Thus, secretin receptor activation may provide a novel therapeutic mechanism for patients with FD and rapid gastric emptying. NEW & NOTEWORTHY The naturally occurring hormone secretin retards gastric emptying of solids without deleteriously affecting gastric accommodation, satiation, other upper gastrointestinal hormones, or postprandial symptoms. Given these findings, a subset of patients with rapid gastric emptying (e.g., the estimated 20% of patients with functional dyspepsia) could be candidates for treatments that stimulate a secretin receptor such as sacubitril, which inhibits neprilysin, an enzyme that degrades secretin.

Abstract Purpose Obesity is associated with alterations in appetite, gastrointestinal hormone levels and excessive fat mass. We previously published a double-blind, placebo-controlled, randomized, 16-week trial on effects of once-daily glucagon-like peptide-1 (GLP-1) analog, liraglutide on weight, satiation, and gastric functions in obese volunteers. The aim of this substudy is to compare to placebo the effects of liraglutide on appetite, taste preference, regional body fat stores, and anthropometric measurements. Methods Forty obese adults received standard instruction for weight management, monthly behavioral intervention utilizing motivational interviews, and 16-week treatment of once-daily liraglutide (escalated to 3 mg SQ daily). At baseline and 16 weeks, the following were measured: appetite and taste preferences rated every 30 min for 5 h after ingesting 300 mL Ensure®; maximal tolerated volume (MTV) with a nutrient drink test; fasting and postprandial bioactive GLP-1 (7–36) and peptide YY (PYY) levels; total and regional body fat with dual-energy X-ray absorptiometry, and waist and hip circumference. Results Thirty-five participants (17 liraglutide; 18 placebo) completed the trial. Compared to placebo group, liraglutide group had significant reductions in MTV; prospective food consumption score; desire to eat something sweet, salty, savory or fatty; and an increase in perceived fullness. Postprandial plasma levels of GLP-1 decreased and PYY levels increased with liraglutide relative to baseline. Significant reductions in total body, trunk, and upper and lower body fat without reduction in lean body mass were observed. Conclusion Liraglutide 3 mg SQ modulates appetite, taste preference, gut hormones, and regional body fat stores in adults with obesity without reduction in lean body mass.

AbstractBackgroundThe relationship between cardiovascular and gastrointestinal (ie, plasma pancreatic polypeptide [PP] response to modified sham feeding [MSF]) indices of vagal function is unclear. Hyperglycemia inhibits PP secretion via vagally mediated mechanisms. Our aims were to (a) compare the PP response, (b) its relationship with glycemia, and (c) the relationship between PP response to MSF, gastric emptying (GE) of solids, and symptoms during GE study in healthy controls, patients with diabetic gastroenteropathy (DM), and non‐ulcer dyspepsia (NUD).MethodsIn 24 healthy controls, 40 DM, and 40 NUD patients, we measured plasma PP concentrations during MSF, cardiovagal functions, GE, and symptoms during a GE study.Key ResultsBaseline PP concentrations were higher in DM than in controls and NUD (P = .01), and in type 2 than in type 1 DM patients (P < .01). The PP increment during MSF was normal (≥20 pg/mL) in 70% of controls, 54% of DM, and 47% of NUD patients. Overall, the PP response and cardiovagal tests were concordant (P = .01). Among patients with a reduced PP increment with MSF, 7/10 of T1DM and 1/7 of T2DM patients had moderate or severe cardiovagal dysfunctions (P < .05). The PP response to MSF was not associated with GE.Conclusions & InferencesUp to 30% of healthy controls have a reduced PP increment during MSF, limiting the utility of this test to detect vagal injury. The PP response is more useful when it is normal than abnormal. A reduced PP response is more likely to be associated with cardiovagal dysfunctions in T1DM than in T2DM.

INTRODUCTION: Increasing rates of obesity have led to increased numbers of bariatric surgeries performed world-wide. However, some patients do not achieve significant weight loss or develop weight regain following these procedures. Other than estimating the size of the gastric remnant at endoscopy or transaxial imaging, there are limited approaches to quantitate the function of the post-surgical stomach in order to evaluate the disparate weight patterns, or to develop strategy for future treatments, e.g., pharmacotherapy or endoscopic intervention. We hypothesize that altered gastric function in the pre- and post-surgical periods may offer an explanation. Studies performed thus far are difficult to interpret due to heterogeneity in approaches to diagnostic evaluation. The aims of this project were: to assess the feasibility of a new protocol for simultaneous evaluation of gastric accommodation and gastric emptying in the post-bariatric state; and to report normative values in healthy volunteers. METHODS: Methods: We utilized single photon emission computed tomography (SPECT) and gamma scintigraphy to concurrently study postprandial gastric accommodation responses and gastric emptying rates of a limited size meal designed for subsequent use in post-bariatric patients. The standard meal consisted of 1 egg and 1 extra egg yolk scrambled with 111 Indium-activated charcoal (∼130kcal, 9.5g fat) and 120mL 2% milk (130kcal, 4.4g fat). Gastric accommodation was measured using 99m Technetium-SPECT. SPECT imaging was obtained concomitant with gastric emptying of the 111 In-labeled meal. Anterior and posterior scans of the abdomen were obtained for estimating gastric emptying parameters every 15 minute until 90 minutes, and then in 30-minute intervals until 240 minutes or complete emptying. RESULTS: Data on 28/30 healthy volunteers (35.7% men; 67% Caucasian) with completed studies to date are shown in the Table 1 (data presented as mean ± standard deviation). Gastric emptying proportion at 1, 2, and 4 hours, T 1/2 , and gastric volumes including accommodation are graphically depicted in Figures 1 and 2, respectively. CONCLUSION: Discussion: This study has demonstrated feasibility of simultaneous measurement of gastric emptying and accommodation and provides normal values; this sets the stage for future baseline and post-operative scans on patients undergoing sleeve gastrectomy.

AbstractBackgroundNon‐ulcer dyspepsia (NUD) is a heterogeneous disorder, which is characterized by upper gastrointestinal symptoms and sensorimotor disturbances, including abnormal gastric emptying (GE) and increased intestinal chemosensitivity, and associated with greater plasma glucagon‐like peptide‐1 (GLP‐1) levels during duodenal lipid infusion. However, the relationship(s) between these disturbances and daily symptoms in NUD is variable. We hypothesize that abnormal GE and symptoms during a GE study and during duodenal lipid infusion are associated with the severity of daily symptoms and that GLP‐1 mediates symptoms during duodenal lipid infusion in NUD.MethodsGastric emptying of solids, symptoms during the GE study and duodenal lipid infusion, and daily gastrointestinal symptoms (2 week diary) were measured in 24 healthy controls and 40 NUD patients. During duodenal lipid infusion, participants received the GLP‐1 antagonist exendin 9‐39 or placebo.Key ResultsIn controls and patients, GE of solids was normal in 75% and 75%, delayed in 8% and 12.5%, or rapid in 17% and 12.5%, respectively. No controls but 26 patients (65%) had severe symptoms during the GE study. During lipid infusion, gastrointestinal symptoms were greater (P = .001) in patients and not affected by exendin. Symptoms during GE study and lipid infusion accounted for respectively 62% and 37% of variance in daily symptom severity.ConclusionsIn NUD, symptoms during a GE study and to a lesser extent during lipid infusion explain the variance in daily symptoms. Intestinal chemosensitivity is not reduced by GLP‐1 antagonist. Assessment of symptoms during a GE study may provide a useful biomarker for NUD in research and clinical practice.

AbstractObjectiveTo compare estimates of gastric accommodation (GA) with single photon emission computed tomography (SPECT) to measurements based on intragastric meal distribution immediately post‐meal ingestion (IMD0).MethodsWe evaluated 108 diabetics with upper gastrointestinal (UGI) symptoms who had undergone gastric emptying of solids (GE) by scintigraphy and GA measurements by SPECT. Immediately after ingestion of a 99mTc‐labeled egg meal (time 0), we estimated IMD0 as radioactive counts or area of the proximal half of the stomach on two‐dimensional images. Gastric volume (GV) during fasting and after 300 mL Ensure® was measured by SPECT to quantify accommodation volume (AV) or postprandial to fasting volume ratio (GVR). From the measured proximal gastric area, we estimated the volume of proximal stomach (4/3 × π × r3). We performed regression analyses to assess relationships between IMD0 and GA (AV) and GVR.ResultsThere was a significant correlation between area and radioactivity counts in the proximal stomach (r = 0.67, P < 0.001); however, there was considerable interpersonal variation [bias 0.20 (95% CI −0.07, 0.47)]. There were no significant correlations between total GV or AV or VR by SPECT and measurements using IMD0: proximal gastric counts, area, and estimated volume as continuous variables of dichotomized patient groups, based on published cutoff values. There were no significant differences in total gastric area or the IMD0 parameters (% area or % radioactive counts) between those with and without UGI symptoms except for fullness and satiety.ConclusionsIntragastric meal distribution immediately post‐meal ingestion is not significantly correlated with GA measurement by SPECT.

SummaryBackgroundBiomarkers in irritable bowel syndrome (IBS) may guide targeted therapy in this multifactorial disease. It has been suggested that 75% accuracy and cost <$500 categorise biomarkers as cost‐effective.AimTo identify differences in faecal bile acids, faecal fat and fasting serum C4 (7a‐hydroxy‐4‐cholesten‐3‐one) and fibroblast growth factor 19 (FGF19) among patients with IBS‐D, IBS‐C and healthy controls and to determine accurate, cost‐effective biomarkers for clinically relevant diarrhoea and constipation.MethodsWe assessed daily stool frequency and consistency (Bristol Stool Form Scale) from validated bowel diaries, 48 hours total and individual faecal bile acids, 48 hours faecal fat and weight, fasting serum C4 and FGF19, and colonic transit by scintigraphy from healthy volunteers (HV) and patients with IBS‐D and IBS‐C (Rome III criteria). We utilised multivariate logistic regression to determine biomarkers of clinically significant diarrhoea or constipation based on stool frequency, consistency and weight.ResultsAmong the 126 HV (44M/82F, 37.5 ± 10.9 years [SD]), 64 IBS‐D (5M/59F, 41.9 ± 12.2 years), and 30 IBS‐C (0M/30F, 44.6 ± 10 years) patients, there were significant differences between all groups in stool weight, frequency, and consistency; in addition, there were differences in colonic transit at 48 hours, faecal fat, and total and individual faecal bile acids between IBS‐D and IBS‐C. Reduced total and primary faecal bile acids and increased faecal lithocholic acid were significant predictors of decreased faecal weight, frequency and consistency with AUC > 0.82 (sensitivity >76%, specificity >72%). Total and primary faecal bile acids and faecal fat were significant predictors of increased stool weight, frequency and consistency with AUC > 0.71 (sensitivity >55%, specificity >74%).The faecal parameters had a 11.5 positive likelihood ratio in predicting elevated faecal weight.ConclusionsFaecal bile acids and faecal fat are cost‐effective and accurate biomarkers associated with significant bowel dysfunction among IBS‐D and IBS‐C patients.

Abstract Background Nausea, vomiting, and constipation ( OIC ) are common adverse effects of acute or chronic opioid use. Naloxegol (25 mg) is an approved peripherally active mu‐opiate opioid receptor antagonist. Aim To compare the effects on pan‐gut transit of treatment with codeine, naloxegol, or combination in healthy volunteers. Methods We conducted a randomized, double‐blind, placebo‐controlled, single‐center, parallel‐group study in 72 healthy opioid‐naïve adults, randomized to: codeine (30 mg q.i.d.), naloxegol (25 mg daily), codeine and naloxegol, or matching placebo. During 3 days of treatment, we measured gastric emptying ( GE ) T 1/2 , colonic filling at 6 hours ( CF 6), colonic geometric center at 24 and 48 hours, and ascending colon emptying ( ACE ) T 1/2 . Key Results Participants were 59.7% women, median BMI 25.0 kg/m 2 , and median age 33.8 years. Codeine significantly retarded GE T 1/2, CF 6, overall colonic transit, and ACE T 1/2 . There was significant difference ( P = .026) in GE T 1/2 between codeine (144.0 min [ IQR 110.5‐238.6]) and naloxegol (95.5 min [89.1‐135.4]). There was a significant overall group difference in CF 6 ( P = .023), with significant difference ( P = .019) between codeine (11.0% [0.0‐45.0]) and naloxegol (51% [18.8‐76.2]). However, no significant differences were found between codeine‐treated participants concomitantly receiving placebo or naloxegol. Conclusions and Inferences Short‐term administration of naloxegol (25 mg) in healthy, opioid‐naïve volunteers does not reverse the retardation of gastric, small bowel, or colonic transit induced by acute administration of codeine. Further studies with naloxegol at higher dose are warranted to assess the ability to reverse the retardation of transit caused by acute administration of codeine in opioid‐naïve subjects.