Effect of different macronutrients in excess on gastric sensory and motor functions and appetite in normal-weight, overweight, and obese humans.

BACKGROUND: The effects of supplementation with different macronutrients on gastric sensory and motor functions are unclear. OBJECTIVE: We aimed to compare the effects of 2 wk of supplementation with different classes of macronutrients on gastric function, satiation, and appetite in healthy and overweight subjects. DESIGN: In a parallel-group, double-blind study, 52 (14 men, 38 women) healthy normal-weight, overweight, and obese participants [body mass index (BMI; in kg/m(2)): 19.4-47.0] aged 18-64 y were randomly assigned to consume different isocaloric diets (n = 13 per diet group) adjusted for BMI and activity level. The standard diet provided 20% of energy as protein, 30% as fat, and 50% as carbohydrate. The high-protein, high-fat, and high-carbohydrate diets contained 500 additional kcal in each nutrient class. On 3 separate days, we measured gastric emptying of solids, gastric volumes, postprandial symptoms, appetite, and food choice with validated methods. Age, sex, BMI, and baseline satiation were covariates in the analysis of covariance. RESULTS: Fat supplementation was associated with increased maximum tolerated volume (MTV) in subjects with a high baseline MTV (P < 0.05), irrespective of BMI. Gastric emptying and volumes, postprandial symptoms, total calories, and food choices at an ad libitum meal were not significantly different after each dietary preload. Fasting gastric volumes tended to be higher with the high-fat than with the high-carbohydrate or high-protein diets (P 30). CONCLUSION: Supplementation with 500 kcal fat in excess of required calories for 2 wk increased food tolerance in healthy normal-weight and obese subjects with a high baseline MTV without significantly changing gastric motor functions.

Alterations in expression of p11 and SERT in mucosal biopsy specimens of patients with irritable bowel syndrome.

BACKGROUND & AIMS: The pathophysiology of irritable bowel syndrome (IBS) remains enigmatic; abnormalities in serotonin metabolism have been implicated. Two proteins that influence the function of serotonin and serotonergic receptors are serotonin transporter protein (SERT or soluble carrier protein, SLC6A4) and p11 (S-100A10, or calpactin I light chain). Both proteins are reported to be associated with depression-like states, a frequent comorbid condition in IBS. We explored the hypothesis that expression of these 2 proteins in colonic and rectal mucosa is abnormal in patients with IBS as compared with healthy controls. METHODS: Messenger RNA (mRNA) expression of SLC6A4 and p11 was measured in sigmoid and rectal mucosal biopsy specimens. Genotype of the promoter for SLC6A4 was also assessed in all participants. Validation studies explored reproducibility of 2 biopsy specimens taken from the same region and biopsy specimens taken an average of approximately 3 months apart. RESULTS: We found normal colonic mucosal expression of SLC6A4 in diarrhea (IBS-D)- or constipation-predominant IBS (IBS-C). On the other hand, p11 expression was increased in IBS. No significant effect on p11 mRNA expression in sigmoid colon or rectum was noted from antidepressant treatment in any of the analyzed subgroups. CONCLUSIONS: Colonic mucosal expression of SLC6A4 in IBS is normal. Given that overexpression of p11 can increase serotonergic receptor functions (eg, 5-HT(1B) receptors), these data support the need for further study of the interaction between p11 expression in health and disease and its role in the therapeutic response to serotonergic agents, including antidepressants.

Is there an association between GNbeta3-C825T genotype and lower functional gastrointestinal disorders?

BACKGROUND & AIMS: GNbeta3 influences G-protein translation of a majority of ligand-receptor activations. It has been reported that functional dyspepsia (FD) is associated with homozygous genotypes of the C825T polymorphism in the GNbeta3 gene. It is unknown whether the GNbeta3 genotype is associated with lower functional gastrointestinal disorders (FGID). We aimed to compare the prevalence of the different GNbeta3-C825T genotypes in patients with lower FGID and healthy controls and to test the associations of these genetic variations with subgroups of irritable bowel syndrome (IBS), functional abdominal pain (FAP), lower FGID-FD overlap, and high somatic symptom scores. METHODS: GNbeta3-C825T polymorphism was analyzed in DNA from blood samples of 233 patients with lower FGID and 152 healthy controls. A validated bowel questionnaire characterized the FGID phenotype: 82 with IBS constipation, 94 with IBS diarrhea, 38 with IBS alternating bowel function, and 19 with FAP. There were 159 patients with lower FGID and overlap FD using Rome II criteria. Regression analyses assessed associations of the GNbeta3 genotypes with lower FGID as a group, and subgroups of FGID and somatic symptom scores. RESULTS: GNbeta3-C825T genotype distributions were similar between healthy controls (50.7% CC, 40.8% TC) and patients with lower FGID (8.6% TT, 51.5% CC, 40.8% TC, and 7.7% TT). There were no significant associations of GNbeta3-C825T polymorphism with lower FGID overall or with the separate symptom subgroups including IBS, FAP, lower FGID-FD overlap, or high somatic symptom scores. CONCLUSIONS: In contrast to the reported association with FD, GNbeta3-C825T polymorphism is not associated significantly with lower FGID, with different IBS or FAP phenotypes, or lower FGID-FD overlap.

Gastric sensorimotor functions and hormone profile in normal weight, overweight, and obese people.

BACKGROUND & AIMS: Peptide YY (PYY) levels are reported to be decreased in obesity. The relation between gastric functions, satiation, and gut hormones in obesity is incompletely understood. The aim of this study was to compare gastric volumes, emptying, maximum tolerated volumes, postchallenge symptoms, and selected gut hormones in normal, overweight, or obese healthy volunteers. METHODS: In 73 nonbulimic normal, overweight, or obese participants weighing less than 137 kg, we measured gastric emptying of solids and liquids by scintigraphy (gastric emptying half-time [GE t(1/2)]); gastric volumes by single-photon emission computed tomography; maximum tolerated volumes and symptoms by satiation test; and plasma leptin, ghrelin, insulin, glucagon-like peptide 1, and PYY levels. Groups were compared using 1-way analysis of covariance adjusted for sex. Univariate associations among measured responses were assessed using Spearman correlations. Multiple linear regression models, adjusting for weight and sex, assessed the independent ability of gastric functions and hormones to predict satiation volume. RESULTS: Obese and overweight subjects had significantly lower postprandial gastric volumes, higher fasting and postprandial insulin and leptin levels, and lower fasting ghrelin and lower postprandial reduction in ghrelin levels. PYY levels were not different in obese or overweight subjects compared with controls. The GE t(1/2) was correlated inversely with postprandial PYY; increased body weight was associated with faster GE t(1/2) of solids (r(s) = 0.33, P = .005) and liquids (r(s) = 0.24, P = .04). Postprandial changes in gastric volume and PYY were independent predictors of satiation (both P = .01). CONCLUSIONS: Overweight or obesity are associated with lower postprandial gastric volumes and normal PYY levels. Gastric emptying influences postprandial PYY levels. Postprandial PYY and gastric volume independently predict satiation volume in nonbulimic people across a wide body mass index range.

A study of candidate genotypes associated with dyspepsia in a U.S. community.

BACKGROUND: The role of genetic predisposition to the development of dyspepsia is unclear. Recently, a significant association was reported with CC genotype of GNbeta3. AIM: To explore the association of candidate genotypes altering adrenergic, serotonergic, CCKergic, and G protein functions, and dyspepsia in a sample from a U.S. community. METHODS: Dyspeptics and healthy controls were identified among community respondents who had been randomly selected to complete validated questionnaires. Other diseases were excluded by face-to-face history and physical examination. Polymorphisms of candidate genes for alpha(2A), alpha(2C), 5-HT(1A), 5-HT(2A), 5-HT(2C), CCK-1 receptors and CCK promoter, GNbeta3 protein, and SERT-promoter (SERT-P) were studied. The association between polymorphisms and meal-related or meal-unrelated dyspepsia, high somatic symptom scores, and somatization were evaluated using Fisher's exact test. RESULTS: DNA was available from 41 dyspeptics and 47 healthy controls from Olmsted County. Community dyspepsia unrelated to meals was associated with both homozygous GNbeta3 protein 825T and C alleles. There were no significant associations with meal-related dyspepsia. Using Rome II subgroups, the same genotype was associated with dysmotility-like and other dyspepsia. Higher somatization scores were not significantly associated with any of the candidate genes when considered as single factors. CONCLUSION: Meal-unrelated dyspepsia in a U.S. community study is associated with the homozygous 825T or C alleles of GNbeta3 protein. Candidate genes controlling adrenergic, serotonergic, and CCKergic functions do not appear to be associated with dyspepsia.

Effect of somatostatin analog on postprandial satiation in obesity.

OBJECTIVE: Altered satiation may impact postprandial symptoms and potentially change food intake in obesity. Our aim was to compare effects of octreotide and placebo on postprandial symptoms, satiation, and gastric volumes in obesity. RESEARCH METHODS AND PROCEDURES: In a randomized, parallel-group, double-blind, placebo-controlled study, 26 obese but otherwise healthy participants received 100 mug of octreotide or placebo subcutaneously 30 minutes before each study. Studies were performed on 2 separate days and included validated non-invasive techniques: (99m)Tc-single photon emission computed tomography imaging to measure fasting stomach volume and gastric volume changes after 90 mL of water and 240 mL of Ensure and a standardized nutrient drink test to measure the maximum tolerated volume and postprandial symptoms. RESULTS: Relative to placebo, octreotide increased gastric volume after 90 mL of water; however, fasting and gastric volume change post-Ensure and maximum tolerated volume of Ensure were not different. Octreotide decreased sensations of fullness (p = 0.035) and bloating (p = 0.05) and tended to reduce aggregate symptoms (p = 0.07) after the fully satiating meal. DISCUSSION: In obese individuals, somatostatin analog significantly reduced postprandial sensations after a satiating meal without altering maximum tolerated meal volume or postnutrient gastric volume, suggesting an effect on upper gut sensation. The role of somatostatin as a permissive factor in the development of obesity by reducing postprandial sensations deserves further study.

Gastric sensory and motor dysfunction in adolescents with functional dyspepsia.

OBJECTIVES: Validated, noninvasive studies were used to compare sensation and motor function of the upper gastrointestinal tract in adolescents with functional dyspepsia (FD) and in control subjects. STUDY DESIGN: Fifteen adolescents with FD and 15 healthy participants underwent standardized symptom assessment, a satiation nutrient drink test, and 13 C-Spirulina platensis breath test for gastric emptying of solids. Adolescents with FD also underwent measurements of fasting and postprandial gastric volume by means of single-photon emission computed tomography, and their results were compared with those from 15 healthy volunteers (age, 18 to 25 years). RESULTS: Compared with control subjects, adolescents with FD had significantly higher postprandial symptoms 30 minutes after reaching maximum satiation with the nutrient drink test and significant delay in the T 1/2 for gastric emptying of solids. Compared with healthy 18- to 25-year-old adults, adolescents had a diminished postprandial gastric volume response. By means of single-photon emission computed tomography, frequent baseline dyspeptic symptoms were associated with prolonged T 1/2 for gastric emptying and higher postprandial aggregate symptom score. A baseline increased severity of dyspepsia symptoms was associated with prolonged T 1/2 for gastric emptying. CONCLUSIONS: Adolescents with FD demonstrate increased postprandial symptoms after challenge, delayed gastric emptying, and a reduced gastric volume response to feeding.

Effect of gastric volume or emptying on meal-related symptoms after liquid nutrients in obesity: a pharmacologic study.

BACKGROUND & AIMS: Altered postprandial satiation influences food intake in obesity. The aim of this study was to evaluate the contribution of gastric motor functions to intra- and postprandial symptoms in obese, otherwise healthy, people. METHODS: In a randomized, parallel-group, double-blind design, 40 obese (body mass index>30 kg/m2) healthy volunteers (n=10/group) received intravenous saline (placebo), atropine (.02 mg/kg), or erythromycin (1 or 3 mg/kg) to alter gastric volume and emptying after liquid nutrient meals, measured by validated imaging methods. The nutrient drink test assessed the volume ingested at maximum satiation, and intra- and early postprandial symptoms. Relationships between gastric motor functions, meal size, and symptoms were assessed by using multiple regression. Circulating levels of candidate upper-gut hormones involved in satiation were measured. RESULTS: Relative to placebo, atropine retarded gastric emptying and increased gastric volumes; erythromycin accelerated gastric emptying and reduced gastric volumes during fasting. Although similar maximal tolerated volumes were recorded across treatments, intra- and immediate postprandial symptoms were increased by these perturbations, particularly nausea and bloating. Upper-gut hormonal profiles generally reflected changes in gastric emptying. Regression analysis showed that fasting predrug gastric volume was a significant predictor of intra- and postprandial bloating. Change in gastric volume postdrug or postmeal did not contribute additionally to predicting intra- or postprandial symptoms. There was significant (negative) association between gastric emptying and fullness score, and significant (positive) association with hunger score 30 minutes postprandially. CONCLUSIONS: In obese individuals, fasting gastric volumes and gastric emptying, but not postprandial gastric volumes, were associated with intra- and postprandial symptoms. Understanding the determinants of gastric volume may provide insights on mechanisms controlling satiation.

Relationship of gastric emptying and volume changes after a solid meal in humans.

Noninvasive imaging has been developed to measure gastric volumes. The relationship between gastric emptying and volume postprandially is unclear. The aims were to 1) develop a 3-dimensional (3D) single photon emission-computed tomography (SPECT) method to simultaneously measure gastric volume and emptying postprandially, 2) describe the course of gastric volume change during emptying of the meal, and 3) assess a 3D method measuring gastric emptying. In 30 healthy volunteers, we used (111)In-planar and (99m)Tc-SPECT imaging to estimate gastric emptying and volume after a radiolabeled meal. A customized analysis program of SPECT imaging assessed gastric emptying. A Bland-Altman plot assessed the performance of the new SPECT analysis compared with planar analysis. Gastric volume postprandially exceeds the fasting volume plus meal volume. The course of volume change and gastric emptying differ over time. Higher differences in volumes exist relative to fasting plus residual meal volumes at 15 min (median 763 vs. 568 ml, respectively, P < 0.001), 1 h (median 632 vs. 524 ml, P < 0.001), and 2 h (median 518 vs. 428 ml, P < 0.02), in contrast to similar volumes at 3 h (median 320 vs. 314 ml, P = 0.85). Analysis of SPECT imaging accurately measures gastric emptying compared with planar imaging with median differences of 1% (IQR -2.25 to 2.0) at 1 h, 1% (-3.25 to 2.25) at 2 h, and -2.5% (-4 to 0) at 3 h. Gastric volume exceeds meal volume during the first 2 postprandial hours, and simultaneous measurements of gastric volume and emptying can be achieved with a novel 3D SPECT method.

Contributions of gastric volumes and gastric emptying to meal size and postmeal symptoms in functional dyspepsia.

BACKGROUND & AIMS: The aim was to assess relative contributions of gastric volumes (GV) and gastric emptying (GE) to meal size and postprandial symptoms in patients with functional dyspepsia. METHODS: Patients with chronic upper gastrointestinal symptoms were prospectively evaluated. GV during fasting and after 300 mL Ensure was measured with 99m Tc-single-photon emission computed tomography imaging and solid GE (99m Tc-egg) by scintigraphy. Maximum tolerated volume (MTV) and symptoms were measured after Ensure challenge. RESULTS: Of 57 adult patients evaluated, 39 (23 women, 16 men) met Rome II criteria for functional dyspepsia and had no other diagnosis to account for dyspepsia. The most frequent symptoms were abdominal pain (90%), pain predominantly after meals (76%), nausea (85%), and early fullness after meals (79%). Relative to established laboratory normal values, MTV was abnormal in 82%, aggregate symptom score >209 in 72%, GE (at 1 hour) accelerated in 41%, GE (at 4 hours) delayed in 41%, and postmeal GV reduced in 52%. Lower body mass was associated with lower MTV and higher postchallenge symptoms. Lower fasting (not postprandial) GV and faster GE were independent predictors of lower MTV, explaining 18% of the variance after adjusting for body weight (32% of variance). GE was an independent predictor of postchallenge symptoms (10% of variance) after adjusting for volume ingested (10%), age (20%), and weight (10%). CONCLUSIONS: In adults with functional dyspepsia seen in a tertiary referral practice, decreased meal size and postmeal symptoms are associated with low fasting GV and faster GE. These data provide physiologic targets for ameliorating symptoms of functional dyspepsia.

Selective effects of serotonergic psychoactive agents on gastrointestinal functions in health.

This study evaluated the effects of serotonergic psychoactive agents on gastrointestinal functions in healthy human subjects. Participants received one of four regimens in a randomized, double-blind manner: buspirone, a 5-HT(1A) receptor agonist (10 mg twice daily); paroxetine, a selective serotonin reuptake inhibitor (20 mg daily); venlafaxine-XR, a selective serotonin and norepinephrine reuptake inhibitor (75 mg daily); or placebo for 11 days. Physiological testing performed on days 8-11 included scintigraphic assessment of gastrointestinal and colonic transit, the nutrient drink test, and assessment of the postprandial change in gastric volume. Fifty-one healthy adults (40 females, 11 males) participated in this study. No effects on gastric emptying or colonic transit were identified with any agent. Small bowel transit of a solid meal was accelerated by paroxetine. Buspirone decreased postprandial aggregate symptom and nausea scores. Venlafaxine-XR increased the postprandial change in gastric volume. Buspirone, paroxetine, and venlafaxine-XR affect upper gastrointestinal functions in healthy humans. These data support the need for clinical and physiological studies of these agents in functional gastrointestinal disorders.

A community-based, controlled study of the epidemiology and pathophysiology of dyspepsia.

BACKGROUND & AIMS: Dyspepsia is common in clinical practice and in the community. The relationship of the symptoms to meals and the pathophysiology in community dyspeptic patients is unclear. The purpose of this study was to measure symptoms, demographic features, and gastric motor and sensory functions associated with dyspepsia in the community. METHODS: A Modified Bowel Disease Questionnaire was mailed to a random sample of Olmsted County, MN, residents. Dyspeptic patients and healthy controls identified among community respondents completed further questionnaires, Helicobacter pylori serology, gastric emptying by scintigraphy, gastric accommodation by 99mTc-single-photon emission computed tomography imaging, and postprandial symptoms and satiation by a nutrient drink test. RESULTS: A total of 34.1% of community respondents reported dyspepsia within the past year, frequent (at least 25% of the time in the past year) in 17.5%, and 18.4% reported meal-related dyspepsia. Dyspepsia was frequent and related to meals in 10.8% of respondents. Compared with nondyspeptic controls, community dyspepsia was associated with higher aggregate symptom scores and bloating after a fully satiating meal. Community dyspepsia also was associated with higher somatization scores (P = .001), reporting of other somatic symptoms (P = .07), and general severity score on the symptom checklist 90 (P = .01), but not with disordered motor or sensory function. Gastric volumes, gastric emptying, and maximum tolerated volumes were not significantly different between community controls and dyspeptic patients. CONCLUSIONS: Meal-related dyspepsia is an important component of dyspepsia in the community. Community dyspeptic patients have higher symptom scores after a fully satiating meal, consistent with gastric hypersensitivity. This is associated with higher somatization scores rather than disorders of gastric emptying or volumes.

Effect of oral CCK-1 agonist GI181771X on fasting and postprandial gastric functions in healthy volunteers.

CCK influences satiation and gastric and gallbladder emptying. GI181771X is a novel oral CCK-1 agonist; its effects on gastric emptying of solids, accommodation, and postprandial symptoms are unclear. Effects of four dose levels of the oral CCK-1 agonist GI181771X and placebo on gastric functions and postprandial symptoms were compared in 61 healthy men and women in a randomized, gender-stratified, double-blind, double-dummy placebo-controlled, parallel group study. Effects of 0.1, 0.5, and 1.5 mg of oral solution and a 5.0-mg tablet of GI181771X on gastric emptying of solids by scintigraphy, gastric volume by (99m)Tc-single photon emission computed tomographic imaging, maximum tolerated volume of Ensure, and postprandial nausea, bloating, fullness, and pain were studied. On each of 3 study days, participants received their randomly assigned treatment. Adverse effects and safety were monitored. There were overall group effects of GI181771X on gastric emptying (P < 0.01) and fasting and postprandial volumes (P = 0.036 and 0.015, respectively). The 1.5-mg oral solution of GI181771X significantly delayed gastric emptying of solids (P < 0.01) and increased fasting (P = 0.035) gastric volumes without altering postprandial (P = 0.056) gastric volumes or postprandial symptoms relative to placebo. The effect of the 5.0-mg tablet on gastric emptying of solids did not reach significance (P = 0.052). Pharmacokinetic profiles showed the highest area under the curve over 4 h for the 1.5-mg solution and a similar area under the curve for the 0.5-mg solution and 5-mg tablet. Adverse effects were predominantly gastrointestinal and occurred in a minority of participants. GI181771X delays gastric emptying of solids and exhibits an acceptable safety profile in healthy participants. CCK-1 receptors can be modulated to increase fasting gastric volume.

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

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 (99m)Tc-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.