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BACKGROUND: Glucagon-like peptide 1 (GLP-1) contributes to satiety and plays a pivotal role in insulin secretion and glucose homeostasis. Similar to GLP-1, peptide YY (PYY) and cholecystokinin also influence food intake. The secretion of these hormones by enteroendocrine cells along the intestine is modulated by nutrients. Preparations from the Stevia rebaudiana plant, including rebaudioside A, are increasingly being used as noncaloric sweeteners. OBJECTIVE: We investigated the effects of rebaudioside A on enteroendocrine cells by assessing both cell numbers as well as their secretory capacity in an organoid model. METHODS: A 2-dimensional organoid model derived from duodenal, jejunal, and ileal crypts of a C57BL/6J mouse was developed and characterized with the use of gene expression and immunofluorescence. We stimulated these organoids with 10 mmol/L rebaudioside A for 1 h and measured their GLP-1, PYY, and cholecystokinin release. We also analyzed the effects of rebaudioside A on gene expression in enteroendocrine cells after an 18-h incubation. RESULTS: The 2-dimensional organoids contained crypt cells and differentiated villus cells, including enterocytes and goblet and enteroendocrine cells. These enteroendocrine cells stained positive for GLP-1, PYY, and serotonin. The cultured 2-dimensional organoids maintained their location-specific gene expression patterns. Compared with the control, rebaudioside A induced GLP-1 secretion 1.7-fold in the duodenum (P < 0.01), 2.2-fold in the jejunum (P < 0.01), and 4.3-fold in the ileum (P < 0.001). PYY release was increased by rebaudioside A 3-fold in the ileum compared with the control (P < 0.05). Long-term (18-h) stimulation with the sweetener induced the expression of the enteroendocrine-specific markers chromogranin A, glucagon, Pyy, and cholecystokinin 3.5- (P < 0.001), 3.5- (P < 0.001), 3.8- (P < 0.05), and 6.5-fold (P < 0.001), respectively. CONCLUSIONS: These results show novel ex vivo effects of rebaudioside A on enteroendocrine cells of the mouse small intestine and highlight potentially new applications for rebaudioside A in metabolic diseases.

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BACKGROUND: Taste receptors are expressed not only in taste buds but also in the gastrointestinal tract. It has been hypothesized that these receptors may play a role in satiety and food intake. OBJECTIVE: This study investigated the effect of intraduodenal tastant infusions (bitter, sweet, and umami) on food intake, hunger and fullness, gastrointestinal symptoms, and gastrointestinal peptide release. DESIGN: Fifteen healthy volunteers [6 male; mean ± SEM age: 23.9 ± 2.0 y; mean ± SEM body mass index (in kg/m(2)): 22.4 ± 0.3] received 5 treatments in a double-blind, randomized, placebo-controlled crossover design. Test days started with the insertion of a nasoduodenal catheter followed by a standardized liquid breakfast. Participants received an intraduodenal infusion 150 min after breakfast, containing quinine (bitter), rebaudioside A (sweet), monosodium glutamate (umami), a combination of the 3 tastants, or placebo (tap water) over a period of 60 min. Food intake was measured during an ad libitum meal, and visual analog scales were used to monitor gastrointestinal complaints and hunger and fullness scores. Blood samples were drawn at regular intervals for cholecystokinin, glucagon-like peptide 1 (GLP-1), and peptide YY (PYY) analysis. RESULTS: Infusion of the combination of tastants substantially decreased food intake (422 ± 97 compared with 486 ± 104 kcal for placebo, P < 0.05), whereas both a combination of tastants and umami decreased hunger scores compared with placebo. No change in cholecystokinin, GLP-1, or PYY concentrations was observed during the infusions. Intraduodenal infusions of the tastants did not result in gastrointestinal symptoms. CONCLUSIONS: Intraduodenal infusion of umami and a combination of tastants inhibits feelings of hunger, but only the latter also reduces food intake. However, these alterations were not accompanied by changes in the plasma concentrations of the gut-derived peptides cholecystokinin, GLP-1, or PYY. This trial was registered at clinicaltrials.gov as NCT01956838.

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BACKGROUND: In-silico models that attempt to capture and describe the physiological behavior of biological organisms, including humans, are intrinsically complex and time consuming to build and simulate in a computing environment. The level of detail of description incorporated in the model depends on the knowledge of the system's behavior at that level. This knowledge is gathered from the literature and/or improved by knowledge obtained from new experiments. Thus model development is an iterative developmental procedure. The objective of this paper is to describe a new plug and play scheme that offers increased flexibility and ease-of-use for modeling and simulating physiological behavior of biological organisms. METHODS: This scheme requires the modeler (user) first to supply the structure of the interacting components and experimental data in a tabular format. The behavior of the components described in a mathematical form, also provided by the modeler, is externally linked during simulation. The advantage of the plug and play scheme for modeling is that it requires less programming effort and can be quickly adapted to newer modeling requirements while also paving the way for dynamic model building. RESULTS: As an illustration, the paper models the dynamics of gastric emptying behavior experienced by humans. The flexibility to adapt the model to predict the gastric emptying behavior under varying types of nutrient infusion in the intestine (ileum) is demonstrated. The predictions were verified with a human intervention study. The error in predicting the half emptying time was found to be less than 6%. CONCLUSIONS: A new plug-and-play scheme for biological systems modeling was developed that allows changes to the modeled structure and behavior with reduced programming effort, by abstracting the biological system into a network of smaller sub-systems with independent behavior. In the new scheme, the modeling and simulation becomes an automatic machine readable and executable task.

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BACKGROUND: Fetuin-A, a liver-derived glycoprotein that impairs insulin-signalling, has emerged as a biomarker for diabetes risk. Although moderate alcohol consumption has been inversely associated with fetuin-A, data from clinical trials are lacking. Thus, we evaluated whether moderate alcohol consumption decreases circulating levels of fetuin-A. METHODS: We analyzed data of three separate open-label, randomized, crossover trials: 1) 36 postmenopausal women consuming 250 ml white wine (25 g alcohol) or white grape juice daily for 6 weeks, 2) 24 premenopausal women consuming 660 ml beer (26 g alcohol) or alcohol-free beer daily for 3 weeks, and 3) 24 young men consuming 100 ml vodka (30 g alcohol) orange juice or only orange juice daily for 4 weeks. After each treatment period fasting blood samples were collected. RESULTS: Circulating fetuin-A concentrations decreased in men after vodka consumption (Mean ± SEM: 441 ± 11 to 426 ± 11 µg/ml, p = 0.02), but not in women after wine (448 ± 17 to 437 ± 17 µg/ml, p = 0.16) or beer consumption (498 ± 15 to 492 ± 15 µg/ml, p = 0.48) compared to levels after each corresponding alcohol-free treatment. Post-hoc power analyses indicated that the statistical power to detect a similar effect as observed in men was 30% among the postmenopausal women and 31% among the premenopausal women. CONCLUSIONS: In these randomized crossover trials, moderate alcohol consumption decreased fetuin-A in men but not in women. This sex-specific effect may be explained by the relatively short intervention periods or the low statistical power in the trials among women. TRIALS REGISTRATION: ClinicalTrials.gov ID no's: NCT00285909, NCT00524550, NCT00918918.

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N-acylethanolamines (NAEs), such as anandamide (AEA), are a group of endogenous lipids derived from a fatty acid linked to ethanolamine and have a wide range of biological activities, including regulation of metabolism and food intake. We hypothesized that i) NAE plasma levels are associated with levels of total free fatty acids (FFAs) and their precursor fatty acid in fasting and non-fasting conditions and ii) moderate alcohol consumption alters non-fasting NAE levels. In a fasting and non-fasting study we sampled blood for measurements of specific NAEs and FFAs. In the fasting study blood was drawn after an overnight fast in 22 postmenopausal women. In the non-fasting study blood was sampled before and frequently after a standardized lunch with beer or alcohol-free beer in 19 premenopausal women. Fasting AEA levels correlated with total FFAs (r = 0.84; p < 0.001) and arachidonic acid levels (r = 0.42; p < 0.05). Similar results were observed for other NAEs with both total FFAs and their corresponding fatty acid precursors. In addition, AEA (r = 0.66; p < 0.01) and OEA levels (r = 0.49; p <0.02) positively related with BMI. Changes over time in non-fasting AEA levels were correlated with changes in total FFA levels, both after a lunch with beer (r = 0.80; 95% confidence interval: 0.54-0.92) and alcohol-free beer (r = 0.73; 0.41-0.89). Comparable correlations were found for other NAEs, without differences in correlations of each NAE between beer and alcohol free beer with lunch. In conclusion, i) in fasting and non-fasting states circulating anandamide and other N-acylethanolamines were associated with free fatty acid levels and ii) moderate alcohol consumption does not affect non-fasting NAE levels. This suggests that similar physiological stimuli cause the release of plasma N-acylethanolamines and free fatty acids in blood. The trials are registered at ClinicalTrials.gov numbers: NCT00524550 and NCT00652405.

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BACKGROUND: Low-grade chronic inflammation in overweight subjects is thought to play an important role in disease development. OBJECTIVE: It was hypothesized that specific dietary components are able to reduce low-grade inflammation as well as metabolic and oxidative stress. DESIGN: Dietary products [resveratrol, green tea extract, alpha-tocopherol, vitamin C, n-3 (omega-3) polyunsaturated fatty acids, and tomato extract] selected for their evidence-based antiinflammatory properties were combined and given as supplements to 36 healthy overweight men with mildly elevated plasma C-reactive protein concentrations in a double-blind, placebo-controlled, crossover study with treatment periods of 5 wk. Inflammatory and oxidative stress defense markers were quantified in plasma and urine. Furthermore, 120 plasma proteins, 274 plasma metabolites (lipids, free fatty acids, and polar compounds), and the transcriptomes of peripheral blood mononuclear cells and adipose tissue were quantified. RESULTS: Plasma adiponectin concentrations increased by 7%, whereas C-reactive protein (principal inflammation marker) was unchanged. However, a multitude of subtle changes were detected by an integrated analysis of the "omics" data, which indicated modulated inflammation of adipose tissue, improved endothelial function, affected oxidative stress, and increased liver fatty acid oxidation. CONCLUSION: An intervention with selected dietary products affected inflammatory processes, oxidative stress, and metabolism in humans, as shown by large-scale profiling of genes, proteins, and metabolites in plasma, urine, and adipose tissue. This trial was registered at clinical trials.gov as NCT00655798.

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