Transgenerational transmission of aspartame-induced anxiety and changes in glutamate-GABA signaling and gene expression in the amygdala.

We report the effects of aspartame on anxiety-like behavior, neurotransmitter signaling and gene expression in the amygdala, a brain region associated with the regulation of anxiety and fear responses. C57BL/6 mice consumed drinking water containing 0.015% or 0.03% aspartame, a dose equivalent of 8 to 15% of the FDA recommended maximum human daily intake, or plain drinking water. Robust anxiety-like behavior (evaluated using open field test and elevated zero maze) was observed in male and female mice consuming the aspartame-containing water. Diazepam, an allosteric modulator of the GABA-A receptor, alleviated the anxiety-like behavior. RNA sequencing of the amygdala followed by KEGG biological pathway analysis of differentially expressed genes showed glutamatergic and GABAergic synapse pathways as significantly enriched. Quantitative PCR showed upregulation of mRNA for the glutamate NMDA receptor subunit 2D (Grin2d) and metabotropic receptor 4 (Grm4) and downregulation of the GABA-A receptor associated protein (Gabarap) mRNA. Thus, taken together, our diazepam and gene expression data show that aspartame consumption shifted the excitation-inhibition equilibrium in the amygdala toward excitation. Even more strikingly, the anxiety-like behavior, its response to diazepam, and changes in amygdala gene expression were transmitted to male and female offspring in two generations descending from the aspartame-exposed males. Extrapolation of the findings to humans suggests that aspartame consumption at doses below the FDA recommended maximum daily intake may produce neurobehavioral changes in aspartame-consuming individuals and their descendants. Thus, human population at risk of aspartame's potential mental health effects may be larger than current expectations, which only include aspartame-consuming individuals.

Xylitol is prothrombotic and associated with cardiovascular risk.

BACKGROUND AND AIMS: The pathways and metabolites that contribute to residual cardiovascular disease risks are unclear. Low-calorie sweeteners are widely used sugar substitutes in processed foods with presumed health benefits. Many low-calorie sweeteners are sugar alcohols that also are produced endogenously, albeit at levels over 1000-fold lower than observed following consumption as a sugar substitute. METHODS: Untargeted metabolomics studies were performed on overnight fasting plasma samples in a discovery cohort (n = 1157) of sequential stable subjects undergoing elective diagnostic cardiac evaluations; subsequent stable isotope dilution liquid chromatography tandem mass spectrometry (LC-MS/MS) analyses were performed on an independent, non-overlapping validation cohort (n = 2149). Complementary isolated human platelet, platelet-rich plasma, whole blood, and animal model studies examined the effect of xylitol on platelet responsiveness and thrombus formation in vivo. Finally, an intervention study was performed to assess the effects of xylitol consumption on platelet function in healthy volunteers (n = 10). RESULTS: In initial untargeted metabolomics studies (discovery cohort), circulating levels of a polyol tentatively assigned as xylitol were associated with incident (3-year) major adverse cardiovascular event (MACE) risk. Subsequent stable isotope dilution LC-MS/MS analyses (validation cohort) specific for xylitol (and not its structural isomers) confirmed its association with incident MACE risk [third vs. first tertile adjusted hazard ratio (95% confidence interval), 1.57 (1.12-2.21), P < .01]. Complementary mechanistic studies showed xylitol-enhanced multiple indices of platelet reactivity and in vivo thrombosis formation at levels observed in fasting plasma. In interventional studies, consumption of a xylitol-sweetened drink markedly raised plasma levels and enhanced multiple functional measures of platelet responsiveness in all subjects. CONCLUSIONS: Xylitol is associated with incident MACE risk. Moreover, xylitol both enhanced platelet reactivity and thrombosis potential in vivo. Further studies examining the cardiovascular safety of xylitol are warranted.

Acesulfame potassium upregulates PD-L1 in HCC cells by attenuating autophagic degradation.

Artificial sweeteners, which contain no or few calories, have been widely used in various foods and beverages, and are regarded as safe alternatives to sugar by the Food and Drug Administration. While several studies suggest that artificial sweeteners are not related to cancer development, some research has reported their potential association with the risk of cancers, including hepatocellular carcinoma (HCC). Here, we investigated whether acesulfame potassium (Ace K), a commonly used artificial sweetener, induces immune evasion of HCC cells by upregulating programmed death ligand-1 (PD-L1). Ace K elevated the protein levels of PD-L1 in HCC cells without increasing its mRNA levels. The upregulation of PD-L1 protein levels in HCC cells by Ace K was induced by attenuated autophagic degradation of PD-L1, which was mediated by the Ace K-stimulated ERK1/2-mTORC1 signaling pathway. Ace K-induced upregulation of PD-L1 attenuated T cell-mediated death of HCC cells, thereby promoting immune evasion of HCC cells. In summary, the present study suggests that Ace K promotes HCC progression by upregulating the PD-L1 protein level.

Associations of artificial sweetener intake with cardiometabolic disorders and mortality: a population-based study.

Artificial sweeteners are generally used and recommended to alternate added sugar for health promotion. However, the health effects of artificial sweeteners remain unclear. In this study, we included 6371 participants from the National Health and Nutrition Examination Survey with artificial sweetener intake records. Logistic regression and Cox regression were applied to explore the associations between artificial sweeteners and risks of cardiometabolic disorders and mortality. Mendelian randomisation was performed to verify the causal associations. We observed that participants with higher consumption of artificial sweeteners were more likely to be female and older and have above medium socio-economic status. After multivariable adjustment, frequent consumers presented the OR (95 % CI) for hypertension (1·52 (1·29, 1·80)), hypercholesterolaemia (1·28 (1·10, 1·50)), diabetes (3·74 (3·06, 4·57)), obesity (1·52 (1·29, 1·80)), congestive heart failure (1·89 (1·35, 2·62)) and heart attack (1·51 (1·10, 2·04)). Mendelian randomisation confirmed the increased risks of hypertension and type 2 diabetes. Moreover, an increased risk of diabetic mortality was identified in participants who had artificial sweeteners ≥ 1 daily (HR = 2·62 (1·46, 4·69), P = 0·001). Higher consumption of artificial sweeteners is associated with increased risks of cardiometabolic disorders and diabetic mortality. These results suggest that using artificial sweeteners as sugar substitutes may not be beneficial.

Association of coffee consumption with cardiometabolic multimorbidity: A prospective cohort study in the UK biobank.

BACKGROUND AND AIMS: Previous observational studies have investigated the association between coffee consumption and single cardiometabolic disease. Yet, the extent to which coffee might confer health advantages to individuals with a singular cardiometabolic disease remains unclear. This study aimed to further investigate the association of coffee consumption and the onset and progression from single cardiometabolic disease to cardiometabolic multimorbidity (CMM). METHODS AND RESULTS: This prospective cohort study included 185,112 participants from the UK Biobank who were enrolled between 2006 and 2010 and followed up until 2020. Coffee consumption was collected using a 24-h dietary questionnaire. CMM was defined as the coexistence of at least two cardiometabolic diseases, including type 2 diabetes (T2D), coronary heart disease (CHD) and stroke. Cox proportional hazards and multi-state models estimated the associations between coffee consumption and CMM. During a median follow-up of 11.4 years, 1585 participants developed CMM. Compared with nonconsumers, coffee consumers had lower risks for the transitions from baseline to single cardiometabolic disease, with the respective lowest hazard ratios and 95% confidence intervals (CIs) for the transitions from baseline to T2D, CHD and stroke after multivariable adjustment being 0.79 (CI, 0.72-0.87), 0.91 (CI, 0.86-0.97) and 0.87 (CI, 0.78-0.96). Coffee consumption resulted in a significant reduction in the risk of the transitions from CHD and stroke to CMM, with the lowest estimates were 0.56 (CI, 0.43-0.73) and 0.60 (CI, 0.43-0.83). Similar associations were observed in unsweetened coffee. Sugar-sweetened coffee was associated with some transitions at low levels of consumption. The associations between artificially sweetened coffee and CMM were less consistent. CONCLUSIONS: Coffee consumption was associated with lower risk for almost all transition phases of CMM development and consistent findings were observed with unsweetened coffee.

Association between low-calorie sweetener consumption during pregnancy and child health: A systematic review and meta-analysis.

We examined the association between low-calorie sweeteners (LCS) consumption during preconception, pregnancy, and breastfeeding and child health outcomes. A systematic search of electronic databases in PubMed, Embase, Cumulated Index to Nursing and Allied Health Literature, the Cochrane Library, Scopus, Web of Science, PsycINFO, ProQuest Health and Medical, ClinicalTrials.gov, and Google Scholar was conducted up to 21 September 2023. A random effects model with restricted maximum likelihood estimation was used for the meta-analysis. Seventeen eligible studies were included. The standardised mean difference (SMD) and 95% confidence interval (CI) in birth weight between those who frequently consumed LCS (≥1 serve/day) during pregnancy and those who did not consume LCS was 0.04 (0.00, 0.08) (four cohort studies). Any LCS consumption during pregnancy compared with no consumption was not associated with birth weight [SMD (95% CI) = 0.03 (-0.03, 0.08)] (four cohort studies). Any LCS consumption during pregnancy was not associated with body mass index z-scores. The weighted mean difference (95% CI) was 0.00 (-0.05, 0.06) at birth, 0.06 (-0.29, 0.40) at 6 months, -0.04 (-0.19, 0.10) at 1 year, 0.00 (-0.16, 0.17) at 3 years, and 0.10 (-0.15, 0.34) at 7 years of the child age, compared with no intake (five cohort studies). The odds of being overweight at 1 year among children exposed to LCS during pregnancy was 1.19 (OR [95% CI]: 1.19 [0.81, 1.58]) compared with unexposed children (two cohort studies). The effect sizes were not precise for all the outcomes as the 95% CI indicated the effect estimates could range from small protective to a higher risk. The effect of LCS consumption on child behaviour and cognition was inconsistent. There is not enough evidence to confirm LCS consumption during pregnancy affects birth weight and risk of overweight in children. However, frequent consumption increased birth weight and the risk of overweight at different ages, though the effects were imprecise. More robust research evidence is required as the quality of evidence is low.

Benchmarking the Persistence of Active Pharmaceutical Ingredients in River Systems.

Assessing the persistence of organic micropollutants from field data has been notoriously laborious, requiring extensive data including emissions and chemical properties, and the application of detailed mass-balance models, which often contain parameters that are impossible to measure. To overcome some of these obstacles, we developed the concept of persistence benchmarking for large rivers that receive numerous emissions and provide enough residence time to observe the dissipation of compounds. We estimated the dissipation rate constants of 41 compounds (mostly active pharmaceutical ingredients) from five measurement campaigns in the Rhine and Danube rivers using concentration rate profiles with respect to carbamazepine. Dissipation rates clearly distinguished between known fast- and slow-degrading compounds, and campaign-specific boundary conditions had an influence on a minor subset of compounds only. Benchmarking provided reasonable estimates on summer total system half-lives in the Rhine compared to previous laboratory experiments and a mass-balance modeling study. Consequently, benchmarking can be a straightforward persistence assessment method of continuously emitted organic micropollutants in large river systems, especially when it is supported by field monitoring campaigns of proper analytical quality and spatial resolution.

Prolonged Consumption of Sweetened Beverages Lastingly Deteriorates Cognitive Functions and Reward Processing in Mice.

We investigated the detrimental effects of chronic consumption of sweet or sweetened beverages in mice. We report that consumption of beverages containing small amounts of sucrose during several weeks impaired reward systems. This is evidenced by robust changes in the activation pattern of prefrontal brain regions associated with abnormal risk-taking and delayed establishment of decision-making strategy. Supporting these findings, we find that chronic consumption of low doses of artificial sweeteners such as saccharin disrupts brain regions' activity engaged in decision-making and reward processes. Consequently, this leads to the rapid development of inflexible decisions, particularly in a subset of vulnerable individuals. Our data also reveal that regular consumption, even at low doses, of sweet or sweeteners dramatically alters brain neurochemistry, i.e., dopamine content and turnover, and high cognitive functions, while sparing metabolic regulations. Our findings suggest that it would be relevant to focus on long-term consequences on the brain of sweet or sweetened beverages in humans, especially as they may go metabolically unnoticed.

Comparison of aspartame- and sugar-sweetened soft drinks on postprandial metabolism.

Aim: We compared the impact of artificially- and sugar-sweetened beverages co-ingested with a mixed meal on postprandial fat and carbohydrate oxidation, blood glucose, and plasma insulin and triglyceride concentrations. Methods: Eight college-aged, healthy males completed three randomly assigned trials, which consisted of a mixed macronutrient meal test with 20oz of Diet-Coke (AS), Coca-Cola (NS), or water (CON). One week separated each trial and each participant served as his own control. Resting energy expenditure (REE) via indirect calorimetry, blood pressure, and blood samples were obtained immediately before, 5, 10, 30, 60, 120, and 180 min after meal and beverage ingestion. A two-way (treatment × time) repeated-measures ANOVA was conducted to assess REE, fat and carbohydrate oxidation rates, blood glucose, and plasma insulin and triglyceride concentrations. Results: There was a significant main effect of treatment on total fat oxidation (P = 0.006), fat oxidation was significantly higher after AS (P = 0.006) and CON (P = 0.001) compared to following NS. There was a significant main effect of treatment on total carbohydrate oxidation (P = 0.005), carbohydrate oxidation was significantly lower after AS (P = 0.014) and CON (P = 0.001) compared to following NS. Plasma insulin concentration AUC was significantly lower after AS (P = 0.019) and trended lower in CON (P = 0.054) compared to following NS. Conclusion: Ingestion of a mixed meal with an artificially-sweetened beverage does not impact postprandial metabolism, whereas a sugar-sweetened beverage suppresses fat oxidation and increases carbohydrate oxidation compared to artificially-sweetened beverage and water.

Impact of Long-Term Cyclamate and Saccharin Consumption on Biochemical Parameters in Healthy Individuals and Type 2 Diabetes Mellitus Patients.

BACKGROUND: Previous studies on saccharin and cyclamate were either limited to experimental animals or lacked evaluation of their long-term consumption effects in humans. OBJECTIVES: This study evaluated the effect of chronic consumption of saccharin and cyclamate on biochemical parameters in healthy individuals and patients with type 2 diabetes mellitus. MATERIAL AND METHODS: Healthy and diabetic individuals were classified into two groups based on whether they consumed sweeteners or not. The participants were classified according to the amount of sweetener consumed per day and duration of consumption. Serum catalase activity, peroxynitrite, ceruloplasmin, and malondialdehyde concentrations were determined. Glycated hemoglobin, fasting glucose, creatinine, alanine transaminase, and lipid profile were also evaluated. The results suggest that saccharin and cyclamate increased HbA1C (+11.16%), MDA (+52.38%), TG (+16.74%), LDL (+13.39%), and TC/HDL (+13.11%) in healthy volunteers. Diabetic patients consuming sweeteners showed increased FSG (+17.51%), ceruloplasmin (+13.17%), and MDA (+8.92%). Diabetic patients showed a positive correlation between the number of tablets consumed per day with FSG and serum creatinine. A positive correlation was found between the duration of sweetener consumption and FSG as well as TG. CONCLUSION: Consumption of saccharin and cyclamate affected biochemical parameters related to metabolic functions in a time and dose-dependent manner and appear to increase oxidative stress in healthy and diabetic type 2 patients.

Acesulfame potassium induces dysbiosis and intestinal injury with enhanced lymphocyte migration to intestinal mucosa.

BACKGROUND AND AIM: The artificial sweetener acesulfame potassium (ACK) is officially approved as safe for intake and has been used in processed foods. However, ACKs have been reported to induce metabolic syndrome, along with alteration of the gut microbiota in mice. In recent years, studies have suggested that this artificial sweetener promotes myeloperoxidase reactivity in Crohn's disease-like ileitis. We aimed to investigate the effect of ACK on the intestinal mucosa and gut microbiota of normal mice. METHODS: Acesulfame potassium was administered to C57BL/6J mice (8 weeks old) via free drinking. Intestinal damage was evaluated histologically, and messenger RNA (mRNA) levels of TNF-α, IFN-γ, IL1-ß, MAdCAM-1, GLP1R, and GLP2R were determined with quantitative reverse transcription polymerase chain reaction (qRT-PCR). Immunohistochemistry was performed to examine the expression of MAdCAM-1 in the small intestine. The composition of gut microbiota was assessed using high-throughput sequencing. We performed intravital microscopic observation to examine if ACK altered lymphocyte migration to the intestinal microvessels. RESULTS: Acesulfame potassium increased the expression of proinflammatory cytokines, decreased the expression of GLP-1R and GLP-2R, and induced small intestinal injury with an increase in intestinal permeability, and ACK treatment induced microbial changes, but the transfer of feces alone from ACK mice did not reproduce intestinal damage in recipient mice. ACK treatment significantly increased the migration of lymphocytes to intestinal microvessels. CONCLUSION: Acesulfame potassium induces dysbiosis and intestinal injury with enhanced lymphocyte migration to intestinal mucosa. Massive use of non-caloric artificial sweeteners may not be as safe as we think.

Aspartame and cancer - new evidence for causation.

BACKGROUND: Aspartame is one of the world's most widely used artificial sweeteners and is an ingredient in more than 5000 food products globally. A particularly important use is in low-calorie beverages consumed by children and pregnant women. The Ramazzini Institute (RI) reported in 2006 and 2007 that aspartame causes dose-related increases in malignant tumors in multiple organs in rats and mice. Increased cancer risk was seen even at low exposure levels approaching the Acceptable Daily Intake (ADI). Prenatal exposures caused increased malignancies in rodent offspring at lower doses than in adults. These findings generated intense controversy focused on the accuracy of RI's diagnoses of hematopoietic and lymphoid tissue tumors (HLTs). Critics made the claim that pulmonary lesions observed in aspartame-exposed animals were inflammatory lesions caused by Mycoplasma infection rather than malignant neoplasms. METHODS: To address this question, RI subjected all HLTs from aspartame-exposed animals to immunohistochemical analysis using a battery of markers and to morphological reassessment using the most recent Internationally Harmonized Nomenclature and Diagnostic (INHAND) criteria. FINDINGS: This immunohistochemical and morphological re-evaluation confirmed the original diagnoses of malignancy in 92.3% of cases. Six lesions originally diagnosed as lymphoma (8% of all HLTs) were reclassified: 3 to lymphoid hyperplasia, and 3 to chronic inflammation with fibrosis. There was no evidence of Mycoplasma infection. INTERPRETATION: These new findings confirm that aspartame is a chemical carcinogen in rodents. They confirm the very worrisome finding that prenatal exposure to aspartame increases cancer risk in rodent offspring. They validate the conclusions of the original RI studies. These findings are of great importance for public health. In light of them, we encourage all national and international public health agencies to urgently reexamine their assessments of aspartame's health risks - especially the risks of prenatal and early postnatal exposures. We call upon food agencies to reassess Acceptable Daily Intake (ADI) levels for aspartame. We note that an Advisory Group to the International Agency for Research on Cancer has recommended high-priority reevaluation of aspartame's carcinogenicity to humans.

Degradation of the low-calorie sugar substitute 5-ketofructose by different bacteria.

There is an increasing public awareness about the danger of dietary sugars with respect to their caloric contribution to the diet and the rise of overweight throughout the world. Therefore, low-calorie sugar substitutes are of high interest to replace sugar in foods and beverages. A promising alternative to natural sugars and artificial sweeteners is the fructose derivative 5-keto-D-fructose (5-KF), which is produced by several Gluconobacter species. A prerequisite before 5-KF can be used as a sweetener is to test whether the compound is degradable by microorganisms and whether it is metabolized by the human microbiota. We identified different environmental bacteria (Tatumella morbirosei, Gluconobacter japonicus LMG 26773, Gluconobacter japonicus LMG 1281, and Clostridium pasteurianum) that were able to grow with 5-KF as a substrate. Furthermore, Gluconobacter oxydans 621H could use 5-KF as a carbon and energy source in the stationary growth phase. The enzymes involved in the utilization of 5-KF were heterologously overproduced in Escherichia coli, purified and characterized. The enzymes were referred to as 5-KF reductases and belong to three unrelated enzymatic classes with highly different amino acid sequences, activities, and structural properties. Furthermore, we could show that 15 members of the most common and abundant intestinal bacteria cannot degrade 5-KF, indicating that this sugar derivative is not a suitable growth substrate for prokaryotes in the human intestine. KEY POINTS: • Some environmental bacteria are able to use 5-KF as an energy and carbon source. • Four 5-KF reductases were identified, belonging to three different protein families. • Many gut bacteria cannot degrade 5-KF.

Acute diet soda consumption alters brain responses to food cues in humans: A randomized, controlled, cross-over pilot study.

BACKGROUND: Diet soda consumption has frequently been linked to obesity and its comorbidities in epidemiological studies. Whether this link is causal and a potential mechanism remains to be determined. AIM/METHODS: This randomized, cross-over, controlled pilot study sought to determine whether there may be changes in reward-related brain activations to visual food cues after acute consumption of diet soda versus regular soda or carbonated water using functional magnetic resonance imaging. RESULTS: Diet soda as compared to carbonated water consumption increased activation of reward-related caudate to highly versus less desirable food cues. Diet soda as compared to regular soda increased reward-related insula and decreased activation of cognitive control-related dorsolateral prefrontal cortex to food cues versus non-food cues. No changes in ratings of hunger an hour after beverage consumption were observed. CONCLUSIONS: These results may suggest a potential mechanism for diet soda to increase food palatability through activation of the reward system and suppression of inhibitory control that remains to be confirmed by future studies.

Performance of ultraviolet/persulfate process in degrading artificial sweetener acesulfame.

The degradation of the artificial sweetener acesulfame (ACE) was investigated using an ultraviolet (UV)365-activated peroxydisulfate (PDS) process. The results demonstrated that the ACE reaction rate with the UV/PDS process followed pseudo first-order kinetics (R2 > 0.9) under various conditions. A high dosage of PDS, alkaline condition, and the existence of NO3- and Cl- enhanced ACE degradation; however, a high dosage of ACE, the existence of HCO3-, humic acid, and fulvic acid, and a real water matrix did not facilitate the degradation of ACE. Four types of transformation products were detected in the degradation of ACE by UV/PDS, and the primary degradation pathways were oxidation, hydroxyl substitution, hydrolysis, and hydration. The hydroxyl radicals played a predominant role (71.31%) in the degradation of ACE by the UV/PDS process, followed by sulfate radicals (14.57%) and UV photolysis (8.83%). Both the degradation and mineralization rates of ACE using the UV/PDS process had significant advantages over that of the UV/H2O2 process regarding ACE degradation, indicating that the UV/PDS process is more promising for treating water containing ACE.

Health benefits of xylitol.

Many diseases, including caries, chronic inflammatory diseases, diabetes, and obesity, are associated with uncontrolled sugar consumption. Artificial sweeteners are commonly used in food and pharmaceutical industries as sugar substitutes for the prevention of several dental and body diseases; they also have a favorable impact on body weight as they may help to restrict simple sugar consumption. Xylitol is a sugar alcohol that is commonly used as a sweetener. It can be found naturally or artificially prepared mainly from plant materials chemically or by fermentation of hemicelluloses from agricultural biomass by yeast or bacteria strains. This polyol has a significant antiplaque effect on teeth surface and can reduce the gingival inflammation; it is being used as a preventive agent for dental caries due to decreasing the growth levels of pathogenic Streptococcus mutans and Streptococcus sangui at the very early stages. Xylitol can bind with calcium ion leading to consequent remineralization of teeth enamel; it is also able to prevent osteoporosis. This polyol can treat respiratory tract and middle ear diseases due to its antibacterial and anti-inflammatory potential and prevent some diseases which cannot be cured through antibiotics or surgery. Xylitol can reduce constipation, diabetes, obesity, and other body syndromes or illnesses; it has also revealed its stimulating effect on digestion and immune system. However, it can produce some side effects such as irritable bowel syndrome, diarrhea, nephrolithiasis, etc., when consumed in excessive amounts. Different vehicles are used for delivering the xylitol into the human body, but chewing gums occupy a leading position. The present review is devoted to comprehensive analyses of the positive and negative effects of this polyol on human health.Key Points• The health benefits of xylitol are not limited to oral hygiene.• Xylitol efficiently stimulates the immune system, digestion, lipid and bone metabolism.• Xylitol helps in glycemic and obesity control; reduces ear and respiratory infections.• Xylitol treats diseases that cannot be cured through antibiotics or by surgery.

The Structural Signs of Sweetness in Artificial Sweeteners: A Rotational Study of Sorbitol and Dulcitol.

A gas-phase study on the artificial sweeteners sorbitol and dulcitol has been carried out for the first time by using a combination of chirped-pulse Fourier-transform microwave (CP-FTMW) spectroscopy and laser ablation (LA). The isolation conditions provided by the supersonic expansion reveal the intrinsic conformational structures of these sweeteners. The three and five observed conformers for sorbitol and dulcitol, respectively, are stabilized by networks of cooperative intramolecular hydrogen bonds between vicinal hydroxyl groups in clockwise or counterclockwise arrangements. Suitable places in the structure of seven out of eight conformers identified for both polyalcohols meet the requirements of the glucophore proposed by Shallenberger and Acree's molecular theory of sweet taste. Present results provide the first linkage between sweetness and structure in sugar alcohols.

A histological assessment of effects of sucralose on liver of albino rats.

OBJECTIVE OF THE STUDY: Sucralose is an artificial sweetener freely available under different brand names over the counter. This study is aimed at evaluating the histopathological changes in the liver after administration of sub lethal dose of pure sucralose. MATERIALS AND METHODS: Inbred adult Wistar albino rats weighing about 150-200g of either sex, were divided into 6 control rats and 6 experimental rats. Experimental rats were given sucralose orally by gavage in the dose of 3g/kg/day dissolved in distilled water for 30 days whereas Control rats received equal quantity of distilled water by the same route. The animals were anesthetized with anesthetic ether and then perfused with 10% formal saline. Livers were dissected out. Pieces each having thickness 5mm were taken for paraffin sectioning. 5 micron thick sections were cut using a rotary microtome. Hundred slides were made from each liver and stained with hematoxylin and eosin, periodic acid-schiff (PAS) and Masson's trichrome stain. Slides were evaluated for histomorphological changes. RESULTS: Experimental rats showed features of patchy degeneration of hepatocytes along with Kupffer cells hyperplasia, lymphocytic infiltration, sinusoidal dilatation and fibrosis indicating a definite hepatic damage on regular ingestion of sucralose. Sinusoidal width was also found to be increased in experimental animals as compared to controls. CONCLUSION: It is suggestive that sucralose should be taken with caution to avoid hepatic damage. Effects of ingestion of sucralose on human subjects should be investigated further.

Glucose elicits cephalic-phase insulin release in mice by activating KATP channels in taste cells.

The taste of sugar elicits cephalic-phase insulin release (CPIR), which limits the rise in blood glucose associated with meals. Little is known, however, about the gustatory mechanisms that trigger CPIR. We asked whether oral stimulation with any of the following taste stimuli elicited CPIR in mice: glucose, sucrose, maltose, fructose, Polycose, saccharin, sucralose, AceK, SC45647, or a nonmetabolizable sugar analog. The only taste stimuli that elicited CPIR were glucose and the glucose-containing saccharides (sucrose, maltose, Polycose). When we mixed an α-glucosidase inhibitor (acarbose) with the latter three saccharides, the mice no longer exhibited CPIR. This revealed that the carbohydrates were hydrolyzed in the mouth, and that the liberated glucose triggered CPIR. We also found that increasing the intensity or duration of oral glucose stimulation caused a corresponding increase in CPIR magnitude. To identify the components of the glucose-specific taste-signaling pathway, we examined the necessity of Calhm1, P2X2+P2X3, SGLT1, and Sur1. Among these proteins, only Sur1 was necessary for CPIR. Sur1 was not necessary, however, for taste-mediated attraction to sugars. Given that Sur1 is a subunit of the ATP-sensitive K+ channel (KATP) channel and that this channel functions as a part of a glucose-sensing pathway in pancreatic ß-cells, we asked whether the KATP channel serves an analogous role in taste cells. We discovered that oral stimulation with drugs known to increase (glyburide) or decrease (diazoxide) KATP signaling produced corresponding changes in glucose-stimulated CPIR. We propose that the KATP channel is part of a novel signaling pathway in taste cells that mediates glucose-induced CPIR.

Health outcomes of non-nutritive sweeteners: analysis of the research landscape.

BACKGROUND: Food products containing non-nutritive sweeteners (NNSs) instead of sugar have become increasingly popular in the last decades. Their appeal is obviously related to their calorie-free sweet taste. However, with the dramatic increase in their consumption, it is reasonable and timely to evaluate their potential health benefits and, more importantly, potential adverse effects. The main aim of this scoping review was to map the evidence about health outcomes possibly associated with regular NNS consumption by examining the extent, range, and nature of research activity in this area. METHODS: We systematically searched Ovid MEDLINE, EMBASE and the Cochrane CENTRAL databases for studies on NNSs (artificial sweeteners or natural, non-caloric sweeteners, either used individually or in combination) using text terms with appropriate truncation and relevant indexing terms. All human studies investigating any health outcomes of a NNS intervention or exposure were eligible for inclusion. No studies were excluded based on language, study design or methodological quality. Data for each health outcome were summarized in tabular form and were discussed narratively. RESULTS: Finally, we included 372 studies in our scoping review, comprising 15 systematic reviews, 155 randomized controlled trials (RCTs), 23 non-randomized controlled trials, 57 cohort studies, 52 case-control studies, 28 cross sectional studies and 42 case series/case reports. In healthy subjects, appetite and short term food intake, risk of cancer, risk of diabetes, risk of dental caries, weight gain and risk of obesity are the most investigated health outcomes. Overall there is no conclusive evidence for beneficial and harmful effects on those outcomes. Numerous health outcomes including headaches, depression, behavioral and cognitive effects, neurological effects, risk of preterm delivery, cardiovascular effects or risk of chronic kidney disease were investigated in fewer studies and further research is needed. In subjects with diabetes and hypertension, the evidence regarding health outcomes of NNS use is also inconsistent. CONCLUSIONS: This scoping review identifies the needs for future research to address the numerous evidence gaps related to health effects of NNSs use.It also specifies the research questions and areas where a systematic review with meta-analyses is required for the proper evaluation of health outcomes associated to regular NNSs consumption.