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The savory or umami taste of the amino acid glutamate is synergistically enhanced by the addition of the purines inosine 5'-monophosphate (IMP) and guanosine 5'-monophosphate (GMP) disodium salt. We hypothesized that the addition of purinergic ribonucleotides, along with the pyrimidine ribonucleotides, would decrease the absolute detection threshold of (increase sensitivity to) l-glutamic acid potassium salt (MPG). To test this, we measured both the absolute detection threshold of MPG alone and with a background level (3 mM) of 5 different 5'-ribonucleotides. The addition of the 3 purines IMP, GMP, and adenosine 5'-monophosphate (AMP) lowered the MPG threshold in all participants (P < 0.001), indicating they are positive modulators or enhancers of glutamate taste. The average detection threshold of MPG was 2.08 mM, and with the addition of IMP, the threshold was decreased by approximately 1.5 orders of magnitude to 0.046 mM. In contrast to the purines, the pyrimidines uridine 5'-monophosphate (UMP) and cytidine 5'-monophosphate (CMP) yielded different results. CMP reliably raised glutamate thresholds in 10 of 17 subjects, suggesting it is a negative modulator or diminisher of glutamate taste for them. The rank order of effects on increasing sensitivity to glutamate was IMP > GMP> AMP >> UMP// CMP. These data confirm that ribonucleotides are modulators of glutamate taste, with purines enhancing sensitivity and pyrimidines displaying variable and even negative modulatory effects. Our ability to detect the co-occurrence of glutamate and purines is meaningful as both are relatively high in evolutionarily important sources of nutrition, such as insects and fermented foods.
Assuntos
Ácido Glutâmico , Ribonucleotídeos , Humanos , Ribonucleotídeos/farmacologia , Paladar , Guanosina Monofosfato/metabolismo , Uridina Monofosfato , Purinas , Inosina Monofosfato/metabolismo , Glutamato de SódioRESUMO
The evolutionary history of sour taste has been little studied. Through a combination of literature review and trait mapping on the vertebrate phylogenetic tree, we consider the origin of sour taste, potential cases of the loss of sour taste, and those factors that might have favoured changes in the valence of sour taste-from aversive to appealing. We reconstruct sour taste as having evolved in ancient fish. By contrast to other tastes, sour taste does not appear to have been lost in any major vertebrate taxa. For most species, sour taste is aversive. Animals, including humans, that enjoy the sour taste triggered by acidic foods are exceptional. We conclude by considering why sour taste evolved, why it might have persisted as vertebrates made the transition to land and what factors might have favoured the preference for sour-tasting, acidic foods, particularly in hominins, such as humans.
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Paladar , Animais , Humanos , FilogeniaRESUMO
Children have difficulty swallowing capsules. Yet, when presented with liquid formulations, children often reject oral medications due to their intense bitterness. Presently, effective strategies to identify methods, reagents, and tools to block bitterness remain elusive. For a specific bitter-tasting drug, identification of the responsible bitter receptors and discovery of antagonists for those receptors can provide a method to block perceived bitterness. We have identified a compound (6-methylflavone) that can block responses to an intensely bitter-tasting anti-human immunodeficiency virus (HIV) drug, tenofovir alafenamide (TAF), using a primary human taste bud epithelial cell culture as a screening platform. Specifically, TAS2R39 and TAS2R1 are the main type 2 taste receptors responding to TAF observed via heterologously expressing specific TAS2R receptors into HEK293 cells. In this assay, 6-methylflavone blocked the responses of TAS2R39 to TAF. In human sensory testing, 8 of 16 subjects showed reduction in perceived bitterness of TAF after pretreating (or "prerinsing") with 6-methylflavone and mixing 6-methylflavone with TAF. Bitterness was completely and reliably blocked in two of these subjects. These data demonstrate that a combined approach of human taste cell culture-based screening, receptor-specific assays, and human psychophysical testing can successfully discover molecules for blocking perceived bitterness of pharmaceuticals, such as the HIV therapeutic TAF. Our hope is to use bitter taste blockers to increase medical compliance with these vital medicines. SIGNIFICANCE STATEMENT: Identification of a small molecule that inhibits bitter taste from tenofovir alafenamide may increase the compliance in treating children with human immunodeficiency virus infections.
Assuntos
Adenina/análogos & derivados , Aromatizantes/administração & dosagem , Aromatizantes/química , Papilas Gustativas/efeitos dos fármacos , Paladar/efeitos dos fármacos , Adenina/efeitos adversos , Adenina/química , Adulto , Alanina , Antivirais/efeitos adversos , Antivirais/química , Linhagem Celular , Feminino , Flavonas/administração & dosagem , Flavonas/química , Células HEK293 , Humanos , Masculino , Receptores de Superfície Celular/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Papilas Gustativas/metabolismo , Tenofovir/análogos & derivadosRESUMO
To learn more about the mechanisms of human dietary fat perception, 398 human twins rated fattiness and liking for six types of potato chips that differed in triglyceride content (2.5, 5, 10, and 15% corn oil); reliability estimates were obtained from a subset (n = 50) who did the task twice. Some chips also had a saturated long-chain fatty acid (hexadecanoic acid, 16:0) added (0.2%) to evaluate its effect on fattiness and liking. We computed the heritability of these measures and conducted a genome-wide association study (GWAS) to identify regions of the genome that co-segregate with fattiness and liking. Perceived fattiness and liking for the potato chips were reliable (r = 0.31-0.62, p < 0.05) and heritable (up to h2 = 0.29, p < 0.001, for liking). Adding hexadecanoic acid to the potato chips significantly increased ratings of fattiness but decreased liking. Twins with the G allele of rs263429 near GATA3-AS1 or the G allele of rs8103990 within ZNF729 reported more liking for potato chips than did twins with the other allele (multivariate GWAS, p < 1×10-5), with results reaching genome-wide suggestive but not significance criteria. Person-to-person variation in the perception and liking of dietary fat was (a) negatively affected by the addition of a saturated fatty acid and (b) related to inborn genetic variants. These data suggest liking for dietary fat is not due solely to fatty acid content and highlight new candidate genes and proteins within this sensory pathway.
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Potassium chloride (KCl) has proven useful as a salty taste replacer to help reduce dietary sodium. But unlike sodium, which in simple aqueous solutions blocks the perception of bitterness of selected compounds, KCl does not blocker bitterness. We tested the ability of potassium to block bitterness in a more complex translational system by presenting model chicken broths to healthy adults. Broths were presented in three added salt conditions: (1) no added salt, (2) salted with sodium chloride (NaCl), or (3) salted with KCl. To create a model bitter off-taste, four concentrations of l-tryptophan (l-tryp, present in chicken meat) were added to each broth. In Experiment 1, the base broth consisted of chicken flavor only. In Experiment 2, the base broth was more complex, containing savory (umami) ingredients. In both experiments, subjects rated broths with either added NaCl or KCl as saltier than unsalted broths. Only NaCl, however, suppressed bitterness (by about 30%, across a wide range of l-tryp concentrations). Accordingly, when complex foods have sodium reduced and potassium increased to balance salty taste, the bitterness reducing properties of sodium will need to be replaced independently, since potassium does not share this effect.
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BACKGROUND: Human perception of bitter substances is partially genetically determined. Previously we discovered a single nucleotide polymorphism (SNP) within the cluster of bitter taste receptor genes on chromosome 12 that accounts for 5.8% of the variance in the perceived intensity rating of quinine, and we strengthened the classic association between TAS2R38 genotype and the bitterness of propylthiouracil (PROP). Here we performed a genome-wide association study (GWAS) using a 40% larger sample (n = 1999) together with a bivariate approach to detect previously unidentified common variants with small effects on bitter perception. RESULTS: We identified two signals, both with small effects (< 2%), within the bitter taste receptor clusters on chromosomes 7 and 12, which influence the perceived bitterness of denatonium benzoate and sucrose octaacetate respectively. We also provided the first independent replication for an association of caffeine bitterness on chromosome 12. Furthermore, we provided evidence for pleiotropic effects on quinine, caffeine, sucrose octaacetate and denatonium benzoate for the three SNPs on chromosome 12 and the functional importance of the SNPs for denatonium benzoate bitterness. CONCLUSIONS: These findings provide new insights into the genetic architecture of bitter taste and offer a useful starting point for determining the biological pathways linking perception of bitter substances.
Assuntos
Cromossomos Humanos Par 12 , Cromossomos Humanos Par 7 , Estudo de Associação Genômica Ampla , Família Multigênica , Percepção Gustatória/genética , Adolescente , Adulto , Criança , Feminino , Pleiotropia Genética , Genótipo , Humanos , Masculino , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Receptores Acoplados a Proteínas G/genética , Papilas Gustativas/metabolismo , Adulto JovemRESUMO
T1R2-T1R3 is a heteromeric receptor that binds sugars, high potency sweeteners, and sweet taste blockers. In rodents, T1R2-T1R3 is largely responsible for transducing sweet taste perception. T1R2-T1R3 is also expressed in non-taste tissues, and a growing body of evidence suggests that it helps regulate glucose and lipid metabolism. It was previously shown that clofibric acid, a blood lipid-lowering drug, binds T1R2-T1R3 and inhibits its activity in vitro The purpose of this study was to determine whether clofibric acid inhibits sweetness perception in humans and is, therefore, a T1R2-T1R3 antagonist in vivo Fourteen participants rated the sweetness intensity of 4 sweeteners (sucrose, sucralose, Na cyclamate, acesulfame K) across a broad range of concentrations. Each sweetener was prepared in solution neat and in mixture with either clofibric acid or lactisole. Clofibric acid inhibited sweetness of every sweetener. Consistent with competitive binding, inhibition by clofibric acid was diminished with increasing sweetener concentration. This study provides in vivo evidence that the lipid-lowering drug clofibric acid inhibits sweetness perception and is, therefore, a T1R carbohydrate receptor inhibitor. Our results are consistent with previous in vitro findings. Given that T1R2-T1R3 may in part regulate glucose and lipid metabolism, future studies should investigate the metabolic effects of T1R inhibition.
Assuntos
Clofibrato/farmacologia , Edulcorantes/farmacologia , Paladar/efeitos dos fármacos , Paladar/fisiologia , Adolescente , Adulto , Feminino , Humanos , Masculino , Receptores Acoplados a Proteínas G/metabolismo , Adulto JovemRESUMO
Perceived intensities of sweetness and bitterness are correlated with one another and each is influenced by genetics. The extent to which these correlations share common genetic variation, however, remains unclear. In a mainly adolescent sample ( n = 1901, mean age 16.2 years), including 243 monozygotic (MZ) and 452 dizygotic (DZ) twin pairs, we estimated the covariance among the perceived intensities of 4 bitter compounds (6- n -propylthiouracil [PROP], sucrose octa-acetate, quinine, caffeine) and 4 sweeteners (the weighted mean ratings of glucose, fructose, neohesperidine dihydrochalcone, aspartame) with multivariate genetic modeling. The sweetness factor was moderately correlated with sucrose octa-acetate, quinine, and caffeine ( rp = 0.35-0.40). This was mainly due to a shared genetic factor ( rg = 0.46-0.51) that accounted for 17-37% of the variance in the 3 bitter compounds' ratings and 8% of the variance in general sweetness ratings. In contrast, an association between sweetness and PROP only became evident after adjusting for the TAS2R38 diplotype ( rp increased from 0.18 to 0.32) with the PROP genetic factor accounting for 6% of variance in sweetness. These genetic associations were not inflated by scale use bias, as the cross-trait correlations for both MZ and DZ twins were weak. There was also little evidence for mediation by cognition or behavioral factors. This suggests an overlap of genetic variance between perceptions of sweetness and bitterness from a variety of stimuli, which includes PROP when considering the TAS2R38 diplotype. The most likely sources of shared variation are within genes encoding post-receptor transduction mechanisms common to the various taste G protein-coupled receptors.
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Salivary amylase is a glucose-polymer cleavage enzyme that is produced by the salivary glands. It comprises a small portion of the total amylase excreted, which is mostly made by the pancreas. Amylases digest starch into smaller molecules, ultimately yielding maltose, which in turn is cleaved into two glucose molecules by maltase. Starch comprises a significant portion of the typical human diet for most nationalities. Given that salivary amylase is such a small portion of total amylase, it is unclear why it exists and whether it conveys an evolutionary advantage when ingesting starch. This review will consider the impact of salivary amylase on oral perception, nutrient signaling, anticipatory metabolic reflexes, blood sugar, and its clinical implications for preventing metabolic syndrome and obesity.
Assuntos
Amilases/fisiologia , Síndrome Metabólica/prevenção & controle , Saliva/enzimologia , Glicemia/análise , Humanos , Obesidade/prevenção & controle , Amido/metabolismoRESUMO
Investigations on the relationship between sweet taste perception and body mass index (BMI) have been inconclusive. Here, we report a longitudinal analysis using a genetically informative sample of 1,576 adolescent Australian twins to explore the relationship between BMI and sweet taste. First, we estimated the phenotypic correlations between perception scores for four different sweet compounds (glucose, fructose, neohesperidine dihydrochalcone (NHDC), and aspartame) and BMI. Then, we computed the association between adolescent taste perception and BMI in early adulthood (reported 9 years later). Finally, we used twin modeling and polygenic risk prediction analysis to investigate the genetic overlap between BMI and sweet taste perception. Our findings revealed that BMI in early adulthood was significantly associated with each of the sweet perception scores, with the strongest correlation observed in aspartame with r = 0.09 (p = .007). However, only limited evidence of association was observed between sweet taste perception and BMI that was measured at the same time (in adolescence), with the strongest evidence of association observed for glucose with a correlation coefficient of r = 0.06 (p = .029) and for aspartame with r = 0.06 (p = .035). We found a significant (p < .05) genetic correlation between glucose and NHDC perception and BMI. Our analyses suggest that sweet taste perception in adolescence can be a potential indicator of BMI in early adulthood. This association is further supported by evidence of genetic overlap between the traits, suggesting that some BMI genes may be acting through biological pathways of taste perception.
Assuntos
Índice de Massa Corporal , Genótipo , Fenótipo , Irmãos , Edulcorantes/administração & dosagem , Percepção Gustatória/genética , Gêmeos/genética , Adolescente , Adulto , Criança , Feminino , Seguimentos , Humanos , Masculino , Característica Quantitativa HerdávelRESUMO
Bitter taste perception influences human nutrition and health, and the genetic variation underlying this trait may play a role in disease susceptibility. To better understand the genetic architecture and patterns of phenotypic variability of bitter taste perception, we sequenced a 996 bp region, encompassing the coding exon of TAS2R16, a bitter taste receptor gene, in 595 individuals from 74 African populations and in 94 non-Africans from 11 populations. We also performed genotype-phenotype association analyses of threshold levels of sensitivity to salicin, a bitter anti-inflammatory compound, in 296 individuals from Central and East Africa. In addition, we characterized TAS2R16 mutants in vitro to investigate the effects of polymorphic loci identified at this locus on receptor function. Here, we report striking signatures of positive selection, including significant Fay and Wu's H statistics predominantly in East Africa, indicating strong local adaptation and greater genetic structure among African populations than expected under neutrality. Furthermore, we observed a "star-like" phylogeny for haplotypes with the derived allele at polymorphic site 516 associated with increased bitter taste perception that is consistent with a model of selection for "high-sensitivity" variation. In contrast, haplotypes carrying the "low-sensitivity" ancestral allele at site 516 showed evidence of strong purifying selection. We also demonstrated, for the first time, the functional effect of nonsynonymous variation at site 516 on salicin phenotypic variance in vivo in diverse Africans and showed that most other nonsynonymous substitutions have weak or no effect on cell surface expression in vitro, suggesting that one main polymorphism at TAS2R16 influences salicin recognition. Additionally, we detected geographic differences in levels of bitter taste perception in Africa not previously reported and infer an East African origin for high salicin sensitivity in human populations.
Assuntos
Álcoois Benzílicos/química , População Negra/genética , Glucosídeos/química , Receptores Acoplados a Proteínas G/genética , Paladar/genética , Alelos , Evolução Molecular , Éxons , Estudos de Associação Genética , Variação Genética , Haplótipos , Humanos , Malária/epidemiologia , Malária/genética , Modelos Genéticos , Filogenia , Filogeografia , Polimorfismo de Nucleotídeo Único , Receptores Acoplados a Proteínas G/metabolismo , Seleção GenéticaRESUMO
The perception of sweetness varies among individuals but the sources of this variation are not fully understood. Here, in a sample of 1,901 adolescent and young adults (53.8% female; 243 MZ and 452 DZ twin pairs, 511 unpaired individuals; mean age 16.2±2.8, range 1226 years), we studied the variation in the perception of sweetness intensity of two monosaccharides and two high-potency sweeteners: glucose, fructose, neohesperidine dihydrochalcone (NHDC), and aspartame. Perceived intensity for all sweeteners decreased with age (25% per year) and increased with the history of otitis media (69%). Males rated aspartame slightly stronger than females (7%). We found similar heritabilities for sugars (glucose: h2=0.31, fructose: h2=0.34) and high-potency sweeteners (NHDC: h2=0.31, aspartame: h2=0.30); all were in the modest range. Multivariate modeling showed that a common genetic factor accounted for >75% of the genetic variance in the four sweeteners, suggesting that individual differences in perceived sweet intensity, which are partly due to genetic factors, may be attributed to a single set of genes. This study provided evidence of the shared genetic pathways between the perception of sugars and high-potency sweeteners.
Assuntos
Metabolismo dos Carboidratos/genética , Edulcorantes/metabolismo , Paladar/genética , Adolescente , Adulto , Aspartame/administração & dosagem , Aspartame/metabolismo , Chalconas/administração & dosagem , Chalconas/metabolismo , Criança , Feminino , Frutose/administração & dosagem , Frutose/metabolismo , Glucose/administração & dosagem , Glucose/metabolismo , Hesperidina/administração & dosagem , Hesperidina/análogos & derivados , Hesperidina/metabolismo , Humanos , Masculino , Edulcorantes/administração & dosagem , Gêmeos Dizigóticos/genética , Gêmeos Monozigóticos/genética , Adulto JovemRESUMO
Bitter taste perception, mediated by receptors encoded by the TAS2R loci, has important roles in human health and nutrition. Prior studies have demonstrated that nonsynonymous variation at site 516 in the coding exon of TAS2R16, a bitter taste receptor gene on chromosome 7, has been subject to positive selection and is strongly correlated with differences in sensitivity to salicin, a bitter anti-inflammatory compound, in human populations. However, a recent study suggested that the derived G-allele at rs702424 in the TAS2R16 promoter has also been the target of recent selection and may have an additional effect on the levels of salicin bitter taste perception. Here, we examined alleles at rs702424 for signatures of selection using Extended Haplotype Homozygosity (EHH) and FST statistics in diverse populations from West Central, Central and East Africa. We also performed a genotype-phenotype analysis of salicin sensitivity in a subset of 135 individuals from East Africa. Based on our data, we did not find evidence for positive selection at rs702424 in African populations, suggesting that nucleotide position 516 is likely the site under selection at TAS2R16. Moreover, we did not detect a significant association between rs702424 alleles and salicin bitter taste recognition, implying that this site does not contribute to salicin phenotypic variance. Overall, this study of African diversity provides further information regarding the genetic architecture and evolutionary history of a biologically-relevant trait in humans.
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Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Receptores Acoplados a Proteínas G/genética , Percepção Gustatória/genética , África Oriental , Alelos , Anti-Inflamatórios/farmacologia , Álcoois Benzílicos/farmacologia , Evolução Molecular , Estudos de Associação Genética , Glucosídeos/farmacologia , Humanos , Receptores Acoplados a Proteínas G/metabolismoRESUMO
Vitamin A deficiency (VAD) is an overwhelming public health problem that affects hundreds of millions of people worldwide. A definitive solution to VAD has yet to be identified. Because it is an essential nutrient, vitamin A or its carotenoid precursor ß-carotene can only be obtained from food or supplements. In this study, we wanted to establish whether ß-carotene produced in the mouse intestine by bacteria synthesizing the provitamin A carotenoid could be delivered to various tissues within the body. To achieve this, we took advantage of the Escherichia coli MG1655*, an intestine-adapted spontaneous mutant of E. coli MG1655, and the plasmid pAC-BETA, containing the genes coding for the 4 key enzymes of the ß-carotene biosynthetic pathway (geranylgeranyl pyrophosphate synthase, phytoene synthase, phytoene desaturase, and lycopene cyclase) from Erwinia herbicola. We engineered the E. coli MG1655* to produce ß-carotene during transformation with pAC-BETA (MG1655*-ßC) and gavaged wild-type and knockout mice for the enzyme ß-carotene 15,15'-oxygenase with this recombinant strain. Various regimens of bacteria administration were tested (single vs. multiple and low vs. high doses). ß-Carotene concentration was measured by HPLC in mouse serum, liver, intestine, and feces. Enumeration of MG1655*-ßC cells in the feces was performed to assess efficiency of intestinal colonization. We demonstrated in vivo that probiotic bacteria could be used to deliver vitamin A to the tissues of a mammalian host. These results have the potential to pave the road for future investigations aimed at identifying alternative, novel approaches to treat VAD.
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Erwinia/enzimologia , Escherichia coli/enzimologia , Intestinos/microbiologia , Deficiência de Vitamina A/terapia , Vitamina A/biossíntese , beta Caroteno/metabolismo , Animais , Carotenoides/metabolismo , Erwinia/genética , Escherichia coli/genética , Fezes/microbiologia , Feminino , Geranil-Geranildifosfato Geranil-Geraniltransferase/genética , Geranil-Geranildifosfato Geranil-Geraniltransferase/metabolismo , Mucosa Intestinal/metabolismo , Liases Intramoleculares/genética , Liases Intramoleculares/metabolismo , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Oxirredutases/genética , Oxirredutases/metabolismo , Probióticos , Deficiência de Vitamina A/metabolismo , Deficiência de Vitamina A/microbiologia , beta-Caroteno 15,15'-Mono-Oxigenase/genética , beta-Caroteno 15,15'-Mono-Oxigenase/metabolismoRESUMO
Cough is among the most common symptoms with which people present for medical attention, but evidence-based treatments remain limited. One issue compromising interpretation of clinical trials of cough preparations is that control formulations often are nearly as effective as those that contain active ingredients. This observation has caused some researchers to propose that one or more nominally inactive ingredients may have some physiological effects. For example, most liquid cough preparations are highly sweetened, and it has been suggested that sweet taste might modulate cough sensitivity. The fact that honey has been used for thousands of years as a cough remedy is consistent with this idea. However, empirical evidence for modulation of cough sensitivity by taste was lacking. Evidence is still sparse, but relevant experiments have now been published: rinsing the mouth with a sweet sucrose solution increased cough thresholds in a single-inhalation capsaicin challenge. Furthermore, rinsing the mouth with a bitter solution did not affect thresholds, an important demonstration of specificity. The underlying mechanisms of cough suppression by sweet taste are still unclear. However, extant data suggest that modulation of cough sensitivity by taste is a promising area for further investigation. Such work may lead to greater understanding of apparent placebo effects in clinical trials and provide empirical support for therapies based on stimulation of taste nerves.
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Tosse/fisiopatologia , Reflexo , Paladar , Antitussígenos/uso terapêutico , Ensaios Clínicos Controlados como Assunto/métodos , Tosse/diagnóstico , Tosse/tratamento farmacológico , Tosse/etiologia , Medicina Baseada em Evidências , Humanos , Efeito Placebo , Reflexo/efeitos dos fármacos , Projetos de Pesquisa , Edulcorantes/uso terapêutico , Paladar/efeitos dos fármacos , Resultado do TratamentoRESUMO
The sweet taste receptor, TAS1R2-TAS1R3, is expressed in taste bud cells, where it conveys sweetness, and also in intestinal enteroendocrine cells, where it may facilitate glucose absorption and assimilation. In the present study, our objective was to determine whether TAS1R2-TAS1R3 influences glucose metabolism bidirectionally via hyperactivation with 5 mM sucralose (n = 12) and inhibition with 2 mM sodium lactisole (n = 10) in mixture with 75 g glucose loads during oral glucose tolerance tests (OGTTs) in healthy humans. Plasma glucose, insulin, and glucagon were measured before, during, and after OGTTs up to 120 minutes post-prandially. We also assessed individual participants' sweet taste responses to sucralose and their sensitivities to lactisole sweetness inhibition. The addition of sucralose to glucose elevated plasma insulin responses to the OGTT (F(1, 11) = 4.55, p = 0.056). Sucralose sweetness ratings were correlated with early increases in plasma glucose (R2 = 0.41, p<0.05), as well as increases in plasma insulin (R2 = 0.38, p<0.05) when sucralose was added to the OGTT (15 minute AUC). Sensitivity to lactisole sweetness inhibition was correlated with decreased plasma glucose (R2 = 0.84, p<0.01) when lactisole was added to the OGTT over the whole test (120 minute AUC). In summary, stimulation and inhibition of the TAS1R2-TAS1R3 receptor demonstrates that TAS1R2-TAS1R3 helps regulate glucose metabolism in humans and may have translational implications for metabolic disease risk.
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Derivados de Benzeno , Glicemia , Teste de Tolerância a Glucose , Insulina , Receptores Acoplados a Proteínas G , Sacarose , Sacarose/análogos & derivados , Humanos , Receptores Acoplados a Proteínas G/metabolismo , Masculino , Adulto , Feminino , Sacarose/metabolismo , Glicemia/metabolismo , Insulina/metabolismo , Insulina/sangue , Paladar/fisiologia , Adulto Jovem , Tiazóis/farmacologia , Glucose/metabolismo , Glucagon/metabolismo , Glucagon/sangue , Edulcorantes/farmacologiaRESUMO
BACKGROUND AND PURPOSE: Many medications taste intensely bitter. The innate aversion to bitterness affects medical compliance, especially in children. There is a clear need to develop bitter blockers to suppress the bitterness of vital medications. Bitter taste is mediated by TAS2R receptors. Because different pharmaceutical compounds activate distinct sets of TAS2Rs, targeting specific receptors may only suppress bitterness for certain, but not all, bitter-tasting compounds. Alternative strategies are needed to identify universal bitter blockers that will improve the acceptance of every medication. Taste cells in the mouth transmit signals to afferent gustatory nerve fibres through the release of ATP, which activates the gustatory nerve-expressed purine receptors P2X2/P2X3. We hypothesized that blocking gustatory nerve transmission with P2X2/P2X3 inhibitors (e.g. 5-(5-iodo-4-methoxy-2-propan-2-ylphenoxy)pyrimidine-2,4-diamine [AF-353]) would reduce bitterness for all medications and bitter compounds. EXPERIMENTAL APPROACH: Human sensory taste testing and mouse behavioural analyses were performed to determine if oral application of AF-353 blocks perception of bitter taste and other taste qualities but not non-gustatory oral sensations (e.g. tingle). KEY RESULTS: Rinsing the mouth with AF-353 in humans or oral swabbing it in mice suppressed the bitter taste and avoidance behaviours of all compounds tested. We further showed that AF-353 suppressed other taste qualities (i.e. salt, sweet, sour and savoury) but had no effects on other oral or nasal sensations (e.g, astringency and oral tingle). CONCLUSION AND IMPLICATIONS: This is the first time a universal, reversible taste blocker in humans has been reported. Topical application of P2X2/P2X3 inhibitor to suppress bitterness may improve medical compliance.
Assuntos
Antagonistas do Receptor Purinérgico P2X , Receptores Purinérgicos P2X3 , Paladar , Humanos , Paladar/efeitos dos fármacos , Animais , Receptores Purinérgicos P2X3/metabolismo , Masculino , Feminino , Antagonistas do Receptor Purinérgico P2X/farmacologia , Antagonistas do Receptor Purinérgico P2X/administração & dosagem , Adulto , Camundongos , Receptores Purinérgicos P2X2/metabolismo , Administração Tópica , Adulto Jovem , Pirimidinas/farmacologia , Pirimidinas/administração & dosagem , Camundongos Endogâmicos C57BLRESUMO
Although human bitter taste perception is hypothesized to be a dietary adaptation, little is known about genetic signatures of selection and patterns of bitter taste perception variability in ethnically diverse populations with different diets, particularly from Africa. To better understand the genetic basis and evolutionary history of bitter taste sensitivity, we sequenced a 2,975 bp region encompassing TAS2R38, a bitter taste receptor gene, in 611 Africans from 57 populations in West Central and East Africa with diverse subsistence patterns, as well as in a comparative sample of 132 non-Africans. We also examined the association between genetic variability at this locus and threshold levels of phenylthiocarbamide (PTC) bitterness in 463 Africans from the above populations to determine how variation influences bitter taste perception. Here, we report striking patterns of variation at TAS2R38, including a significant excess of novel rare nonsynonymous polymorphisms that recently arose only in Africa, high frequencies of haplotypes in Africa associated with intermediate bitter taste sensitivity, a remarkably similar frequency of common haplotypes across genetically and culturally distinct Africans, and an ancient coalescence time of common variation in global populations. Additionally, several of the rare nonsynonymous substitutions significantly modified levels of PTC bitter taste sensitivity in diverse Africans. While ancient balancing selection likely maintained common haplotype variation across global populations, we suggest that recent selection pressures may have also resulted in the unusually high level of rare nonsynonymous variants in Africa, implying a complex model of selection at the TAS2R38 locus in African populations. Furthermore, the distribution of common haplotypes in Africa is not correlated with diet, raising the possibility that common variation may be under selection due to their role in nondietary biological processes. In addition, our data indicate that novel rare mutations contribute to the phenotypic variance of PTC sensitivity, illustrating the influence of rare variation on a common trait, as well as the relatively recent evolution of functionally diverse alleles at this locus.
Assuntos
População Negra/genética , Evolução Molecular , Receptores Acoplados a Proteínas G/genética , Paladar/genética , Adaptação Biológica/genética , África , Alelos , Variação Genética , Haplótipos/genética , Humanos , Mutação , FenótipoRESUMO
Taste sensitivity is assessed with various techniques, including absolute detection and quality recognition. For any stimulus, one might expect individual differences in sensitivity to be reflected in all measures, but they are often surprisingly independent. Here, we focus on sensitivity to sour and salty taste, in part because processing of these qualities is poorly understood relative to other tastes. In Study 1, we measured retest reliability for detection (modified, forced-choice staircase method) and recognition (modified Harris-Kalmus procedure) for both citric acid (CA) and sodium chloride (NaCl). Despite good retest reliability, individual differences in detection and recognition were weakly correlated, suggesting that detection and recognition of sour and salty stimuli may reflect different physiological processes. In Study 2, a subset of subjects returned to contribute full detection (psychometric) functions for CA and NaCl. Thresholds estimated from full detection functions correlated with both staircase and recognition thresholds, suggesting that both tasks may reflect absolute sensitivity to some extent. However, the ranges of individual differences were systematically compressed for staircase thresholds relative to those from full detection functions. Thus, individual differences in sensitivity appear to interact with different test methodologies in lawful ways. More work will be required to understand how different taste phenotypes relate to one another.
Assuntos
Ácido Cítrico/metabolismo , Cloreto de Sódio/metabolismo , Limiar Gustativo , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Psicometria/métodos , Psicofísica/métodos , Adulto JovemRESUMO
Oleocanthal, a major phenolic compound in extra-virgin olive oil with antiinflammatory properties, elicits an unusual oral pungency sensed almost exclusively in the throat. This contrasts with most other common oral irritants, such as cinnamaldehyde, capsaicin, and alcohol, which irritate mucus membranes throughout the oral cavity. Here, we show that this rare irritation pattern is a consequence of both the specificity of oleocanthal for a single sensory receptor and the anatomical restriction of this sensory receptor to the pharynx, within the oral cavity. We demonstrate, in vitro, that oleocanthal selectively activates the hTRPA1 channel in HEK 293 cells and that its ability to excite the trigeminal nervous system in rodents requires a functional TRPA1. Moreover, we similarly demonstrate that the over-the-counter analgesic, ibuprofen, which elicits the same restricted pharyngeal irritation as oleocanthal, also specifically excites rodent sensory neurons via TRPA1. Using human sensory psychophysical studies and immunohistochemical TRPA1 analyses of human oral and nasal tissues, we observe an overlap of the anatomical distribution of TRPA1 and the regions irritated by oleocanthal in humans. These results suggest that a TRPA1 (ANKTM1) gene product mediates the tissue sensitivity to oleocanthal within the oral cavity. Furthermore, we demonstrate that, despite the fact that oleocanthal possesses the classic electrophilic reactivity of many TRPA1 agonists, it does not use the previously identified activation mechanism via covalent cysteine modification. These findings provide an anatomical and molecular explanation for a distinct oral sensation that is elicited by oleocanthal and ibuprofen and that is commonly experienced around the world when consuming many extra-virgin olive oils.