Glucose receptors -
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We thank the Bristol Chemical Synthesis Doctoral Training Centre for a studentship to R. School of Chemistry, University of Bristol, Bristol, UK.
Robert A. Tromans, Matthew P. Ziylo Ltd. Tom S. Carter, Laurent Chabanne, Johnathan V. School of Physiology, Pharmacology and Neuroscience, University of Bristol, Biomedical Sciences Building, University Walk, Bristol, UK. You can also search for this author in PubMed Google Scholar.
designed and carried out the synthetic route to receptor 2. and J. assisted in optimisation of the synthesis of compound 7. performed and analysed the binding studies, with assistance from T.
and L. in some cases. prepared the biological media. and M. were responsible for the structural NMR work, and H. performed the cytotoxicity studies. designed the receptor and directed the study. The paper was written by A. with input from the other authors.
Correspondence to Anthony P. While this paper was under consideration, Ziylo Ltd was purchased by Novo Nordisk with a view to the development of glucose-responsive insulin. A new company Carbometrics was created to collaborate with Ziylo and explore other applications.
was a director and shareholder of Ziylo, and is now a director and shareholder of Carbometrics. were employees of Ziylo, J. are now employees of Carbometrics. Synthesis and characterization of receptor 2; synthetic methods, NMR spectra, stability and toxicity.
Details of binding studies; methods and media, summary of binding results, binding data and analyses. Details of modelling studies. Reprints and permissions.
Tromans, R. A biomimetic receptor for glucose. Nature Chem 11 , 52—56 Download citation. Received : 31 December Accepted : 05 September Published : 12 November Issue Date : January Anyone you share the following link with will be able to read this content:.
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nature nature chemistry articles article. Subjects Carbohydrate chemistry Molecular capsules Monosaccharides Supramolecular chemistry. Abstract Specific molecular recognition is routine for biology, but has proved difficult to achieve in synthetic systems.
Access through your institution. Buy or subscribe. Change institution. Learn more. Data availability The data supporting this study are provided in the Supplementary Information and are also available from the authors upon reasonable request.
References Persch, E. Article CAS Google Scholar Schrader, T. Book Google Scholar Smith, B. Article CAS Google Scholar Ma, X. Article CAS Google Scholar Oshovsky, G.
Article CAS Google Scholar Kataev, E. The AFDS, though a relatively small study in a homogeneous population, has exhibited sufficient power to identify or replicate at least two T2DM risk alleles that are replicated in other populations [39] , [40]. However, association studies of rs in genetically heterogeneous populations may be further complicated by population stratification, as the frequency of the rs alleles varies greatly across human populations Supplementary data, Table S2.
Further genetic and mechanistic analyses will be needed to determine the extent to which contributions of specific TAS2R variants to glucose dysregulation are found in other populations.
We also provide important biological validation of the association data: a physiological consequence of the TAS2R9 polymorphism i. The rs SNP predicts an amino acid change in the second extracellular loop or fifth transmembrane domain of TAS2R9, a region suggested to form part of the ligand binding pocket and to be important for receptor activation [33] , [41] , [42].
In contrast, rs affects an amino acid in the C-terminal domain of TAS2R7, a region unlikely to directly impact ligand interactions, and the rs SNP is a non-coding polymorphism.
While any of these SNPs could potentially impact TAS2R expression or function, and therefore glucose and insulin homeostasis, we reasoned that the TAS2R9 variant was the most likely to significantly alter receptor function.
The observation that TAS2R9, but not TAS2R7, is expressed in human enteroendocrine cells Figure 3 further supports a key role for TAS2R9. The single amino acid change from Ala to Val at position has a profound effect on TAS2R9 function, abolishing responses to three different ligands Figure 2.
No systematic structure-function analyses have been performed for TAS2Rs, and studies that can differentiate ligand binding from other aspects of receptor activation have been limited to TAS1Rs e.
Though we cannot resolve whether the Ala to Val change specifically impacts ligand binding, binding-induced conformational changes, or effective G protein coupling, the inability of the Val variant to respond to any of three different ligands provides compelling evidence that this variant is incapable of transducing stimuli.
The observation that TAS2R9 is expressed in enteroendocrine cells and that a TAS2R9 ligand can elicit GLP-1 secretion suggests a possible mechanism, regulation of incretin response in the gut, by which variation in taste receptor function could impact glucose and insulin regulation.
Gut TAS2Rs could be stimulated by a number of compounds, including ingested toxins or bitter-tasting peptides that result from the fermentation of proteins such as casein [45]. Gut flora, which can vary dramatically between obese and lean individuals [46] , [47] , could also serve as a source of TAS2R stimuli in normal or pathogenic states.
Many TAS2Rs are broadly tuned to multiple stimuli, and some bitter stimuli activate more than one TAS2R [12] , [20] , [41] , [42] , [48] — [50]. The three TAS2R9 ligands identified in this study, ofloxacin, pirenzapine and procainamide, are not natural ligands for this receptor, some of which would be expected to activate TAS2R9 with a higher efficacy.
Even so, they do serve as effective tools to assay the consequences of the AlaVal mutation Figure 2. Interestingly, some fluoroquinolones, particularly gatifloxacin and levofloxacin the L-isomer of ofloxacin , have been associated with dysglycemia in diabetic and non-diabetic patients [51].
TAS2R9 does not respond to the three other fluoroquinolones we tested gatifloxacin, ciprofloxacin and enoxacin; Supplementary data, Table S1 , but it is intriguing to consider whether some bitter-tasting pharmaceuticals may affect glucose homeostasis, at least in part, through actions on TAS2Rs.
However, we cannot rule out alternative physiological mechanisms that link TAS2R function to the modulation of glucose homeostasis. For example, taste receptors could affect glucose homeostasis through a gustatory mechanism by altering the perceived qualities of food and impacting food preference and intake [6] , [30].
Indeed, taste receptor polymorphisms affect the ability to recognize taste stimuli by altering the perceived qualities of food and impacting food preference and intake [1] , [6].
Intragastric infusion of sweet- and bitter-tasting compounds also impacts taste preference [52] , [53]. Therefore, blindness to particular bitter-tasting compounds could lead to increased ingestion of toxins [3] ; alternatively, hypersensitivity could result in avoidance of otherwise beneficial foods for example, individuals with the phenylthiocarbamide-sensitive version of TAS2R38 are more sensitive to the bitterness of certain vegetables [6].
It is also unclear to what extent the unique lifestyle and history of the Amish impacts the contribution of TAS2R variants to manifestations of dysregulated glucose and insulin homeostasis, including the development of insulin resistance and T2DM.
In any case, our studies reveal that bitter taste receptors can influence glucose and insulin homeostasis. The novel role of TAS2Rs in maintenance of glucose homeostasis should help elucidate the relative contributions of taste receptor-mediated chemoreception in diverse alimentary tissues and suggests new lines of investigation for ameliorating risk of metabolic disease and for developing novel avenues for treatment.
The University of Maryland School of Medicine's Institutional Review Board approved all studies. The Amish Family Diabetes Study AFDS is an ongoing effort to identify genetic contributors to obesity, diabetes, cardiovascular disease and related disorders [28] , [39] , [54]. Detailed descriptions of the population the Old Order Amish of Lancaster County, Pennsylvania, USA , study design, recruitment methods, phenotypic characterization, clinical characteristics of the subjects and statistical methods have been published previously [28].
Informed consent, including permission to contact relatives, was obtained before participation [28]. In brief, probands were defined as individuals with previously diagnosed diabetes age of diagnosis between 35 and 65 years. First- and second-degree relatives of the probands were also recruited, as were first- and second-degree relatives of any additional diabetic individuals identified.
Currently, the AFDS includes over subjects. Participants in the AFDS, the Old Order Amish of Lancaster, Pennsylvania, have a common lifestyle and socioeconomic status, and possess detailed genealogical records dating to the period of their early migration from Europe in the 's [28].
In total, 70 TAS1R - and TAS2R -associated SNPs were genotyped in the AFDS. Forty-five of these SNPs were polymorphic in the AFDS and passed quality control filters and were subsequently analyzed see below and Tables 1 — 3. All SNPs were genotyped using the TaqMan platform Applied Biosystems according to manufacturer's protocols.
Genotype frequencies of all SNPs were tested for consistency with Hardy—Weinberg expectations by the χ 2 test. Receptor expression and functional assays were performed as previously described [20] , [49].
We used FLIPR Molecular Devices to screen the function of TAS2R9 and to establish dose-response curves for the tested compounds Supplementary data, Table S1. We cloned the cDNAs encoding the TAS2R9 Ala and Val variants into a pEAKderived vector Edge Biosystems, Gaithersburg, MD.
The vector was engineered to generate translational fusion to the N-terminus of the rat somatostatin type 3 receptor 45 amino acids , and the C-terminus of the herpes simplex virus HSV glycoprotein D epitope, as described [49].
Cells were plated into well plates and after 24—30 hr loaded for 1 h with the calcium-sensitive dye Fluo4-AM and stimulated with bitter compounds. Calcium signals were recorded simultaneously from each well after excitation at nm.
Responses of four wells containing cells expressing the same receptor and receiving the same stimulus were averaged. Calculations were based on at least three independent transfection experiments.
Total RNA was isolated from human enteroendocrine NCI-H cells with Trizol reagent, then reverse transcribed with random hexamer probes. A reaction without reverse transcriptase was included to control for genomic DNA contamination.
Human cecum cDNA was obtained from Biochain Institute Hayward, CA. TAS2R7 GeneID: and TAS2R9 GeneID: gene specific primers recognized the single coding exons of each gene. TAS1R3 GeneID: gene specific primers were directed against exons 4 and 6.
All PCR products were verified by sequencing. Human enteroendocrine NCI-H cells were maintained and assayed for GLP-1 secretion as described by Jang et al.
Control samples received PBS only. GLP-1 was measured by ELISA and normalized to protein content. For siRNA knockdown experiments, an α-gustducin-specific siRNA see [15] was transfected into subconfluent NCI-H cells 48 hr prior to ofloxacin stimulation and GLP-1 secretion analysis.
Reduction of α-gustducin message was verified by quantitative real time PCR. The efficacy of the stimulation was significantly reduced after knockdown of the G protein α-gustducin by RNA interference Figure S1B, C , indicating that ofloxacin-dependent GLP-1 secretion is mediated by a G protein-coupled receptor.
Associations with SNP genotype and the various phenotypes were performed using pedigree-based analysis by regressing the effect of the marker genotype while accounting for residual familial correlations among related individuals using age, sex, and body mass index BMI as covariates age and BMI are positively correlated with T2DM in the AFDS.
To account for the relatedness among family members, we employed the measured genotype approach, in which we estimated the likelihood of specific genetic models given the pedigree structure. Parameter estimates were obtained by maximum likelihood methods and the significance of association was tested by likelihood ratio tests.
When discrete outcome traits were analyzed, a threshold model was assumed. All analyses of the AFDS were carried out using the Sequential Oligogenic Linkage Analysis Routines SOLAR software program [60]. When analyzing data from non-diabetic AFDS subjects, a dominant model was assumed.
To control for an inflation in the type I error rate due to the number of comparisons in our initial T2DM association analyses, we use the P ACT statistic [61] , which attains the accuracy of permutation or simulation-based correction through the adjustment of correlated p-values.
Unadjusted P values are reported in all tables. Pairwise LD between the SNPs and haplotype block analysis was computed using Haploview 4. Concentration-response curves and EC50 values derived from the heterologous expression and functional assays were calculated in SigmaPlot by nonlinear regression.
We thank A. Shuldiner, S. Snitker, A. Naj, P. McCardle and the Munger lab for helpful discussions, X. Shi, L. Reinhart for technical assistance, and the AFDS participants. Conceived and designed the experiments: CDD XL NIS SDM. Performed the experiments: CDD LZ HX YKS SV SO AEE HJC HS JME BM.
Analyzed the data: CDD LZ HX YKS SV SO AEE HJC HS JME BM XL NIS SDM. Wrote the paper: CDD SDM. Edited the paper: SDM CDD SV JEM BM XL NIS. Browse Subject Areas? Click through the PLOS taxonomy to find articles in your field.
Article Authors Metrics Comments Media Coverage Reader Comments Figures. Abstract TAS1R- and TAS2R-type taste receptors are expressed in the gustatory system, where they detect sweet- and bitter-tasting stimuli, respectively. Introduction Taste strongly influences food preference and intake [1] — [3] , and taste receptor variants have been associated with differences in taste perception [4] — [6] , alcohol consumption [7] — [9] and tobacco use [10].
Results Glucose dysregulation, including elevated plasma glucose, increased hepatic gluconeogenesis, and decreased insulin mediated glucose transport, is a hallmark of type 2 diabetes mellitus T2DM [29]. Download: PPT. Table 1. Genotyping statistics for chromosome 12 TAS2R SNPs tested in the AFDS.
Table 2. Genotyping Statistics for chromosome 5 and 7 TAS2R SNPs tested in the AFDS. Table 3. Genotyping Statistics for TAS1R SNPs tested in the AFDS. Table 4. Age and BMI values, according to genotype, for AFDS subjects in Table 1.
Figure 1. Haplotype structure of TAS2R SNPs on chromosome 12 in the AFDS. Table 5. Associations with insulin and glucose metrics from OGTT in non-diabetic AFDS subjects.
Discussion By combining human genetic approaches with high-throughput receptor screening, we have identified an important link between taste receptor function and the modulation of glucose homeostasis. Materials and Methods Subjects The University of Maryland School of Medicine's Institutional Review Board approved all studies.
Heterologous expression and functional assay Receptor expression and functional assays were performed as previously described [20] , [49].
Reverse transcription PCR Total RNA was isolated from human enteroendocrine NCI-H cells with Trizol reagent, then reverse transcribed with random hexamer probes. GLP-1 assays Human enteroendocrine NCI-H cells were maintained and assayed for GLP-1 secretion as described by Jang et al. Statistical Analysis Associations with SNP genotype and the various phenotypes were performed using pedigree-based analysis by regressing the effect of the marker genotype while accounting for residual familial correlations among related individuals using age, sex, and body mass index BMI as covariates age and BMI are positively correlated with T2DM in the AFDS.
Supporting Information. Table S1. s 0. Table S2. Acknowledgments We thank A. Author Contributions Conceived and designed the experiments: CDD XL NIS SDM. References 1. Duffy VB Variation in oral sensation: implications for diet and health. Curr Opin Gastroenterol — View Article Google Scholar 2.
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