Glucose receptors -
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S2CID Bibcode : Natur. Reversible redox-dependent interconversions of tetrameric and dimeric GLUT1". The Journal of Biological Chemistry. Evidence for cytosolic sugar binding sites in erythrocytes".
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Experimental Physiology. The insight from this time that remains in all current text books is the notion of Robert Crane published originally as an appendix to a symposium paper published in Crane et al. The key point here was 'flux coupling', the cotransport of sodium and glucose in the apical membrane of the small intestinal epithelial cell.
Half a century later this idea has turned into one of the most studied of all transporter proteins SGLT1 , the sodium—glucose cotransporter. Membrane proteins , carrier proteins : membrane transport proteins solute carrier TC 2A. high affinity glutamate and neutral amino-acid transporter SLC1A1 2 3 4 5 6 7.
facilitative GLUT transporter SLC2A1 2 3 4 5 6 7 8 9 10 11 12 13 heavy subunits of heterodimeric amino-acid transporters SLC3A1 2. bicarbonate transporter SLC4A1 2 3 4 5 6 7 8 9 10 sodium glucose cotransporter SLC5A1 2 3 4 5 6 7 8 9 10 11 sodium - and chloride - dependent sodium:neurotransmitter symporters SLC6A1 SLC6A2 SLC6A3 SLC6A4 SLC6A5 SLC6A6 SLC6A7 SLC6A8 SLC6A9 SLC6A10 SLC6A11 SLC6A12 SLC6A13 SLC6A14 SLC6A15 SLC6A16 SLC6A17 SLC6A18 SLC6A19 SLC6A sodium bile salt cotransport SLC10A1 SLC10A2 SLC10A3 SLC10A4 SLC10A5 SLC10A6 SLC10A7 10A1 10A2 10A3 10A7.
proton coupled metal ion transporter SLC11A1 SLC11A2 11A3. electroneutral cation-Cl cotransporter SLC12A1 SLC12A2 SLC12A3 SLC12A4 SLC12A5 SLC12A6 SLC12A7 SLC12A8 SLC12A9. urea transporter SLC14A1 SLC14A2. proton oligopeptide cotransporter SLC15A1 SLC15A2 SLC15A3 SLC15A4.
monocarboxylate transporter SLC16A1 SLC16A2 SLC16A3 SLC16A4 SLC16A5 SLC16A6 SLC16A7 SLC16A8 SLC16A9 SLC16A10 SLC16A11 SLC16A12 SLC16A13 SLC16A Vesicular glutamate transporter 1 SLC17A1 SLC17A2 SLC17A3 SLC17A4 SLC17A5 SLC17A6 SLC17A7 SLC17A8 SLC17A9.
vesicular monoamine transporter SLC18A1 SLC18A2 SLC18A3. 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.
Bartoshuk LM, Duffy VB, Hayes JE, Moskowitz HR, Snyder DJ Psychophysics of sweet and fat perception in obesity: problems, solutions and new perspectives. Philos Trans R Soc Lond B Biol Sci — View Article Google Scholar 3. Mattes RD Nutritional implications of taste and smell.
In: Doty RL, editor. Handbook of Olfaction and Gustation. New York: Marcel Dekker, Inc. Kim UK, Jorgenson E, Coon H, Leppert M, Risch N, et al.
Thank you for visiting nature. You are using Topical antifungal treatments for skin infections browser version with limited support for CSS. To obtain receprors Fat-blocking agents Glucoes, we Gluckse you use a more up Blood glucose level monitor date browser Fat-blocking agents turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Specific molecular recognition is routine for biology, but has proved difficult to achieve in synthetic systems. Carbohydrate substrates are especially challenging, because of their diversity and similarity to water, the biological solvent. Here we report a synthetic receptor for glucose, which is biomimetic in both design and capabilities. More Glucose receptors. June 20, Levels of blood rwceptors, or blood sugar, are tightly controlled by the body. People with diabetes have difficulty controlling blood glucose levels. High levels of blood glucose can cause serious health problems over time.
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