Dataset Information

The Ile191Val Variant of the TAS1R2 Subunit of Sweet Taste Receptors Is Associated With Reduced HbA_1c in a Human Cohort With Variable Levels of Glucose Homeostasis.

ABSTRACT: The Ile191Val variant of the TAS1R2 gene of sweet taste receptors causes a partial loss-of-function and is associated with reduced glucose excursions in a healthy lean cohort. However, it is unclear whether this polymorphism contributes to the regulation of glucose homeostasis in metabolically unhealthy individuals. Thus, we used participants with variable glycemic profiles and obesity to assess the effects of the TAS1R2-Ile191Val variant. We found that the Val minor allele carriers had lower HbA_1c at all levels of fasting glucose and glucose tolerance. These effects were not due to differences in beta-cell function or insulin sensitivity assessed with a frequently sampled intravenous glucose tolerance test. This study extends our previous findings and provides further evidence that sweet taste receptor function may contribute to glucose regulation in humans.

SUBMITTER: Serrano J

PROVIDER: S-EPMC9160323 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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The Ile191Val Variant of the TAS1R2 Subunit of Sweet Taste Receptors Is Associated With Reduced HbA<sub>1c</sub> in a Human Cohort With Variable Levels of Glucose Homeostasis.

Serrano Joan J Yi Fanchao F Smith Joshua J Pratley Richard E RE Kyriazis George A GA

Frontiers in nutrition 20220519

The Ile191Val variant of the <i>TAS1R2</i> gene of sweet taste receptors causes a partial loss-of-function and is associated with reduced glucose excursions in a healthy lean cohort. However, it is unclear whether this polymorphism contributes to the regulation of glucose homeostasis in metabolically unhealthy individuals. Thus, we used participants with variable glycemic profiles and obesity to assess the effects of the TAS1R2-Ile191Val variant. We found that the Val minor allele carriers had l ...[more]

PMID: 35662939

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Project description:The human sweet taste receptor is a heterodimeric receptor composed of two distinct G-protein-coupled receptors (GPCRs), TAS1R2 and TAS1R3. The TAS1R2 and TAS1R3 subunits are members of a small family of class C GPCRs whose members share the same architecture, comprising a Venus Flytrap (VFT) module linked to the seven transmembrane domains (TMDs) by a short cysteine-rich region (CRR). The VFT module of TAS1R2 contains the primary binding site for most of the sweet-tasting compounds, including natural sugars and artificial and natural sweeteners. However, cellular assays, molecular docking and site-directed mutagenesis studies have revealed that the VFT, CRR and TMD of TAS1R3 interact with some sweeteners, including the sweet-tasting protein brazzein. The aim of this study was to better understand the contribution of TAS1R2-VFT in the binding of sweet stimuli. To achieve this, we heterologously expressed human TAS1R2-VFT (hTAS1R2-VFT) in Escherichia coli. Circular dichroism spectroscopic studies revealed that hTAS1R2-VFT was properly folded with evidence of secondary structures. Using size-exclusion chromatography coupled with light scattering, we found that hTAS1R2-VFT behaves as a monomer. Ligand binding quantified by intrinsic tryptophan fluorescence showed that hTAS1R2-VFT is capable of binding sweet stimuli with Kd values, in agreement with physiological detection. Furthermore, we investigated whether the impact of point mutations, already shown to have deleterious effects on cellular assays, could impact the ability of hTAS1R2-VFT to bind sweet ligands. As expected, the ligand affinities of hTAS1R2-VFT were drastically reduced through the introduction of single amino acid substitutions (D278A and E382A) known to abolish the response of the full-length TAS1R2/TAS1R3 receptor. This study demonstrates the feasibility of producing milligram quantities of hTAS1R2-VFT to further characterize the mechanism of binding interaction and perform structural studies.

Project description:Aims/hypothesisThe aim of the study was to evaluate longitudinal associations between HbA1c levels, diabetes status and subsequent cognitive decline over a 10 year follow-up period.MethodsData from wave 2 (2004-2005) to wave 7 (2014-2015) of the English Longitudinal Study of Ageing (ELSA) were analysed. Cognitive function was assessed at baseline (wave 2) and reassessed every 2 years at waves 3-7. Linear mixed models were used to evaluate longitudinal associations.ResultsThe study comprised 5189 participants (55.1% women, mean age 65.6 ± 9.4 years) with baseline HbA1c levels ranging from 15.9 to 126.3 mmol/mol (3.6-13.7%). The mean follow-up duration was 8.1 ± 2.8 years and the mean number of cognitive assessments was 4.9 ± 1.5. A 1 mmol/mol increment in HbA1c was significantly associated with an increased rate of decline in global cognitive z scores (-0.0009 SD/year, 95% CI -0.0014, -0.0003), memory z scores (-0.0005 SD/year, 95% CI -0.0009, -0.0001) and executive function z scores (-0.0008 SD/year, 95% CI -0.0013, -0.0004) after adjustment for baseline age, sex, total cholesterol, HDL-cholesterol, triacylglycerol, high-sensitivity C-reactive protein, BMI, education, marital status, depressive symptoms, current smoking, alcohol consumption, hypertension, CHD, stroke, chronic lung disease and cancer. Compared with participants with normoglycaemia, the multivariable-adjusted rate of global cognitive decline associated with prediabetes and diabetes was increased by -0.012 SD/year (95% CI -0.022, -0.002) and -0.031 SD/year (95% CI -0.046, -0.015), respectively (p for trend <0.001). Similarly, memory, executive function and orientation z scores showed an increased rate of cognitive decline with diabetes.Conclusions/interpretationSignificant longitudinal associations between HbA1c levels, diabetes status and long-term cognitive decline were observed in this study. Future studies are required to determine the effects of maintaining optimal glucose control on the rate of cognitive decline in people with diabetes.

Dataset Information

The Ile191Val Variant of the TAS1R2 Subunit of Sweet Taste Receptors Is Associated With Reduced HbA_1c in a Human Cohort With Variable Levels of Glucose Homeostasis.

Publications

The Ile191Val Variant of the TAS1R2 Subunit of Sweet Taste Receptors Is Associated With Reduced HbA<sub>1c</sub> in a Human Cohort With Variable Levels of Glucose Homeostasis.

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Dataset Information

The Ile191Val Variant of the TAS1R2 Subunit of Sweet Taste Receptors Is Associated With Reduced HbA1c in a Human Cohort With Variable Levels of Glucose Homeostasis.

Publications

The Ile191Val Variant of the TAS1R2 Subunit of Sweet Taste Receptors Is Associated With Reduced HbA<sub>1c</sub> in a Human Cohort With Variable Levels of Glucose Homeostasis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

The Ile191Val Variant of the TAS1R2 Subunit of Sweet Taste Receptors Is Associated With Reduced HbA_1c in a Human Cohort With Variable Levels of Glucose Homeostasis.