The Ile191Val is a partial loss-of-function variant of the TAS1R2 sweet-taste receptor and is associated with reduced glucose excursions in humans

Abstract

Objective Sweet taste receptors (STR) are expressed in the gut and other extra-oral tissues, suggesting that STR-mediated nutrient sensing may contribute to human physiology beyond taste. A common variant (Ile191Val) in the TAS1R2 gene of STR is associated with nutritional and metabolic outcomes independent of changes in taste perception. It is unclear whether this polymorphism directly alters STR function and how it may contribute to metabolic regulation. Methods We implemented a combination of in vitro biochemical approaches to decipher the effects of TAS1R2 polymorphism on STR function. Then, as proof-of-concept, we assessed its effects on glucose homeostasis in apparently healthy lean participants. Results The Ile191Val variant causes a partial loss of function of TAS1R2 through reduced receptor availability in the plasma membrane. Val minor allele carriers have reduced glucose excursions during an OGTT, mirroring effects previously seen in mice with genetic loss of function of TAS1R2. These effects were not due to differences in beta-cell function or insulin sensitivity. Conclusions Our pilot studies on a common TAS1R2 polymorphism suggest that STR sensory function in peripheral tissues, such as the intestine, may contribute to the regulation of metabolic control in humans.

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

“…Postprandial hyperglycemia significantly contributes to total daytime hyperglycemia and strongly correlates with HbA 1c ( 30 ). This finding is aligned with the reduced OGTT glucose excursions seen in metabolically healthy lean Val/_ participants ( 10 ). However, we did not observe a direct genotype effects in glucose or insulin responses during an OGTT.…”

“…Taken together these observations suggest that, like in mice, TAS1R2 may have functional roles in peripheral tissues beyond taste perception. We recently used biochemical approaches to show that the Ile191Val substitution causes a partial loss-of-function of TAS1R2 by reducing the availability of the STR dimer in the plasma membrane ( 10 ). Healthy lean Val carriers had reduced glucose excursions during an OGTT ( 10 ), which resembles the effects seen in mice with a genetic loss-of-function of TAS1R2 ( 5 , 27 ), confirming that the Val substitution causes a partial loss-of-function of STRs.…”

“…We recently demonstrated that the TAS1R2 (Ile191Val) polymorphism reduces the levels of STR in the plasma membrane, causing partial loss-of-function ( 10 ). Consequently, Val carriers had a mild reduction in glucose excursions in response to the ingestion of a glucose load, recapitulating the phenotype seen in TAS1R2-KO mice ( 5 ).…”

Saccharin Stimulates Insulin Secretion Dependent on Sweet Taste Receptor-Induced Activation of PLC Signaling Axis

“…Sweet taste sensing and signaling requires the formation of a T1R2/T1R3 heterodimer [ 14 , 41 ]. Although the mRNA expression of T1r2 and T1r3 has been previously reported in whole mouse islets [ 8 , 9 ], commercially available antibodies targeting STR are not specific.…”

Oral Microbiota-Host Interaction Mediated by Taste Receptors

“…Serrano et al. subsequently found that T1R2 gene variant Ile191Val causes a partial loss of function and results in reduced glucose excursions during an OGTT, which is independent of the variations in beta-cell function or insulin sensitivity ( Serrano et al., 2021 ). Additionally, bitter taste receptors have also been revealed of the function to evoke airway smooth muscle relaxation via localized calcium flux, predicting the potential role in counteracting asthmatic bronchoconstriction ( Deshpande et al., 2010 ).…”