Functional variants in the TAS2R38 bitter taste receptor associate with postprandial glycemia

Aims/HypothesisFunctional variants in the TAS2R38 bitter taste receptor influence bitter taste perception and inform dietary and lifestyle behaviors that impact glucose homeostasis. Experimental data suggest that TAS2R38 receptors also mediate postprandial GLP-1 secretions from intestinal L-cells, though human study data are limited. To further establish the role of TAS2R38 in glucose homeostasis in humans, we tested whether functional variants conferring greater TAS2R38 sensitivity associate with lower blood glucose, particularly in the postprandial state, independent of dietary- and lifestyle-mediated effects of TAS2R38 on glucose levels. MethodsWe analyzed participants without type 2 diabetes of European ancestry in the UK Biobank. We used known functional variants in TAS2R38 to assign canonical haplotypes (AVI, PAV) and diplotypes conferring low (AVI/AVI nontasters), moderate (AVI/PAV tasters) or high (PAV/PAV supertasters) TAS2R38 receptor sensitivity and bitter taste perception. Linear models were used to quantify the associations of TAS2R38 diplotype with random glucose, and glucose levels over various time windows spanning postprandial and fasting states, adjusting for demographics and BMI, then sequentially for dietary and lifestyle factors. We used variants in other bitter taste receptors (TAS2R14 and TAS2R19), related to similar dietary and lifestyle behaviors as TAS2R38 but without hypothesized roles in glucose metabolism, to serve as negative controls. ResultsAmong 218,688 individuals, 34%, 49% and 18% were AVI/AVI nontasters, AVI/PAV tasters and PAV/PAV supertasters, respectively. In BMI-adjusted models, each additional PAV haplotype associated with decreases in random glucose levels (beta [95% CI] = -0.07 [-0.13, -0.01] mg/dL; P = 0.021). In analyses stratified by fasting time, associations were only significant in the 0-2 hr postprandial window (-0.24 [-0.39, -0.08] mg/dL per PAV haplotype; P = 0.003). These associations replicated (at the variant-level) in a published GWAS meta-analysis of 2-hr OGTT glucose and persisted after further adjustment for dietary and lifestyle behaviors (adjusted beta = -0.22; P = 0.004). Variants in TAS2R14 and TAS2R19 were related to similar behavioral traits as TAS2R38 but were not associated with 0-2 hr glucose, supporting behaviorally-independent effects of TAS2R38 diplotypes on 0-2 hr glucose. Conclusions/interpretationFunctional variants conferring greater TAS2R38 receptor sensitivity were associated with lower glucose levels in the postprandial state. These findings align with experimental evidence supporting a functional role for TAS2R38 in postprandial glycemia, reinforcing it as a potential target for type 2 diabetes prevention and treatment. Research in ContextO_ST_ABSWhat is already known about this subject?C_ST_ABSO_LITAS2R38 is a specialized G-protein coupled receptor that mediates bitter taste perception in the mouth and has been discovered to act as a peripheral nutrient sensor in intestinal L-cells in the gut. C_LIO_LIFunctional variants in TAS2R38 conferring its sensitivity give rise to three canonical diplotypes with well-defined effects on bitter taste perception and dietary and lifestyle behaviors relevant to glucose homeostasis. C_LIO_LIExperimental studies show that TAS2R38 receptors in human enteroendocrine L-cells contribute to the postprandial secretion of incretin hormone, glucagon-like peptide-1 (GLP-1). C_LI What is the key question?O_LIAre functional variants in the TAS2R38 bitter taste receptor associated with glucose homeostasis in humans, particularly in the postprandial state? C_LI What are the new findings?O_LIIn a large cohort of adults without type 2 diabetes, individuals carrying two copies of the haplotype encoding more sensitive TAS2R38 receptors (PAV) had significantly lower postprandial glucose levels than those with two copies of the non-functional haplotype (AVI), regardless of dietary or lifestyle behaviors, with differences following a dose-response relationship per PAV haplotype. C_LI How might this impact on clinical practice in the foreseeable future?O_LIThese findings provide evidence to support direct TAS2R38 actions in postprandial glycemia, which could inform subsequent experimental work to leverage TAS2R38 as a therapeutic target for impaired glucose regulation. C_LI