<b>Genetic Variants Increasing TAS2R38 Bitter Taste Receptor Sensitivity Are Associated With Lower Postprandial Glycemia</b>

<p dir="ltr">TAS2R38 is a bitter taste receptor that influences bitter taste perception and diet and is also found in intestinal L-cells that store and secrete GLP-1. Preclinical studies have linked TAS2R38 activation to postprandial GLP-1 secretion, fueling interest in TAS2R38 as a therapeutic target for glucose regulation; however, evidence in humans is lacking. To further establish TAS2R38 actions in glucose homeostasis, we analyzed data from ~220,000 European adults without type 2 diabetes in the UK Biobank to test whether functional variants conferring TAS2R38 sensitivity associate with blood glucose. We found that individuals with two copies of a haplotype increasing receptor sensitivity (<i>PAV</i>) had significantly lower 0-2 hour (i.e., postprandial) glucose than those with two copies of a non-functional haplotype (<i>AVI</i>), following a dose-response relationship per PAV haplotype. These associations were replicated in published GWAS of 2-hour glucose, persisted after adjustment for diet and lifestyle behaviors related to bitter taste perception and were not seen for variants in other bitter taste receptors without putative roles in glucose metabolism (<i>TAS2R14 </i>and <i>TAS2R19</i>). Collectively, these findings provide human evidence consistent with direct TAS2R38 actions in postprandial glycemia, supporting TAS2R38 as a novel therapeutic target for glucose regulation.</p>