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UNLABELLED: 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 glucagon-like peptide 1 (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 remains limited. 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 were associated with blood glucose. We found that individuals with two copies of a haplotype increasing receptor sensitivity (PAV) had significantly lower 0-2-h (i.e., postprandial) glucose than those with two copies of a nonfunctional haplotype (AVI), following a dose-response relationship per PAV haplotype. These associations were replicated in published genome-wide association studies of 2-h 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 (TAS2R14 and TAS2R19). Collectively, these findings provide evidence in humans consistent with direct TAS2R38 actions in postprandial glycemia, supporting TAS2R38 as a novel therapeutic target for glucose regulation.ARTICLE HIGHLIGHTS: The TAS2R38 bitter taste receptor, recently identified within intestinal L cells, has been shown to modulate GLP-1 secretion in preclinical models; however, evidence in humans remains limited. We harnessed functional variants comprising three canonical diplotypes of TAS2R38 to study the role of TAS2R38 in glucose homeostasis in humans. In a large sample of adults without type 2 diabetes, we found that individuals with more sensitive TAS2R38 receptors had lower postprandial glucose levels, independent of diet and lifestyle habits. Our findings provide evidence in humans supporting direct TAS2R38 actions in postprandial glycemia and highlight TAS2R38 as a potential therapeutic target for impaired glucose regulation.