ArticleFrontiers in pharmacology2026
Hesperetin and Naringenin promote glucagon-like peptide-1 secretion from L-cell through activation of TGR5 and alleviated type 2 diabetes.
Article in Frontiers in pharmacology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Purpose: Glucagon-like peptide-1 (GLP-1) secretagogues offer therapeutic potential for type 2 diabetes. Bioactive compounds in citrus were supposed to be effective in treating diabetes, while exact compounds activating enteroendocrine L-cell pathways remain underexplored. This study aimed to identify citrus-derived compounds that stimulate GLP-1 secretion from L cells by screening a traditional Chinese medicine library and to elucidate the underlying cellular mechanisms. Methods: A reporter GLUTag cell line (murine L cell line), designed to introduce a luciferase into the proglucagon sequence, was utilized to screen a traditional Chinese medicine library. The effects of selected compounds on GLP-1 secretion were evaluated in both GLUTag cells and primary mouse ileac epithelial cells. Intracellular cAMP levels and calcium flux were measured to elucidate their underlying mechanism, and a dual-luciferase reporter assay was used to confirm their activation on TGR5 target. Results: Hesperetin and Naringenin significantly promoted GLP-1 secretion from L cells. Both compounds increased cAMP accumulation and intracellular calcium influx in L cells, effects that were largely absent in TGR5-deficient L cells. Subsequently, dual-luciferase reporter assays identified them as TGR5 activators. Furthermore, cellular thermal shift assay (CETSA) provided evidence that each flavonoid forms a stable complex with TGR5. Finally, in high-fat-diet-induced diabetic mice, oral administration of either compound enhanced glucose-stimulated serum GLP-1 levels and ameliorated obesity and hyperglycemia under obese diabetic conditions. Conclusion: This study demonstrated that Hesperetin and Naringenin promoted GLP-1 secretion from L-cells through TGR5 activation and alleviated type 2 diabetes.
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