{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T19:47:00Z","timestamp":1792180020393,"version":"4.4.0"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T00:00:00Z","timestamp":1780444800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Purpose<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      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.\n                      <jats:italic>In vivo<\/jats:italic>\n                      effect was confirmed in high-fat-diet-induced diabetic mice by oral administration.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study demonstrated that Hesperetin and Naringenin promoted GLP-1 secretion from L-cells through TGR5 activation and alleviated type 2 diabetes.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1838267","type":"journal-article","created":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T06:07:23Z","timestamp":1780466843000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Hesperetin and Naringenin promote glucagon-like peptide-1 secretion from L-cell through activation of TGR5 and alleviated type 2 diabetes"],"prefix":"10.3389","volume":"17","author":[{"given":"Chen-Yang","family":"Zhang","sequence":"first","affiliation":[{"name":"Beijing Key Laboratory of Diabetes Research and Care, Department of Endocrinology and Metabolism, Beijing Diabetes Institute, Beijing Tongren Hospital, Capital Medical University","place":["Beijing, China"]},{"name":"Laboratory for Clinical Medicine, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zi-Lu","family":"Wang","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Diabetes Research and Care, Department of Endocrinology and Metabolism, Beijing Diabetes Institute, Beijing Tongren Hospital, Capital Medical University","place":["Beijing, China"]},{"name":"Laboratory for Clinical Medicine, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ze-Ju","family":"Jiang","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Diabetes Research and Care, Department of Endocrinology and Metabolism, Beijing Diabetes Institute, Beijing Tongren Hospital, Capital Medical University","place":["Beijing, China"]},{"name":"Laboratory for Clinical Medicine, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanna","family":"Kim","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Diabetes Research and Care, Department of Endocrinology and Metabolism, Beijing Diabetes Institute, Beijing Tongren Hospital, Capital Medical University","place":["Beijing, China"]},{"name":"Laboratory for Clinical Medicine, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang","family":"Liu","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Diabetes Research and Care, Department of Endocrinology and Metabolism, Beijing Diabetes Institute, Beijing Tongren Hospital, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Wang","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Diabetes Research and Care, Department of Endocrinology and Metabolism, Beijing Diabetes Institute, Beijing Tongren Hospital, Capital Medical University","place":["Beijing, China"]},{"name":"Laboratory for Clinical Medicine, Capital Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1133","DOI":"10.3390\/nu13041133","article-title":"Twelve-week mediterranean diet intervention increases citrus bioflavonoid levels and reduces inflammation in people with type 2 diabetes mellitus","volume":"13","author":"Al-Aubaidy","year":"2021","journal-title":"Nutrients"},{"key":"B2","doi-asserted-by":"publisher","first-page":"112188","DOI":"10.1016\/j.diabres.2025.112188","article-title":"The burden of type 2 diabetes in China from 1990 to 2021: a comparative analysis with G20 countries using the global burden of disease study 2021","volume":"224","author":"An","year":"2025","journal-title":"Diabetes Res. Clin. Pract."},{"key":"B3","doi-asserted-by":"publisher","first-page":"390","DOI":"10.1038\/s41574-018-0016-2","article-title":"Glucagon-like peptide 1 in health and disease","volume":"14","author":"Andersen","year":"2018","journal-title":"Nat. Rev. Endocrinol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"4738","DOI":"10.1111\/bph.15896","article-title":"Novel luciferase-based glucagon-like peptide 1 reporter assay reveals naturally occurring secretagogues","volume":"179","author":"Anghel","year":"2022","journal-title":"Br. J. Pharmacol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"372","DOI":"10.2337\/db16-1102","article-title":"The hypothalamic glucagon-like peptide 1 receptor is sufficient but not necessary for the regulation of energy balance and glucose homeostasis in mice","volume":"66","author":"Burmeister","year":"2017","journal-title":"Diabetes"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1203","DOI":"10.3390\/pharmaceutics15041203","article-title":"Pediococcus acidilactici pA1c((R)) improves the beneficial effects of metformin treatment in type 2 diabetes by controlling glycaemia and modulating intestinal microbiota","volume":"15","author":"Cabello-Olmo","year":"2023","journal-title":"Pharmaceutics"},{"key":"B7","doi-asserted-by":"publisher","first-page":"927","DOI":"10.1016\/j.cmet.2017.02.008","article-title":"The role of pancreatic preproglucagon in glucose homeostasis in mice","volume":"25","author":"Chambers","year":"2017","journal-title":"Cell. Metab."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1218880","DOI":"10.3389\/fendo.2023.1218880","article-title":"Exploring the underlying mechanisms of obesity and diabetes and the potential of traditional Chinese medicine: an overview of the literature","volume":"14","author":"Chen","year":"2023","journal-title":"Front. Endocrinol. (Lausanne)"},{"key":"B9","doi-asserted-by":"publisher","first-page":"291","DOI":"10.3390\/biom15020291","article-title":"G-Protein-Coupled receptor (GPCR) signaling and pharmacology in metabolism: physiology, mechanisms, and therapeutic potential","volume":"15","author":"Cho","year":"2025","journal-title":"Biomolecules"},{"key":"B10","doi-asserted-by":"publisher","first-page":"740","DOI":"10.1016\/j.cmet.2018.03.001","article-title":"Mechanisms of action and therapeutic application of glucagon-like Peptide-1","volume":"27","author":"Drucker","year":"2018","journal-title":"Cell Metab."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1646","DOI":"10.1210\/mend.8.12.7535893","article-title":"Activation of proglucagon gene transcription by protein kinase-A in a novel mouse enteroendocrine cell line","volume":"8","author":"Drucker","year":"1994","journal-title":"Mol. Endocrinol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"e078483","DOI":"10.1136\/bmj-2023-078483","article-title":"SGLT-2 inhibitors, GLP-1 receptor agonists, and DPP-4 inhibitors and risk of hyperkalemia among people with type 2 diabetes in clinical practice: population based cohort study","volume":"385","author":"Fu","year":"2024","journal-title":"BMJ"},{"key":"B13","doi-asserted-by":"publisher","first-page":"2907","DOI":"10.3390\/nu12102907","article-title":"Citrus flavonoids as promising phytochemicals targeting diabetes and related complications: a systematic review of in vitro and in vivo studies","volume":"12","author":"Gandhi","year":"2020","journal-title":"Nutrients"},{"key":"B14","doi-asserted-by":"publisher","first-page":"e70718","DOI":"10.1096\/fj.202501267R","article-title":"Characteristics of berberine effects on insulin exocytosis in pancreatic \u03b2 cells","volume":"39","author":"Jiang","year":"2025","journal-title":"FASEB J."},{"key":"B15","doi-asserted-by":"publisher","first-page":"116462","DOI":"10.1016\/j.ejmech.2024.116462","article-title":"Update on the development of TGR5 agonists for human diseases","volume":"271","author":"Jin","year":"2024","journal-title":"Eur. J. Med. Chem."},{"key":"B16","doi-asserted-by":"publisher","first-page":"472","DOI":"10.1038\/sj.ejcn.1602543","article-title":"Pharmacokinetics of the citrus flavanone aglycones hesperetin and naringenin after single oral administration in human subjects","volume":"61","author":"Kanaze","year":"2007","journal-title":"Eur. J. Clin. Nutr."},{"key":"B17","doi-asserted-by":"publisher","first-page":"694284","DOI":"10.3389\/fendo.2021.694284","article-title":"What is an L-cell and how do we study the secretory mechanisms of the L-cell?","volume":"12","author":"Kuhre","year":"2021","journal-title":"Front. Endocrinol. (Lausanne)"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3390\/nu10101415","article-title":"Luteolin targets the toll-like receptor signaling pathway in prevention of hepatic and adipocyte fibrosis and insulin resistance in diet-induced obese mice","volume":"10","author":"Kwon","year":"2018","journal-title":"Nutrients"},{"key":"B19","doi-asserted-by":"publisher","first-page":"155329","DOI":"10.1016\/j.phymed.2023.155329","article-title":"Study on the mechanism of modified Gegen Qinlian decoction in regulating the intestinal flora-bile acid-TGR5 axis for the treatment of type 2 diabetes mellitus based on macro genome sequencing and targeted metabonomics integration","volume":"132","author":"Liu","year":"2024","journal-title":"Phytomedicine"},{"key":"B20","doi-asserted-by":"publisher","first-page":"468","DOI":"10.1016\/j.apsb.2023.11.011","article-title":"Mechanism of action of the bile acid receptor TGR5 in obesity","volume":"14","author":"Lun","year":"2024","journal-title":"Acta Pharm. Sin. B"},{"key":"B21","doi-asserted-by":"publisher","first-page":"1094","DOI":"10.3390\/ijms26031094","article-title":"Type 2 diabetes mellitus: new pathogenetic mechanisms, treatment and the Most important complications","volume":"26","author":"Mlynarska","year":"2025","journal-title":"Int. J. Mol. Sci."},{"key":"B22","doi-asserted-by":"publisher","first-page":"3155","DOI":"10.1080\/10408398.2019.1679085","article-title":"The pharmacokinetics of flavanones","volume":"60","author":"Najmanova","year":"2020","journal-title":"Crit. Rev. Food Sci. Nutr."},{"key":"B23","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1016\/S2213-8587(21)00113-3","article-title":"Treatment of type 2 diabetes: challenges, hopes, and anticipated successes","volume":"9","author":"Nauck","year":"2021","journal-title":"Lancet Diabetes Endocrinol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1186\/s12933-022-01564-y","article-title":"Improvement in insulin sensitivity and prevention of high fat diet-induced liver pathology using a CXCR2 antagonist","volume":"21","author":"Phillips","year":"2022","journal-title":"Cardiovasc Diabetol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"239","DOI":"10.3390\/antiox11020239","article-title":"Bioactive compounds of citrus fruits: a review of composition and health benefits of carotenoids, flavonoids, limonoids, and terpenes","volume":"11","author":"Saini","year":"2022","journal-title":"Antioxidants (Basel)"},{"key":"B26","doi-asserted-by":"publisher","first-page":"187","DOI":"10.2174\/1568026615666141209163013","article-title":"Emerging potential of citrus flavanones as an antioxidant in diabetes and its complications","volume":"15","author":"Sharma","year":"2015","journal-title":"Curr. Top. Med. Chem."},{"key":"B27","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1210\/endrev\/bnaf036","article-title":"Novel GLP-1-Based medications for type 2 diabetes and obesity","volume":"47","author":"Son","year":"2025","journal-title":"Endocr. Rev"},{"key":"B28","doi-asserted-by":"publisher","first-page":"956","DOI":"10.1053\/j.gastro.2020.05.067","article-title":"Bile acids signal via TGR5 to activate intestinal stem cells and epithelial regeneration","volume":"159","author":"Sorrentino","year":"2020","journal-title":"Gastroenterology"},{"key":"B29","doi-asserted-by":"publisher","first-page":"2144","DOI":"10.2337\/db17-0058","article-title":"Mechanisms controlling glucose-induced GLP-1 secretion in human small intestine","volume":"66","author":"Sun","year":"2017","journal-title":"Diabetes"},{"key":"B30","doi-asserted-by":"publisher","first-page":"645","DOI":"10.1016\/0026-0495(95)90123-x","article-title":"Differential effects of fat and sucrose on the development of obesity and diabetes in C57BL\/6J and A\/J mice","volume":"44","author":"Surwit","year":"1995","journal-title":"Metabolism"},{"key":"B31","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1016\/j.cmet.2009.08.001","article-title":"TGR5-mediated bile acid sensing controls glucose homeostasis","volume":"10","author":"Thomas","year":"2009","journal-title":"Cell. Metab."},{"key":"B32","doi-asserted-by":"publisher","first-page":"2178","DOI":"10.1080\/10408398.2021.1971945","article-title":"Citrus polyphenols and risk of type 2 diabetes: evidence from mechanistic studies","volume":"63","author":"Visvanathan","year":"2023","journal-title":"Crit. Rev. Food Sci. Nutr."},{"key":"B33","doi-asserted-by":"publisher","first-page":"1806","DOI":"10.1111\/bph.14938","article-title":"Naringenin attenuates non-alcoholic fatty liver disease by down-regulating the NLRP3\/NF-kappaB pathway in mice","volume":"177","author":"Wang","year":"2020","journal-title":"Br. J. Pharmacol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"103045","DOI":"10.1016\/j.jbc.2023.103045","article-title":"The signaling protein GIV\/girdin mediates the Nephrin-dependent insulin secretion of pancreatic islet \u03b2 cells in response to high glucose","volume":"299","author":"Wang","year":"2023","journal-title":"J. Biol. Chem."},{"key":"B35","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1007\/s00018-024-05134-1","article-title":"KCNH6 channel promotes insulin exocytosis via interaction with Munc18-1 independent of electrophysiological processes","volume":"81","author":"Wang","year":"2024","journal-title":"Cell. Mol. Life Sci."},{"key":"B36","doi-asserted-by":"publisher","first-page":"2540","DOI":"10.1093\/advances\/nmab078","article-title":"Protein- and calcium-mediated GLP-1 secretion: a narrative review","volume":"12","author":"Watkins","year":"2021","journal-title":"Adv. Nutr."},{"key":"B37","doi-asserted-by":"publisher","first-page":"17147","DOI":"10.3390\/ijms242417147","article-title":"Drug therapies for diabetes","volume":"24","author":"Weinberg Sibony","year":"2023","journal-title":"Int. J. Mol. Sci."},{"key":"B38","doi-asserted-by":"publisher","first-page":"1649","DOI":"10.1038\/s41401-023-01081-y","article-title":"TGR5 agonist inhibits intestinal epithelial cell apoptosis via cAMP\/PKA\/c-FLIP\/JNK signaling pathway and ameliorates dextran sulfate sodium-induced ulcerative colitis","volume":"44","author":"Yang","year":"2023","journal-title":"Acta Pharmacol. Sin."},{"key":"B39","doi-asserted-by":"publisher","first-page":"1478","DOI":"10.1002\/ptr.8121","article-title":"Hesperetin promotes diabetic wound healing by inhibiting ferroptosis through the activation of SIRT3","volume":"38","author":"Yu","year":"2024","journal-title":"Phytother. Res."},{"key":"B40","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1038\/s41392-024-01923-z","article-title":"Potassium voltage-gated channel subfamily H member 2 (KCNH2) is a promising target for incretin secretagogue therapies","volume":"9","author":"Yuan","year":"2024","journal-title":"Signal Transduct. Target. Ther."},{"key":"B41","doi-asserted-by":"publisher","first-page":"1651","DOI":"10.3390\/ijms26041651","article-title":"Focus on glucagon-like Peptide-1 target: drugs approved or designed to treat obesity","volume":"26","author":"Zhang","year":"2025","journal-title":"Int. J. Mol. Sci."},{"key":"B42","doi-asserted-by":"publisher","first-page":"4774","DOI":"10.3390\/nu15224774","article-title":"Identification of crocetin as a dual agonist of GPR40 and GPR120 responsible for the antidiabetic effect of saffron","volume":"15","author":"Zhao","year":"2023","journal-title":"Nutrients"}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1838267\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T06:07:24Z","timestamp":1780466844000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1838267\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,3]]},"references-count":42,"alternative-id":["10.3389\/fphar.2026.1838267"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2026.1838267","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,3]]},"article-number":"1838267"}}