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Ashitaba chalcones, 4\u2010hydroxyderricin (4\u2010HD), and xanthoangelol (XAG) have antihyperglycemic effects, but their molecular mechanism, including whether they promote GLP\u20101 secretion is unknown. This study investigates the 4\u2010HD\u2010induced GLP\u20101 secretory mechanisms and its anti\u2010hyperglycemic effects. The secretory mechanisms were examined in STC\u20101 cells and antihyperglycemic effects in male ICR mice. In STC\u20101 cells, 4\u2010HD, but not XAG, stimulated GLP\u20101 secretion through membrane depolarization and intracellular Ca<jats:sup>2+<\/jats:sup> increase [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>, via the L\u2010type Ca<jats:sup>2+<\/jats:sup> channel (VGCC). Verapamil and nifedipine, blockers of VGCC, and treatment in Ca<jats:sup>2+<\/jats:sup>\u2010free buffer abolished 4\u2010HD effects on [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> and GLP\u20101 secretion. Moreover, 4\u2010HD activated CaMKII and ERK1\/2. Consistently, oral 4\u2010HD suppressed postprandial hyperglycemia in mice and increased plasma GLP\u20101 and insulin levels, GLUT4 translocation, and activation of LKB\u20101 and Akt pathways in skeletal muscle. Furthermore, exendin 9\u201339, a GLP\u20101R antagonist, and compound C, an AMPK inhibitor, completely canceled the 4\u2010HD\u2010caused anti\u2010hyperglycemic activities.<\/jats:p><\/jats:sec><jats:sec><jats:label\/><jats:p>4\u2010HD stimulated GLP\u20101 secretion through membrane depolarization coupled with [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> increase via VGCC in L\u2010cells and activated AMPK\u2010 and insulin\u2010induced GLUT4 translocation in skeletal muscle. Thus, 4\u2010HD possesses dual mechanisms for the prevention of hyperglycemia.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mnfr.202400690","type":"journal-article","created":{"date-parts":[[2025,2,11]],"date-time":"2025-02-11T10:23:17Z","timestamp":1739269397000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Ashitaba Chalcone 4\u2010Hydroxydericcin Promotes Glucagon\u2010Like Peptide\u20101 Secretion and Prevents Postprandial Hyperglycemia in Mice"],"prefix":"10.1002","volume":"69","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4977-8561","authenticated-orcid":false,"given":"Kevin","family":"Odongo","sequence":"first","affiliation":[{"name":"Department of Agrobioscience Graduate School of Agricultural Science Kobe University  Kobe Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moe","family":"Ishinaka","sequence":"additional","affiliation":[{"name":"Department of Agrobioscience Graduate 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