Ashitaba Chalcone 4‐Hydroxydericcin Promotes Glucagon‐Like Peptide‐1 Secretion and Prevents Postprandial Hyperglycemia in Mice

Certain polyphenols improve glucose tolerance by stimulating glucagon-like peptide-1 (GLP-1) secretion from intestinal L-cells. Ashitaba chalcones, 4-hydroxyderricin (4-HD), and xanthoangelol (XAG) have antihyperglycemic effects, but their molecular mechanism, including whether they promote GLP-1 secretion is unknown. This study investigates the 4-HD-induced GLP-1 secretory mechanisms and its anti-hyperglycemic effects. The secretory mechanisms were examined in STC-1 cells and antihyperglycemic effects in male ICR mice. In STC-1 cells, 4-HD, but not XAG, stimulated GLP-1 secretion through membrane depolarization and intracellular Ca2+ increase [Ca2+]i, via the L-type Ca2+ channel (VGCC). Verapamil and nifedipine, blockers of VGCC, and treatment in Ca2+-free buffer abolished 4-HD effects on [Ca2+]i and GLP-1 secretion. Moreover, 4-HD activated CaMKII and ERK1/2. Consistently, oral 4-HD suppressed postprandial hyperglycemia in mice and increased plasma GLP-1 and insulin levels, GLUT4 translocation, and activation of LKB-1 and Akt pathways in skeletal muscle. Furthermore, exendin 9-39, a GLP-1R antagonist, and compound C, an AMPK inhibitor, completely canceled the 4-HD-caused anti-hyperglycemic activities. 4-HD stimulated GLP-1 secretion through membrane depolarization coupled with [Ca2+]i increase via VGCC in L-cells and activated AMPK- and insulin-induced GLUT4 translocation in skeletal muscle. Thus, 4-HD possesses dual mechanisms for the prevention of hyperglycemia.