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. 2025 Aug 5:1000:177722.
doi: 10.1016/j.ejphar.2025.177722. Epub 2025 May 8.

Involvement of glucagon-like peptide-1 receptor in fisetin tetramethyl ether-enhanced insulin secretion in MIN6 cells

Kazunori Hashimoto  1 , Chihiro Ito  2 , Eka Takahashi  3 , Rico Nishio  3 , Ryoga Tsurigami  4 , Naoto Kato  3 , Satsuki Miyazaki  5 , Jun-Ichi Miyazaki  6 , Motoyuki Shimizu  7 , Masashi Kato  7 , Hugh T-W Tan  8 , Tomiyasu Murata  9
Affiliations

Involvement of glucagon-like peptide-1 receptor in fisetin tetramethyl ether-enhanced insulin secretion in MIN6 cells

Kazunori Hashimoto et al. Eur J Pharmacol. .

Abstract

Background: Pongamia pinnata (L.) Pierre, long used as a traditional medicine to treat diabetes and metabolic disorders, shows an insulinotropic effect.

Objective: This study aimed to determine the insulinotropic property and underlying mechanism of a constituent of Pongamia pinnata, fisetin tetramethyl ether (FTM).

Methods: The insulinotropic property of FTM was investigated using pancreatic beta cell line MIN6, while secreted insulin and residual insulin were detected by an insulin assay. Furthermore, the underlying mechanism was examined with use of an ATP assay, Ca2+ flux assay, and immunoblot analysis, as well as the insulin assay with pharmacological inhibitors.

Results: FTM increased insulin secretion in a dose-dependent manner. In addition, 10 mM or more of glucose increased insulin secretion regardless of the presence of FTM. Nimodipine, a voltage-dependent Ca channel antagonist, completely eliminated insulin secretion induced by glucose and FTM. However, FTM treatment had minimal effects on ATP and intracellular Ca2+ levels, suggesting its enhancement of glucose-stimulated insulin secretion (GSIS) independent of glucose metabolism. Additionally, a newly developed glucagon-like peptide-1 (GLP-1) receptor antagonist, VU0650991, reduced FTM-enhanced GSIS. Moreover, FTM-enhanced GSIS was reduced by barbadin, an inhibitor of the β-arrestins-mediated signaling pathway, as well as GSK215, a degrader of focal adhesion kinase (FAK), though not by HJC0350, an inhibitor of exchange protein activated by cAMP 2 involved in insulin granule exocytosis.

Conclusion: The GLP-1 receptor-β-arrestins/FAK pathway is involved in FTM-enhanced GSIS. This study showed that FTM, a constituent of Pongamia pinnata, is an insulinotropic phytochemical possessing biased GLP-1 receptor agonistic potential.

Keywords: Fisetin tetramethyl ether; GLP-1 receptor; Insulin secretion; Polymethoxyflavone; Pongamia pinnata.

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Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.