Myricetin Amplifies Glucose–Stimulated Insulin Secretion via the cAMP-PKA-Epac-2 Signaling Cascade
<b>Aim</b>: Myricetin, a natural bioflavonoid, is reported as an anti-diabetic agent since it possesses the ability to inhibit α-glucosidase activity, stimulate insulin action and secretion, manage ROS, and prevent diabetes complications. Myricetin was identified as a new insulin secreta...
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2025-06-01
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| author | Akhtar Ali Zahida Memon Abdul Hameed Zaheer Ul-Haq Muneeb Ali Rahman M. Hafizur |
| author_facet | Akhtar Ali Zahida Memon Abdul Hameed Zaheer Ul-Haq Muneeb Ali Rahman M. Hafizur |
| author_sort | Akhtar Ali |
| collection | DOAJ |
| description | <b>Aim</b>: Myricetin, a natural bioflavonoid, is reported as an anti-diabetic agent since it possesses the ability to inhibit α-glucosidase activity, stimulate insulin action and secretion, manage ROS, and prevent diabetes complications. Myricetin was identified as a new insulin secretagogue that enhances glucose-stimulated insulin secretion and seems like a better antidiabetic drug candidate. Here, we explored the insulinotropic mechanism(s) of myricetin <i>in vitro</i> in mice islets and <i>in silico</i>. <b>Methods</b>: Size-matched pancreatic islets were divided into groups and incubated in the presence or absence of myricetin and agonists/antagonists of major insulin signaling pathways. The secreted insulin was measured by ELISA. Molecular docking studies were performed with the key player of insulin secretory pathways. <b>Results</b>: Myricetin dose-dependently enhanced insulin secretion in isolated mice islets, and its insulinotropic effect was exerted at high glucose concentrations distinctly different from glibenclamide. Myricetin-induced insulin secretion was significantly inhibited using the diazoxide. Furthermore, myricetin amplified glucose-induced insulin secretion in depolarized and glibenclamide-treated islets. Myricetin showed an additive effect with forskolin- and IBMX-induced insulin secretion. Interestingly, H89, a PKA inhibitor, and MAY0132, an Epac-2 inhibitor, significantly inhibited myricetin-induced insulin secretion. The <i>in silico</i> molecular docking studies further validated these <i>in vitro</i> findings in isolated pancreatic islets. <b>Conclusions</b>: Myricetin, a potential natural insulin secretagogue, amplifies glucose-induced insulin secretion <i>via</i> the cAMP-PKA-Epac-2 signaling pathway. |
| format | Article |
| id | doaj-art-b8052bc491ac487cb39abec97cffcb6f |
| institution | Kabale University |
| issn | 2227-9059 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | MDPI AG |
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| series | Biomedicines |
| spelling | doaj-art-b8052bc491ac487cb39abec97cffcb6f2025-08-20T03:27:22ZengMDPI AGBiomedicines2227-90592025-06-01136144710.3390/biomedicines13061447Myricetin Amplifies Glucose–Stimulated Insulin Secretion via the cAMP-PKA-Epac-2 Signaling CascadeAkhtar Ali0Zahida Memon1Abdul Hameed2Zaheer Ul-Haq3Muneeb Ali4Rahman M. Hafizur5Department of Pharmacology, Ziauddin University Karachi, Karachi 75000, PakistanDepartment of Pharmacology, Ziauddin University Karachi, Karachi 75000, PakistanZiauddin College of Molecular Medicine, Ziauddin University Karachi, Karachi 75000, PakistanDr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, PakistanDr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, PakistanDr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan<b>Aim</b>: Myricetin, a natural bioflavonoid, is reported as an anti-diabetic agent since it possesses the ability to inhibit α-glucosidase activity, stimulate insulin action and secretion, manage ROS, and prevent diabetes complications. Myricetin was identified as a new insulin secretagogue that enhances glucose-stimulated insulin secretion and seems like a better antidiabetic drug candidate. Here, we explored the insulinotropic mechanism(s) of myricetin <i>in vitro</i> in mice islets and <i>in silico</i>. <b>Methods</b>: Size-matched pancreatic islets were divided into groups and incubated in the presence or absence of myricetin and agonists/antagonists of major insulin signaling pathways. The secreted insulin was measured by ELISA. Molecular docking studies were performed with the key player of insulin secretory pathways. <b>Results</b>: Myricetin dose-dependently enhanced insulin secretion in isolated mice islets, and its insulinotropic effect was exerted at high glucose concentrations distinctly different from glibenclamide. Myricetin-induced insulin secretion was significantly inhibited using the diazoxide. Furthermore, myricetin amplified glucose-induced insulin secretion in depolarized and glibenclamide-treated islets. Myricetin showed an additive effect with forskolin- and IBMX-induced insulin secretion. Interestingly, H89, a PKA inhibitor, and MAY0132, an Epac-2 inhibitor, significantly inhibited myricetin-induced insulin secretion. The <i>in silico</i> molecular docking studies further validated these <i>in vitro</i> findings in isolated pancreatic islets. <b>Conclusions</b>: Myricetin, a potential natural insulin secretagogue, amplifies glucose-induced insulin secretion <i>via</i> the cAMP-PKA-Epac-2 signaling pathway.https://www.mdpi.com/2227-9059/13/6/1447myricetininsulin secretionsulfonylureaantidiabetic drugsinsulin secretagogues |
| spellingShingle | Akhtar Ali Zahida Memon Abdul Hameed Zaheer Ul-Haq Muneeb Ali Rahman M. Hafizur Myricetin Amplifies Glucose–Stimulated Insulin Secretion via the cAMP-PKA-Epac-2 Signaling Cascade Biomedicines myricetin insulin secretion sulfonylurea antidiabetic drugs insulin secretagogues |
| title | Myricetin Amplifies Glucose–Stimulated Insulin Secretion via the cAMP-PKA-Epac-2 Signaling Cascade |
| title_full | Myricetin Amplifies Glucose–Stimulated Insulin Secretion via the cAMP-PKA-Epac-2 Signaling Cascade |
| title_fullStr | Myricetin Amplifies Glucose–Stimulated Insulin Secretion via the cAMP-PKA-Epac-2 Signaling Cascade |
| title_full_unstemmed | Myricetin Amplifies Glucose–Stimulated Insulin Secretion via the cAMP-PKA-Epac-2 Signaling Cascade |
| title_short | Myricetin Amplifies Glucose–Stimulated Insulin Secretion via the cAMP-PKA-Epac-2 Signaling Cascade |
| title_sort | myricetin amplifies glucose stimulated insulin secretion via the camp pka epac 2 signaling cascade |
| topic | myricetin insulin secretion sulfonylurea antidiabetic drugs insulin secretagogues |
| url | https://www.mdpi.com/2227-9059/13/6/1447 |
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