Ziauddin College of Molecular Medicine, Ziauddin University Karachi, Pakistan.
Ziauddin College of Molecular Medicine, Ziauddin University Karachi, Pakistan; Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
Biomed Pharmacother. 2024 Aug;177:116986. doi: 10.1016/j.biopha.2024.116986. Epub 2024 Jun 20.
Apigenin, a natural bioflavonoid, is reported as an anti-diabetic agent since it possesses the ability to inhibit α-glucosidase activity, cause stimulation of insulin action and secretion, manage ROS, and prevent diabetes complications. Apigenin 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 apigenin in vitro in mice islets and in vivo in diabetic rats.
Size-matched pancreatic islets were divided into groups and incubated in the presence or absence of apigenin and agonists or antagonists of major insulin signaling pathways. The secreted insulin was measured by ELISA. The intracellular cAMP was estimated by cAMP acetylation assay. The acute and chronic effects of apigenin were evaluated in diabetic rats.
apigenin dose-dependently enhanced insulin secretion in isolated mice islets, and its insulinotropic effect was exerted at high glucose concentrations distinctly different from glibenclamide. Furthermore, apigenin amplified glucose-induced insulin secretion in depolarized and glibenclamide-treated islets. Apigenin showed no effect on intracellular cAMP concentration; however, an additive effect was observed by apigenin in both forskolin and IBMX-induced insulin secretion. Interestingly, H89, a PKA inhibitor, and U0126, a MEK kinase inhibitor, significantly inhibited apigenin-induced insulin secretion; however, no significant effect was observed by using ESI-05, an epac2 inhibitor. Apigenin improved glucose tolerance and increased glucose-stimulated plasma insulin levels in diabetic rats. Apigenin also lowered blood glucose in diabetic rats upon chronic treatment.
Apigenin exerts glucose-stimulated insulin secretion by modulating the PKA-MEK kinase signaling cascade independent of K-ATP channels.
芹黄素是一种天然生物类黄酮，具有抑制α-葡萄糖苷酶活性、刺激胰岛素作用和分泌、调节 ROS 以及预防糖尿病并发症的能力，因此被报道为一种抗糖尿病药物。芹黄素被鉴定为一种新的胰岛素促分泌剂，可增强葡萄糖刺激的胰岛素分泌，似乎是一种更好的抗糖尿病药物候选物。在这里，我们在体外的小鼠胰岛和体内的糖尿病大鼠中探索了芹黄素的胰岛素促分泌作用机制。
将大小匹配的胰岛分为几组，在存在或不存在芹黄素以及主要胰岛素信号通路激动剂或拮抗剂的情况下孵育。通过 ELISA 测量分泌的胰岛素。通过 cAMP 乙酰化测定法估计细胞内 cAMP。在糖尿病大鼠中评估了芹黄素的急性和慢性作用。
芹黄素剂量依赖性地增强了分离的小鼠胰岛中的胰岛素分泌，其胰岛素促分泌作用在高葡萄糖浓度下发挥，与格列本脲明显不同。此外，芹黄素增强了去极化和格列本脲处理的胰岛中的葡萄糖诱导的胰岛素分泌。芹黄素对细胞内 cAMP 浓度没有影响；然而，在 forskolin 和 IBMX 诱导的胰岛素分泌中观察到芹黄素的相加作用。有趣的是，PKA 抑制剂 H89 和 MEK 激酶抑制剂 U0126 显著抑制了芹黄素诱导的胰岛素分泌；然而，使用 epac2 抑制剂 ESI-05 则没有观察到显著作用。芹黄素改善了糖尿病大鼠的葡萄糖耐量并增加了葡萄糖刺激的血浆胰岛素水平。芹黄素在慢性治疗中也降低了糖尿病大鼠的血糖。
芹黄素通过调节 PKA-MEK 激酶信号级联来发挥葡萄糖刺激的胰岛素分泌作用，而不依赖于 K-ATP 通道。
