Abstract：
OBJECTIVE: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: Apigenin exerts glucose-stimulated insulin secretion by modulating the PKA-MEK kinase signaling cascade independent of K-ATP channels.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: Apigenin exerts glucose-stimulated insulin secretion by modulating the PKA-MEK kinase signaling cascade independent of K-ATP channels.
摘要：
目的：芹菜素，一种天然的生物类黄酮，被报道为抗糖尿病药物，因为它具有抑制α-葡萄糖苷酶活性的能力，引起胰岛素作用和分泌的刺激，管理ROS，预防糖尿病并发症。芹菜素被确定为一种新的胰岛素促分泌素，可增强葡萄糖刺激的胰岛素分泌，并且似乎是更好的抗糖尿病药物候选物。在这里，我们探讨了芹菜素在小鼠胰岛和糖尿病大鼠体内的促胰岛素作用机制。
方法：将大小匹配的胰岛分成几组，在有或没有芹菜素和主要胰岛素信号通路的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乙酰化测定估计细胞内cAMP。在糖尿病大鼠中评估芹菜素的急性和慢性作用。
结果：芹菜素剂量依赖性地增强了离体小鼠胰岛的胰岛素分泌，其促胰岛素作用在高葡萄糖浓度下明显不同于格列本脲。此外，芹菜素增强了去极化和格列本脲治疗的胰岛中葡萄糖诱导的胰岛素分泌。芹菜素对细胞内cAMP浓度没有影响；然而，芹菜素对毛喉素和IBMX诱导的胰岛素分泌均有累加作用。有趣的是,H89，一种PKA抑制剂，和U0126，一种MEK激酶抑制剂，显着抑制芹菜素诱导的胰岛素分泌；然而，使用epac2抑制剂ESI-05未观察到显著效果.芹菜素可改善糖尿病大鼠的葡萄糖耐量并增加葡萄糖刺激的血浆胰岛素水平。芹菜素还可以降低长期治疗后的糖尿病大鼠的血糖。
结论：芹菜素通过独立于K-ATP通道调节PKA-MEK激酶信号级联来发挥葡萄糖刺激的胰岛素分泌。
方法：将大小匹配的胰岛分成几组，在有或没有芹菜素和主要胰岛素信号通路的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乙酰化测定估计细胞内cAMP。在糖尿病大鼠中评估芹菜素的急性和慢性作用。
结果：芹菜素剂量依赖性地增强了离体小鼠胰岛的胰岛素分泌，其促胰岛素作用在高葡萄糖浓度下明显不同于格列本脲。此外，芹菜素增强了去极化和格列本脲治疗的胰岛中葡萄糖诱导的胰岛素分泌。芹菜素对细胞内cAMP浓度没有影响；然而，芹菜素对毛喉素和IBMX诱导的胰岛素分泌均有累加作用。有趣的是,H89，一种PKA抑制剂，和U0126，一种MEK激酶抑制剂，显着抑制芹菜素诱导的胰岛素分泌；然而，使用epac2抑制剂ESI-05未观察到显著效果.芹菜素可改善糖尿病大鼠的葡萄糖耐量并增加葡萄糖刺激的血浆胰岛素水平。芹菜素还可以降低长期治疗后的糖尿病大鼠的血糖。
结论：芹菜素通过独立于K-ATP通道调节PKA-MEK激酶信号级联来发挥葡萄糖刺激的胰岛素分泌。
