Zhao Ping, Tian Di, Song Guanjun, Ming Qian, Liu Jia, Shen Jinhua, Liu Qing-Hua, Yang Xinzhou
Institute for Medical Biology & Hubei Provincial Key Laboratory for Protection and Application of Special Plants in the Wuling Area of China, College of Life Sciences, South-Central University for Nationalities, Wuhan, China.
National Demonstration Center for Experimental Ethnopharmacology Education, South-Central University for Nationalities, Wuhan, China.
Front Pharmacol. 2019 Sep 4;10:999. doi: 10.3389/fphar.2019.00999. eCollection 2019.
Glucose transporter 4 (GLUT4) is involved in regulating glucose uptake in striated muscle, liver, and adipose tissue. Neferine is a dibenzyl isoquinoline alkaloid derived from dietary lotus seeds and has multiple pharmacological effects. Therefore, this study investigated neferine's role in glucose translocation to cell surface, glucose uptake, and GLUT4 expression. In our study, neferine upregulated GLUT4 expression, induced GLUT4 plasma membrane fusion, increased intracellular Ca, promoted glucose uptake, and alleviated insulin resistance in L6 cells. Furthermore, neferine significantly activated phosphorylation of AMP-activated protein kinase (AMPK) and protein kinase C (PKC). AMPK and PKC inhibitors blocked neferine-induced GLUT4 expression and increased intracellular Ca. While neferine-induced GLUT4 expression and intracellular Ca were inhibited by G protein and PLC inhibitors, only intracellular Ca was inhibited by inositol trisphosphate receptor (IPR) inhibitors. Thus, neferine promoted GLUT4 expression the G protein-PLC-PKC and AMPK pathways, inducing GLUT4 plasma membrane fusion and subsequent glucose uptake and increasing intracellular Ca through the G protein-PLC-IP-IPR pathway. Treatment with 0 mM extracellular Ca + Ca chelator did not inhibit neferine-induced GLUT4 expression but blocked neferine-induced GLUT4 plasma membrane fusion and glucose uptake, suggesting the latter two are Ca-dependent. Therefore, we conclude that neferine is a potential treatment for type 2 diabetes.
葡萄糖转运蛋白4（GLUT4）参与调节横纹肌、肝脏和脂肪组织中的葡萄糖摄取。甲基莲心碱是一种源自食用莲子的双苄基异喹啉生物碱，具有多种药理作用。因此，本研究调查了甲基莲心碱在葡萄糖向细胞表面转运、葡萄糖摄取和GLUT4表达中的作用。在我们的研究中，甲基莲心碱上调了GLUT4的表达，诱导了GLUT4与质膜融合，增加了细胞内钙离子浓度，促进了葡萄糖摄取，并减轻了L6细胞中的胰岛素抵抗。此外，甲基莲心碱显著激活了腺苷酸活化蛋白激酶（AMPK）和蛋白激酶C（PKC）的磷酸化。AMPK和PKC抑制剂阻断了甲基莲心碱诱导的GLUT4表达并增加了细胞内钙离子浓度。虽然甲基莲心碱诱导的GLUT4表达和细胞内钙离子浓度受到G蛋白和磷脂酶C（PLC）抑制剂的抑制，但只有细胞内钙离子浓度受到肌醇三磷酸受体（IPR）抑制剂的抑制。因此，甲基莲心碱通过G蛋白-PLC-PKC和AMPK途径促进GLUT4表达，诱导GLUT4与质膜融合以及随后的葡萄糖摄取，并通过G蛋白-PLC-肌醇三磷酸-IPR途径增加细胞内钙离子浓度。用0 mM细胞外钙离子+钙离子螯合剂处理并未抑制甲基莲心碱诱导的GLUT4表达，但阻断了甲基莲心碱诱导的GLUT4与质膜融合和葡萄糖摄取，表明后两者是钙离子依赖性的。因此，我们得出结论，甲基莲心碱是2型糖尿病的一种潜在治疗药物。
