Antidiabetic Effect of Salvianolic Acid A on Diabetic Animal Models via AMPK Activation and Mitochondrial Regulation
Antidiabetic Effect of Salvianolic Acid A on Diabetic Animal Models via AMPK Activation and Mitochondrial Regulation
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丹酚酸 A 通过 AMPK 激活和线粒体调节对糖尿病动物模型的抗糖尿病作用
DOI：
10.1159/000430258
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发表时间：
2015-01-01
影响因子：
--
通讯作者：
Du, Guanhua
中科院分区：
文献类型：
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作者：
Qiang, Guifen;Yang, Xiuying;Du, Guanhua
背景/目的：以高血糖为特征的糖尿病（DM）可导致大血管和微血管并发症。丹参酸A（Salvioleticacid A，SalA）是从丹参（Salvia miltiorrhiza Bunge）根中分离得到的一种多酚类化合物，是一种广泛用于治疗心血管疾病的中药。然而，对其抗糖尿病作用知之甚少。本研究旨在探讨SalA的体内外抗糖尿病作用及其机制。研究方法：四氧嘧啶诱导的1型糖尿病小鼠和高脂饮食（HFD）和低剂量链脲佐菌素（STZ）诱导的2型糖尿病大鼠接受SalA治疗。监测血糖、口服葡萄糖耐量试验（OGTT）、24 h摄食量和饮水量。在体外，在HepG 2细胞和L 6肌管中测量葡萄糖消耗和摄取。在肝脏和骨骼肌线粒体中检测到线粒体功能。蛋白质印迹法检测AMPK和Akt。结果如下：在1型和2型糖尿病动物中，SalA以剂量依赖性方式降低空腹血糖（FBG）和进食血糖，以及减少24小时食物和水的摄入量。在体外，SalA引起葡萄糖消耗的剂量依赖性增加，并增强葡萄糖摄取。SalA在10 min至12 h显著增加HepG 2细胞和L 6肌管中ATP的产生。有趣的是，SalA降低HepG 2细胞的线粒体膜电位（MMP）。此外，SalA改善肝脏和骨骼肌线粒体功能，增加ATP的产生，并同时降低MMP。SalA通过Ca 2 +/钙调蛋白依赖性蛋白激酶激酶β（CaMKKβ）/AMPK信号通路激活AMPK磷酸化，而不依赖于肝激酶1（LKB 1）/AMPK信号通路。SalA对胰岛素促分泌作用及PI 3 K/Akt信号通路的激活无明显影响。结论：SalA通过CaMKKβ/AMPK信号通路改善糖尿病动物模型线粒体功能，增加ATP生成，降低MMP水平，发挥抗糖尿病作用。
Background/Aims: Diabetes mellitus (DM) characterized by hyperglycemia contributes to macrovascular and microvascular complications. Salvianolic acid A (SalA) is a polyphenolic compound isolated from the root of Salvia miltiorrhiza Bunge, which is a traditional Chinese medicine widely used to treat cardiovascular diseases. However, little is known about its antidiabetic effect. Our study aimed to investigate the in vivo and in vitro antidiabetic effect of SalA and the underlying mechanisms. Methods: Alloxan-induced type 1 diabetic mice and high-fat diet (HFD) and low-dose streptozotocin (STZ)-induced type 2 diabetic rats received SalA treatment. Blood glucose, oral glucose tolerance test (OGTT), 24-h food and water intake were monitored. In vitro, glucose consumption and uptake were measured in HepG2 cells and L6 myotubes. Mitochondrial function was detected in hepatic and skeletal muscle mitochondria. AMP-activated protein kinase (AMPK) and Akt were analyzed by western blot. Results: In both type 1 and type 2 diabetic animals, SalA lowered fasting blood glucose (FBG) and fed blood glucose in dose-dependent manner, as well as reduced 24-h food and water intake. In vitro, SalA caused dose-dependent increase in glucose consumption and enhanced glucose uptake. SalA significantly increased ATP production from 10 min to 12 h in HepG2 cells and L6 myotubes. Interestingly, SalA decreased mitochondrial membrane potential (MMP) in HepG2 cells. Furthermore, SalA improved hepatic and skeletal muscle mitochondrial function, increased ATP production, and concurrently decreased MMP. In particularly, SalA activated AMPK phosphorylation through Ca2+/calmodulin-dependent protein kinase kinase β (CaMKKβ)/AMPK signaling pathway, independent of liver kinase 1 (LKB1)/AMPK pathway. However, SalA didn't show any effect on insulin secretagogue and activation of PI3K/Akt signaling pathway. Conclusion: SalA exhibits the antidiabetic effects in diabetic animal models through improving mitochondrial function, increasing ATP production, and decreasing MMP via CaMKKβ/AMPK signaling pathway.