Department of Pathology, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan.
J Agric Food Chem. 2011 Dec 28;59(24):12874-81. doi: 10.1021/jf2036559. Epub 2011 Nov 28.
AMP-activated protein kinase (AMPK) is an energy sensor that regulates cellular metabolism. Activation of AMPK in skeletal muscles, the liver, and adipose tissues results in a favorable metabolic milieu for preventing and treating type 2 diabetes, i.e., decreased levels of circulating glucose, plasma lipids, and ectopic fat accumulation and enhanced insulin sensitivity. Osthole was extracted from a Chinese herbal medicine, and we found that it had glucose lowering activity in our previous study. However, the detailed glucose lowering mechanisms of osthole are still unclear. In this study, we used skeletal muscle cells to examine the underlying molecular mechanisms of osthole's glucose lowering activity. A Western blot analysis revealed that osthole significantly induced phosphorylation of AMPK and acetyl-CoA carboxylase (ACC). Next, we found that osthole significantly increased the level of translocation of glucose transporter 4 (GLUT4) to plasma membranes and glucose uptake in a dose-dependent manner. Osthole-induced glucose uptake was reversed by treatment with Compound C, an AMPK inhibitor, suggesting that osthole-induced glucose uptake was mediated in an AMPK-dependent manner. The increase in the AMP:ATP ratio was involved in osthole's activation of AMPK. Finally, we found that osthole counteracted hyperglycemia in mice with streptozotocin-induced diabetes. These results suggest that the increase in the AMP:ATP ratio by osthole triggered activation of the AMPK signaling pathway and led to increases in plasma membrane GLUT4 content and glucose uptake level. Therefore, osthole might have potential as an antidiabetic agent for treating diabetes.
AMP 激活的蛋白激酶 (AMPK) 是一种能调节细胞代谢的能量感受器。在骨骼肌、肝脏和脂肪组织中激活 AMPK，会产生有利于预防和治疗 2 型糖尿病的代谢环境，即降低循环葡萄糖、血浆脂质和异位脂肪积累水平，并增强胰岛素敏感性。蛇床子素是从一种中药中提取的，我们在之前的研究中发现它具有降低血糖的活性。然而，蛇床子素降低血糖的详细机制仍不清楚。在这项研究中，我们使用骨骼肌细胞来研究蛇床子素降低血糖活性的潜在分子机制。Western blot 分析显示，蛇床子素能显著诱导 AMPK 和乙酰辅酶 A 羧化酶 (ACC) 的磷酸化。接下来，我们发现蛇床子素能显著增加葡萄糖转运蛋白 4 (GLUT4) 向质膜的转位和葡萄糖摄取，且呈剂量依赖性。用 AMPK 抑制剂 Compound C 处理可逆转蛇床子素诱导的葡萄糖摄取，表明蛇床子素诱导的葡萄糖摄取是通过 AMPK 依赖的方式介导的。AMP:ATP 比值的增加参与了蛇床子素激活 AMPK。最后，我们发现蛇床子素能对抗链脲佐菌素诱导的糖尿病小鼠的高血糖。这些结果表明，蛇床子素引起的 AMP:ATP 比值增加触发了 AMPK 信号通路的激活，导致质膜 GLUT4 含量和葡萄糖摄取水平增加。因此，蛇床子素可能有作为治疗糖尿病的抗糖尿病药物的潜力。
