Estrada D E, Ewart H S, Tsakiridis T, Volchuk A, Ramlal T, Tritschler H, Klip A
Division of Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada.
Diabetes. 1996 Dec;45(12):1798-804. doi: 10.2337/diab.45.12.1798.
Thioctic acid (alpha-lipoic acid), a natural cofactor in dehydrogenase complexes, is used in Germany in the treatment of symptoms of diabetic neuropathy. Thioctic acid improves insulin-responsive glucose utilization in rat muscle preparations and during insulin clamp studies performed in diabetic individuals. The aim of this study was to determine the direct effect of thioctic acid on glucose uptake and glucose transporters. In L6 muscle cells and 3T3-L1 adipocytes in culture, glucose uptake was rapidly increased by (R)-thioctic acid. The increment was higher than that elicited by the (S)-isomer or the racemic mixture and was comparable with that caused by insulin. In parallel to insulin action, the stimulation of glucose uptake by thioctic acid was abolished by wortmannin, an inhibitor of phosphatidylinositol 3-kinase, in both cell lines. Thioctic acid provoked an upward shift of the glucose-uptake insulin dose-response curve. The molar content of GLUT1 and GLUT4 transporters was measured in both cell lines. 3T3-L1 adipocytes were shown to have >10 times more glucose transporters but similar ratios of GLUT4:GLUT1 than L6 myotubes. The effect of (R)-thioctic acid on glucose transporters was studied in the L6 myotubes. Its stimulatory effect on glucose uptake was associated with an intracellular redistribution of GLUT1 and GLUT4 glucose transporters, similar to that caused by insulin, with minimal effects on GLUT3 transporters. In conclusion, thioctic acid stimulates basal glucose transport and has a positive effect on insulin-stimulated glucose uptake. The stimulatory effect is dependent on phosphatidylinositol 3-kinase activity and may be explained by a redistribution of glucose transporters. This is evidence that a physiologically relevant compound can stimulate glucose transport via the insulin signaling pathway.
硫辛酸（α-硫辛酸）是脱氢酶复合物中的一种天然辅因子，在德国被用于治疗糖尿病性神经病变的症状。硫辛酸可改善大鼠肌肉制剂中胰岛素反应性葡萄糖的利用，以及在糖尿病个体中进行胰岛素钳夹研究期间的葡萄糖利用。本研究的目的是确定硫辛酸对葡萄糖摄取和葡萄糖转运蛋白的直接作用。在培养的L6肌肉细胞和3T3-L1脂肪细胞中，(R)-硫辛酸可迅速增加葡萄糖摄取。这种增加高于(S)-异构体或外消旋混合物所引起的增加，并且与胰岛素所引起的增加相当。与胰岛素作用平行，在两种细胞系中，磷脂酰肌醇3-激酶抑制剂渥曼青霉素均可消除硫辛酸对葡萄糖摄取的刺激作用。硫辛酸使葡萄糖摄取胰岛素剂量反应曲线向上移动。在两种细胞系中均测量了GLUT1和GLUT4转运蛋白的摩尔含量。结果显示，3T3-L1脂肪细胞的葡萄糖转运蛋白比L6肌管多10倍以上，但GLUT4:GLUT1的比例相似。在L6肌管中研究了(R)-硫辛酸对葡萄糖转运蛋白的影响。其对葡萄糖摄取的刺激作用与GLUT1和GLUT4葡萄糖转运蛋白的细胞内重新分布有关，类似于胰岛素所引起的情况，而对GLUT3转运蛋白的影响最小。总之，硫辛酸刺激基础葡萄糖转运，并对胰岛素刺激的葡萄糖摄取有积极作用。这种刺激作用依赖于磷脂酰肌醇3-激酶活性，可能通过葡萄糖转运蛋白的重新分布来解释。这证明了一种生理相关化合物可通过胰岛素信号通路刺激葡萄糖转运。
