STIMULATION OF GLUCOSE-UPTAKE BY THE NATURAL COENZYME ALPHA-LIPOIC ACID THIOCTIC ACID - PARTICIPATION OF ELEMENTS OF THE INSULIN SIGNALING PATHWAY

Thioctic acid (alpha-lipoic acid), a natural cofactor in dehydrogenase complexes, is used in Germany in the treatment of symptoms of diabeti c neuropathy. Thioctic acid improves insulin-responsive glucose utiliz ation in rat muscle preparations and during insulin clamp studies perf ormed in diabetic individuals. The aim of this study was to determine the direct effect of thioctic acid on glucose uptake and glucose trans porters. In L6 muscle cells and 3T3-L1 adipocytes in culture, glucose uptake was rapidly increased by (R)-thioctic acid. The increment was h igher than that elicited by the (S)-isomer or the racemic mixture and was comparable with that caused by insulin. In parallel to insulin act ion, 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-upta ke insulin dose-response curve. The molar content of GLUT1 and GLUT4 t ransporters was measured in both cell lines, 3T3-L1 adipocytes were sh own to have >10 times more glucose transporters but similar ratios of GLUT4:GLUT1 than L6 myotubes. The effect of (R)-thioctic acid on gluco se 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 in sulin, with minimal effects on GLUT3 transporters. In conclusion, thio ctic acid stimulates basal glucose transport and has a positive effect on insulin-stimulated glucose uptake. The stimulatory effect is depen dent on phosphatidylinositol 3-kinase activity and may be explained by a redistribution of glucose transporters. This is evidence that a phy siologically relevant compound can stimulate glucose transport via the insulin signaling pathway.