α-lipoic acid inhibits glycogen synthesis in rat soleus muscle via its oxidative activity and the uncoupling of mitochondria

alpha-Lipoic acid (LA) is currently being investigated as a glucose-lowering agent for diabetes control; it is also considered a powerful dietary antioxidant. The objective of this study was to investigate the fate of glucose in isolated rat muscles incubated with LA and determine its effects on intramuscular redox status. Rat soleus muscles were incubated for up to 60 min with 2.4 mmol/L LA in the presence or absence of insulin. Intramuscular concentrations of LA were evaluated (uptake and reduction), and glycogen synthesis, glucose oxidation, intramuscular reactive oxygen species (ROS) production and mitochondrial membrane potential investigated. Insulin enhanced glycogen synthesis, whereas LA decreased rates by >50%. LA elevated ROS production and in combination with t-butylhydroperoxide, an oxidant, additively inhibited glycogen synthesis rates by 80%. Insulin acted as an antioxidant and attenuated ROS production by 30%. LA uncoupled the mitochondria and accelerated glucose oxidation 1.5-fold relative to the control. The glycogen synthesis pathway was found to be dependent on mitochondrial function because treatment with mitochondrial inhibitors eliminated the majority of glycogen synthesis. These data show that in this model, LA acts as a mild prooxidant, causing mitochondrial uncoupling and inhibition of glycogen synthesis. It appears that LA regulates glucose metabolism in the muscle differently than insulin.