alpha-lipoic acid: Effect on glucose uptake, sorbitol pathway, and energy metabolism in experimental diabetic neuropathy

The peripheral nerve of experimental diabetic neuropathy (EDN) is reported to be ischemic and hypoxic, with an increased dependence on anaerobic metab olism, requiring increased energy substrate stores. When glucose stores bec ome reduced, fiber degeneration has been reported. We evaluated glucose upt ake, nerve energy metabolism, the polyol pathway, and protein kinase C (PKC ) activity in EDN induced by streptozotocin. Control and diabetic rats rece ived lipoic acid (0, 10, 25, 50, 100 mg/kg). Duration of diabetes was 1 mon th, and alpha-lipoic acid was administered intraperitoneally 5 times per we ek for the final week of the experiment. Nerve glucose uptake was reduced t o 60, 37, and 30% of control values in the sciatic nerve, L5 dorsal root ga nglion, and superior cervical ganglion (SCG), respectively, in rats with ED N. alpha-Lipoic acid supplementation had no effect on glucose uptake in nor mal nerves at any dose, but reversed the deficit in EDN, with a threshold b etween 10 and 25 mg/kg. Endoneurial glucose, fructose, sorbitol, and myo-in ositol were measured in sciatic nerve. or-lipoic acid had no significant ef fect on either energy metabolism or polyol pathway of normal nerves. In EDN , endoneurial glucose, fructose, and sorbitol were significantly increased, while myo-inositol was significantly reduced. or-lipoic acid had a biphasi c effect: it dose-dependently increased fructose, glucose, and sorbitol, pe aking at 25 mg/kg, and then fell beyond that dose, and it dose-dependently increased myo-inositol. Sciatic nerve cytosolic PKC was increased in EDN. A TP, creatine phosphate, and lactate were measured in sciatic nerve and SCG. alpha-Lipoic acid prevented the reduction in SCG creatine phosphate. We co nclude that glucose uptake is reduced in EDN and that this deficit is dose- dependently reversed by alpha-lipoic acid, a change associated with an impr ovement in peripheral nerve function.