Interactions between hyperglycemia‐induced metabolic abnormalities and vascular factors in experimental diabetic neuropathy

Abstract

Metabolic and vascular changes in diabetes conspire to cause nervous system dysfunction, which is particularly apparent for peripheral nerves. Hyperglycemia and hyperlipidemia give rise to numerous metabolic changes including, elevated polyol pathway flux, oxidative stress, formation of advanced glycation and lipoxidation end products, increased protein kinase C activity, and impaired essential fatty acid utilization. These disturbances interact to target neurons and their vascular supply. Experiments employing joint therapeutic approaches have revealed synergistic interactions between some of these mechanisms for both large and small caliber nerve fibers. Successful drug combinations conferring 5–10‐fold increases in efficacy include protein kinase C inhibitors and antioxidants, statins and angiotensin receptor antagonists, and antioxidants and essential fatty acids. This could provide a potentially important advantage for the treatment of diabetic neuropathy.