Diabetic polyneuropathy: Bridging the translational gap.

Clinical trials for diabetic polyneuropathy (DPN) have failed to identify therapeutic impacts that have arrested or reversed the disorder, despite a long history. This review considers DPN in the context of a unique neurodegenerative disorder that targets peripheral neurons and their companion glial cells. The approach is to examine what cells, cell substructures, and pathways are implicated in causing DPN and how they might be addressed therapeutically. These include axonopathy, neuronopathy, hyperglycemia, polyol flux, advanced glycation endproduct (AGE)-receptor AGE signaling, growth factor disruption, abnormal insulin signaling, and abnormalities of other intrinsic neuron pathways. Mitochondrial dysfunction and lipid toxicity are largely delegated to the companion review in this issue by Stino and Feldman. Finally, the linkage between axon plasticity of cutaneous nerves, peripheral neuroregenerative pathways, and diabetes are discussed.