Pathogenesis of diabetic neuropathy. Factors implicated in the pathogenesis of diabetic neuropathy include the activation of the polyol pathway, the activation of protein kinase C (PKC), increased oxidative stress, the impaired N-6 fatty acid metabolism, auto-oxidation of glucose, the formation of advanced glycation end products (AGEs), and the reduced bioavailability of neurotrophic factors. All these mechanisms are interrelated and can potentiate each other’s detrimental effects. Although the exact mechanisms of their action are not well understood, it is currently believed that these factors lead to reduced Na⁺, K⁺ ATPase activity and vasoconstriction, reduced endoneurial blood flow and nerve hypoxia. The latter changes then lead to reduced nerve conduction velocities, axonal loss, axonal demyelination, and nerve dysfunction. DAG, diacylglycerol.