Pathogenetic Mechanisms

Recent experimental studies suggest a multifactorial pathogenesis of diabetic neuropathy. Most data have been generated in the diabetic rat model, on the basis of which two approaches have been chosen to contribute to the clarification of the pathogenesis of diabetic neuropathy. Firstly, it has been attempted to characterize the pathophysiological, pathobiochemical, and structural abnormalities that result in experimental diabetic neuropathy. Secondly, specific therapeutic interventions have been employed to prevent the development of these alterations, to halt their progression, or to induce their regression despite concomitant hyperglycemia. At present, the following six pathogenetic mechanisms are being discussed which, however, in contrast to previous years are no longer regarded as separate hypotheses but in the first place as a complex interplay with multiple interactions between metabolic and vascular factors:

1. Increased flux through the polyol pathway that leads to accumulation of sorbitol and fructose, myo-inositol depletion, and reduction in Na+,K+-ATPase activity.

2. Disturbances in n-6 essential fatty acid and prostaglandin metabolism which result in alterations of nerve membrane structure and microvascular and hemorrheologic abnormalities.

3. Endoneural microvascular deficits with subsequent ischemia and hypoxia, generation of reactive oxygen species (oxidative stress), activation of the redox-sensitive transcription factor NF-kB, and increased activity of protein kinase C (PKC).

4. Deficits in neurotrophism leading to reduced expression and depletion of neurotrophic factors such as nerve growth factor (NGF), neurotrophin-3, and insulin-like growth factor and alterations in axonal transport.

5. Accumulation of non-enzymatic advanced glycation end products (AGEs) on nerve and/ or vessel proteins.

6. Immunological processes with autoantibodies to vagal nerve, sympathetic ganglia, and adrenal medulla as well as inflammatory changes.

From the clinical point of view it is important to note that, based on these pathogenetic mechanisms, therapeutic approaches could be derived, some of which have been evaluated in randomized clinical trials (see Treatment section).

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