Polyol pathway and diabetic peripheral neuropathy

This chapter critically examines the concept of the polyol pathway and how it relates to the pathogenesis of diabetic peripheral neuropathy. The two enzymes of the polyol pathway, aldose reductase and sorbitol dehydrogenase, are reviewed. The structure, biochemistry, physiological role, tissue distribution, and localization in peripheral nerve of each enzyme are summarized, along with current information about the location and structure of their genes, their alleles, and the possible links of each enzymes and its alleles to diabetic neuropathy. Inhibitors of pathway enzymes and results obtained to date with pathway inhibitors in experimental models and human neuropathy trials are updated and discussed. Experimental and clinical data are analyzed in the context of a newly developed metabolic model of the in vivo relationship between nerve sorbitol concentration and metabolic flux through aldose reductase. Overall, the data will be interpreted as supporting the hypothesis that metabolic flux through the polyol pathway, rather than nerve concentration of sorbitol, is the predominant polyol pathway-linked pathogenic factor in diabetic peripheral nerve. Finally, key questions and future directions for basic and clinical research in this area are considered. It is concluded that robust inhibition of metabolic flux through the polyol pathway in peripheral nerve will likely result in substantial clinical benefit in treating and preventing the currently intractable condition of diabetic peripheral neuropathy. To accomplish this, it is imperative to develop and test a new generation of “super-potent” polyol pathway inhibitors.