Aldose reductase inhibitors as pathobiochemical probes

In tissues susceptible to damage from chronic diabetes, excess glucose is metabolized by aldose reductase (AR) to sorbitol. Originally, AR-catalyzed sorbitol formation (and accumulation) was found in the diabetic lens; the cataractogenicity of this process was proven by preventing cataract formation with an AR inhibitor (ARI). These findings were extended to the hypothesis that, in diabetic tissues, excessive intracellular sorbitol formation initiates a cascade of metabolic abnormalities which gradually progress to loss of functional and structural integrity. The pivotal role of AR as a trigger for such abnormalities was established by preventing their occurrence in diabetic animals treated with an ARI. By inference, this led to the concept that inhibition of AR should prevent, arrest, and, possibly, reverse the development of late diabetic sequelae. In addition to motivating drug-oriented research, the ARI concept provided a rationale for the use of ARIs as experimental tools to probe the pathogenesis of diabetic complications. By helping to elucidate the metabolic, functional, and structural ramifications of the AR-catalyzed disposal of excess glucose in diabetic schemes, and in addition, by helping to define the applicability of animal models for the study of early functional pathogenic alterations occurring in diabetic subjects, ARIs may enable the discrimination in diabetic tissue of arrestible and reversible from the irreversible abnormalities.