The aldose reductase controversy.

ext to the debate as to whether chronic hyperglycemia is the primary cause of the late vascular complications of diabetes, the longest running controversy among researchers and clinicians studying this disease is the role of the sorbitol pathway, particularly its initial enzymatic step, the reduction of glucose to sorbitol by aldose reductase in the pathogenesis of these complications. Because the outcome of the Diabetes Control and Complications Trial (DCCT) (1) appears to have effectively resolved the first issue, the aldose reductase controversy now takes center stage. The sorbitol pathway hypothesis is not the only mechanism for the pathogenesis of the complications of diabetes to have achieved serious consideration. Among others, for example, nonenzymatic glycation of proteins (2) is a plausible, if still largely untested, possibility. But over the more than 30 years since the British biochemist, Ruth vari Heyningen, first demonstrated an excess of sorbitol in the lenses of diabetic rats (3), a substantial accumulation of evidence has supported the sorbitol pathway as the principal actor in at least some of the late complications of diabetes in humans and experimental animals. 'This view is not unchallenged, however. In this discussion, I will summarize some of the evidence supporting the role of aldose reductase in producing several of the late complications of diabetes, but also point out those contradictory findings that render the sorbitol pathway hypothesis controversial.