Most long-term diabetic patients develop microvascular diseases such as retinopathy, nephropathy and neuropathy. Although tight control of
blood glucose greatly reduces the incidence of these complications, a significant fraction of diabetic patients with good
glycemic control still develop these diseases. Therefore, it is imperative to understand the underlying mechanisms of these diseases such that effective treatment or preventive methods can be developed to augment euglycemic control. In animal studies, there is strong evidence that
aldose reductase, the first and rate-limiting
enzyme of the
polyol pathway that converts
glucose to
fructose, plays a key role in the pathogenesis of microvascular complications. However, clinical trials of the
aldose reductase inhibitors were disappointing and several
pharmaceutical companies had abandoned the development of this line of drugs. In this review, the potential pathogenic mechanisms of the
polyol pathway are presented, the evidence for the involvement of the
polyol pathway in
diabetic complications summarized, and the reasons for the unimpressive results of the clinical trials of the aldose inhibitors discussed. It appears that renewed efforts to develop
aldose reductase inhibitors for the treatment and prevention of
diabetic complications are warranted.