Chihiro Nishimura-YABE
Department of Pharmacology, Kyoto Prefectural University of Medicine,
Kyoto 602, Japan
Abstract: Aldose reductase (AR), an enzyme in the polyol pathway,
catalyzes the reduction of glucose to sorbitol. Sorbitol is subsequently
converted to fructose by sorbitol dehydrogenase. The two enzymes constitute
the sorbitol (polyol) pathway, the alternate route of glucose metabolism.
The acceleration of this pathway and ensuing metabolic imbalances have been
postulated to play a key role in the pathogenesis of diabetic complications.
Using a transgenic animal model expressing human AR, we defined the primary
role of this pathway in the development of functional and structural abnormalities
elicited by diabetes. The inhibitors for AR would thus become effective
therapeutic agents for diabetic complications. As AR is a member of the
structurally related, NADPH-dependent aldo-keto reductase superfamily, other
members of this family, coexisting with AR, may interact with the inhibitors
to quench their action against AR. With our new immunoassay system, the
levels of AR expressed in diabetic patients can be measured directly. The
enzyme levels were significantly associated with the presence of complications,
indicating that variable levels of AR expressed in diabetic individuals
may affect the susceptibility or development of pathological changes associated
with diabetes. In this review, recent advances in the understanding of the
pathophysiological significance of AR are presented that would aid in the
effective pharmacological intervention of diabetic complications.
Keywords: diabetic complications; aldose reductase; polyol pathway; aldo-ketoreductase
family; risk factor