OVER the past 10 years our quest for discrete pathogenetic mechanisms for the long-term complications of diabetes has gradually focused on three promising targets for specific therapeutic intervention: nonenzymatic glycosylation of proteins, altered microvascular hemodynamics, and abnormal polyol–inositol metabolism. Glucose-induced alterations in the metabolism of sorbitol and myo-inositol (the most abundant stereoisomer of inositol) and their associated effects on phosphoinositide metabolism, protein kinase C, and sodium–potassium–ATPase have emerged from relative obscurity to become prime candidates for specific therapeutic intervention. Several purposefully designed inhibitors of aldose reductase, the first enzyme in this metabolic cascade, can prevent or reverse early diabetic . . .