Polyol pathway and RAGE: a central metabolic and signaling axis in diabetic complications

There are multiple metabolic and molecular consequences of hyperglycemia. This review will focus on the roles of the polyol pathway and the receptor for advanced glycation end products (RAGE) in the pathogenesis of diabetic complications. The lead enzyme of the polyol pathway, aldose reductase, transduces maladaptive effects of hyperglycemia by multiple mechanisms, at least in part via the generation of the products of nonenzymatic glycation of proteins, the advanced glycation end products (AGEs). Furthermore, seminal shifts in metabolic flux in the intracellular space stimulated by aldose reductase action activate signal transduction pathways, which alter gene expression and change cellular phenotype. Among the ligands of the multi-ligand receptor RAGE are the AGEs. AGE-RAGE stimulation mediates vascular and target cell dysfunction. The intersection and interdependence of the polyol pathway-RAGE connection suggest that targeting this axis may provide benefit in reducing the complications of diabetes.