Nonenzymatically modified adducts of proteins or lipids engage the vascular endothelium by mechanisms distinct from those of the native, unmodified species. These modified adducts, termed advanced glycation end-products (AGEs), are particularly prevalent in diabetes, but accumulate aswell in diseases such as renal failure, in states of intense inflammation, and in aging. Extracellular AGEs mediate their cellular activity by binding to the receptor for age (RAGE). Increasing evidence suggests that disease-associated ligands other than AGE may bind and activate RAGE and thus contribute to diverse tissuedamaging complications. Studies in this area have provided a framework for targeting the ligand–RAGE axis as a novel therapeutic opportunity in diabetes.

THE PROBLEM OF GLYCATION

A range of physiological and pathophysiological states provides a ripe environment for the post-translational modification of proteins and lipids that eventuate in the formation of AGEs. Such modified species bind to and activate specialized receptors (RAGE) present on the surface of multiple cell types, including endothelial cells (ECs). AGE–RAGE interactions result in EC dysfunction, and appear to play an important pathophysiological role in several diseases, including type 1 and type 2 diabetes.

Maillard Reaction and the Formation of Advanced Glycation Endproducts

The nonenzymatic glycation of proteins was first described in 1912, by Louis-Camille Maillard (1). This reaction begins when the carbonyl group (either aldehyde or ketone) of the reducing sugar forms a reversible Schiff base with the amino group of the molecule. Schiff bases may undergo subsequent intramolecular rearrangements to form Amadori products (2). A series of further rearrangements may occur, including dehydration and condensation reactions to form irreversible endproducts, or the AGEs (Figure 47.1).