A large number of studies have focused on the factors involved in the pathogenesis of diabetic complications, most seeking effective therapies, but the exact cellular or molecular basis of these complications has not yet been fully elucidated. Hyperglycemia is still considered the principal cause of diabetes complications. Its deleterious effects are attributable, among other things, to the formation of sugar-derived substances called
advanced glycation end products (AGEs). AGEs form at a constant but slow rate in the normal body, starting in early embryonic development, and accumulate with time. However, their formation is markedly accelerated in diabetes because of the increased availability of glucose.
AGEs are a heterogeneous group of molecules formed from the nonenzymatic reaction of reducing sugars with free amino groups of proteins, lipids, and nucleic acids. The initial product of this reaction is called a Schiff base, which spontaneously rearranges itself into an Amadori product, as is the case of the well-known hemoglobin A1c (A1C). These initial reactions are reversible depending on the concentration of the reactants. A lowered glucose concentration will unhook the sugars from the amino groups to which they are attached; conversely, high glucose concentrations will have the opposite effect, if persistent. A series of subsequent reactions, including successions of dehydrations, oxidation-reduction reactions, and other arrangements lead to the formation of AGEs. Several compounds, e.g., εN-carboxymethyl-lysine, pentosidine, or methylglyoxal derivatives, serve as examples of well-characterized and widely studied AGEs.
A key characteristic of certain reactive or precursor AGEs is their ability for covalent crosslink formation between proteins, which alters their structure and function, as in cellular matrix, basement membranes, and vessel-wall components. Other major features of AGEs relate to their interaction with a variety of cell-surface AGE-binding receptors, leading either to their endocytosis and degradation or to cellular activation and pro-oxidant, pro-inflammatory events.