Getting Better Without AGE New Insights Into the Diabetic Heart

Nearly a century ago, Maillard first observed that incubation of glucose with amino acids led to the formation of a yellow-brown pigment due to nonenzymatic glycosylation.1 This unstable compound known as a Schiff base can undergo rearrangement over several days to form the more stable Amadori-type product.2 One well-known example is hemoglobin A1C, the adduct of glucose with the N-terminal valine amino group of the β-chain of hemoglobin.3 This process of nonenzymatic protein glycation differs from enzyme-dependent o-glycosylation, the latter being a reversible process whereby proteins are modified at specific residues to effect signal transduction much like phosphorylation.R4-128042 4,5 Glycated proteins, in contrast, can further evolve over time, undergoing complex rearrangements to yield crosslinked proteins known as advanced glycation end products (AGEs)R2-128042 2,6 (Figure). Importantly, and in contrast to Amadori product precursors, AGEs are virtually irreversible once formed. Long-lived structural proteins such as collagen are particularly vulnerable to AGE crosslinks by nature of their slow turnover rate.7 Pathophysiology of advanced glycation end products (AGEs). Glucose interacts over several hours with reactive amino groups on proteins to form the unstable and reversible Schiff base. Over longer periods of time (days), this can further develop into an Amadori product, a more stable form of protein glycation. Over periods of months to years, these glycated proteins can undergo further complex rearrangement to generate AGEs. AGEs can serve themselves as signaling molecules, interacting with specific receptors (ie, RAGE), which triggers a broad array of stress and oxidant response signaling, as well as develop crosslinks between a given protein that can alter its tertiary structure and function. This process can be inhibited at several stages: agents that principally prevent the formation of AGE (ie, aminoguanidine [AG], pyridoxamine [pyr], and OBP-9195), those that block AGE interaction with membrane receptors (ie, …