- AGE, advanced glycoxidation end product
- ARB, angiotensin-II receptor blocker
- CML, Nε−carboxymethyllysine
- HMGB1, high-mobility group box 1
- NF-κB, nuclear factor-κB
- PARP, poly(ADP ribose) polymerase
- RAGE, receptors for AGE
- ROS, reactive oxygen species
The morbidity caused by diabetes has traditionally been classified into macro- and microvascular complications. Although macrovascular complications have received greater attention, microvascular complications are unique to diabetes, and hyperglycemia contributes to their development. Numerous hyperglycemia-related mechanisms are hypothesized to mediate micro- and macrovascular complications. These include the aldose reductase–mediated polyol pathway, the hexosamine pathway, protein kinase C activation, generation of reactive oxidant stress, poly(ADP ribose) polymerase (PARP) activation, and accumulation of advanced glycoxidation (also termed advanced glycation or glycosylation) end products (AGEs) (1,2). AGEs are particularly important, as they form intra- and extracellularly (3,4), are imported from food (5–9) and tobacco smoke (10), and can be deleterious, independent of hyperglycemia (9,11–16). They are implicated in the development of macrovascular disease (13,14,17–20), nephropathy (21–30), neuropathy (31,32), and retinopathy (21,33–38). The remediation of AGEs has also been shown to improve diabetic micro- and macrovascular disease (39–44). AGEs thus offer an important target for prevention of diabetic morbidity. The focus of this review will be on the origin of AGEs, their mechanism of injury, and therapeutic options under development.
FORMATION OF AGEs
AGEs are nonenzymatically formed by reducing glucose, lipids, and/or certain amino acids on proteins, lipids, and nucleic acids (Fig. 1A). For example, glucose and a free amino group form reversible intermediates of a Schiff base and an Amadori product (e.g., HbA1c) before a series of reactions that irreversibly generate an AGE (45,46). This process was first identified in 1912 and is known as the Maillard or “browning” reaction due to the associated yellow-brown color change (45,47,48). When formed endogenously, this reaction is driven forward by hyperglycemia (4,49).