Diabetes and Advanced Glycoxidation End Products

  1. Amy G. Huebschmann, MD1,
  2. Judith G. Regensteiner, PHD12,
  3. Helen Vlassara, MD3 and
  4. Jane E.B. Reusch, MD45
  1. 1Division of General Internal Medicine, Department of Medicine, University of Colorado Denver and Health Sciences Center, Denver, Colorado
  2. 2Division of Cardiology, Department of Medicine, University of Colorado Denver and Health Sciences Center, Denver, Colorado
  3. 3Division of Experimental Diabetes and Aging, Department of Geriatrics, Mount Sinai School of Medicine, New York, New York
  4. 4Division of Endocrinology, Department of Medicine, University of Colorado Denver and Health Sciences Center, Denver, Colorado
  5. 5Denver VA Medical Center, Denver, Colorado
  1. Address correspondence and reprint requests to Amy G. Huebschmann, MD, Assistant Professor of Medicine, University of Colorado Denver and Health Sciences Center, P.O. Box 6510, Mailstop F-729, Aurora, CO 80045. E-mail: amy.huebschmann{at}uchsc.edu

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).

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