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The Role of Advanced Glycation End Products in Progression and Complications of Diabetes

Albert Einstein Juvenile Diabetes Research Foundation Centre for Diabetes Complications, Diabetes and Metabolism Division, Baker Medical Research Institute, Melbourne, Victoria, Australia 8008

Address all correspondence and requests for reprints to: Professor Mark E. Cooper, Albert Einstein Juvenile Diabetes Research Foundation Centre for Diabetes Complications, Diabetes and Metabolism Division, Baker Medical Research Institute, P.O. Box 6492, St. Kilda Road Central, Melbourne, Victoria, Australia 8008. E-mail: mark.cooper{at}baker.edu.au.

Context: Diabetic complications appear to be multifactorial in origin, but in particular, the biochemical process of advanced glycation, which is accelerated in diabetes as a result of chronic hyperglycemia and increased oxidative stress, has been postulated to play a central role in these disorders. Advanced glycation involves the generation of a heterogenous group of chemical moieties known as advanced glycated end products (AGEs), this reaction occurring as a result of a nonenzymatic reaction with glucose interacting with proteins, lipids, and nucleic acids, and involves key intermediates such as methylglyoxal.

Evidence Synthesis: In this review we report on how these AGEs may exert deleterious effects in diabetes, as well as address current strategies to interrupt the formation or action of AGEs. First, AGEs act directly to induce cross-linking of long-lived proteins such as collagen to promote vascular stiffness, and, thus, alter vascular structure and function. Second, AGEs can interact with certain receptors, such as the receptor for AGE, to induce intracellular signaling that leads to enhanced oxidative stress and elaboration of key proinflammatory and prosclerotic cytokines. Over the last decade, a large number of preclinical studies have been performed, targeting the formation and degradation of AGEs, as well as the interaction of these AGEs with receptors such as the receptor for AGE.

Conclusion: It is hoped that over the next few years, some of these promising therapies will be fully evaluated in the clinical context with the ultimate aim to reduce the major economical and medical burden of diabetes, its vascular complications.

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