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Annu. Rev. Med. 1995. 46:223–34 Copyright © 1995 by Annual Reviews Inc. All rights reserved

ADVANCED PROTEIN GLYCOSYLATION IN DIABETES AND AGING
Annu. Rev. Med. 1995.46:223-234. Downloaded from arjournals.annualreviews.org by CAPES on 08/27/08. For personal use only.

Michael Brownlee, M.D.
Diabetes Research Center and Departments of Medicine and Pathology, Albert Einstein College ofMedicine, Bronx, New York 10461
KEY WORDS: advanced glycation end products, matrix, receptors, mitogens, DNA, aminoguanidine

ABSTRACT Products of advanced protein glycosylation (advanced glycation end products, or AGEs) accumulate in tissues as a function of time and sugar concentration. AGEs induce permanent abnormalities in extracellular matrix component function, stimulate cytokine and reactiveoxygen species production through AGE-specific receptors, and modify intracellular proteins. Pharmacologic inhibition of AGE formation in long-term diabetic animals prevents diabetic retinopathy, nephropathy, neuropathy, and arterial abnormalities in animal models. Clinical trials in humans are currently in progress.

INTRODUCTION
Advanced protein glycosylation, a process involving thenonenzymatic modification of tissue proteins by physiologic sugars in vivo, appears to play a central role in the pathogenesis of diabetic complications. These sugar-derived modifications, called advanced glycation end products (AGEs), may also figure prominently in the pathogenesis of age-related disorders affecting connective tissue, lens, blood vessels, and nerves. Nearly all in vivo studies of AGEshave focused on diabetes rather than on age-associated disorders because in diabetes, tissue damage develops over a much shorter experimental observaGLYCATION BROWNLEE PRODUCTS AND DIABETES

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tion period. Nevertheless, AGEs do accumulate on long-lived human proteins as a function of age (1) and would be expected to damage tissue by the samemechanisms operative in diabetes. As described below, accumulation of AGEs depends on both sugar concentration and the rate of protein turnover. Thus, some proteins that reach critical levels of AGE modification in sites where diabetic complications occur may turn over too quickly for normal levels of blood glucose to cause functional alterations, while proteins with a longer half-life wouldcontinue to be modified over a longer period of time.

BIOCHEMISTRY OF AGE FORMATION
Annu. Rev. Med. 1995.46:223-234. Downloaded from arjournals.annualreviews.org by CAPES on 08/27/08. For personal use only.

AGEs are generated from the so-called Amadori product, a 1-amino-1deoxyketose produced by the reaction of glucose with protein amino groups. The rate of formation of Amadori products isdirectly proportional to the glucose concentration. Analogous products are formed from the reaction of other aldoses with proteins (2). Studies with antibodies to AGEs suggest that immunologically similar structures form from the reaction of a number of different sugars with proteins (1, 3–5). Highly reactive carbonyl compounds, such as 3-deoxyglucosone, and other sugar fragmentation products areformed by processes requiring reactive oxygen species (6–13). These compounds then react again with protein amino groups to form a variety of intermediate and advanced glycation end products. Urinary and plasma levels of the relatively inactive 3-deoxyglucosone reduction product, deoxyfructose, have been measured to ascertain whether the AGE intermediate 3-deoxyglucosone is actually produced insignificant quantities in normal humans (14). From the results obtained, one can calculate that several milligrams of 3-deoxyglucosone are formed in the nondiabetic body per day and detoxified by reduction to 3-deoxyfructose. The prominence of 3-deoxyfructose in plasma and urine strongly suggests that the body contains specific reductase enzymes that detoxify AGE precursors and prevent AGE formation....