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Diabetes 54:3103-3111, 2005
© 2005 by the American Diabetes Association, Inc.

Glycation and Carboxymethyllysine Levels in Skin Collagen Predict the Risk of Future 10-Year Progression of Diabetic Retinopathy and Nephropathy in the Diabetes Control and Complications Trial and Epidemiology of Diabetes Interventions and Complications Participants With Type 1 Diabetes

Saul Genuth1, Wanjie Sun2, Patricia Cleary2, David R. Sell3, William Dahms4, John Malone5, William Sivitz6, Vincent M. Monnier3,7, and for the DCCT Skin Collagen Ancillary Study Group*

1 Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio
2 Biostatistics Center, George Washington University, Rockville, Maryland
3 Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio
4 Department of Pediatrics, Rainbow Babies and Children’s Hospital and University Hospitals of Cleveland, Cleveland, Ohio
5 Department of Pediatrics, University of South Florida, Tampa, Florida
6 Department of Medicine, Veterans Administration Hospital, University of Iowa, Iowa City, Iowa
7 Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, Ohio

Several mechanistic pathways linking hyperglycemia to diabetes complications, including glycation of proteins and formation of advanced glycation end products (AGEs), have been proposed. We investigated the hypothesis that skin collagen glycation and AGEs predict the risk of progression of microvascular disease. We measured glycation products in the skin collagen of 211 Diabetes Control and Complications Trial (DCCT) volunteers in 1992 who continued to be followed in the Epidemiology of Diabetes Interventions and Complications study for 10 years. We determined whether the earlier measurements of glycated collagen and AGE levels correlated with the risk of progression of retinopathy and nephropathy from the end of the DCCT to 10 years later. In multivariate analyses, the combination of furosine (glycated collagen) and carboxymethyllysine (CML) predicted the progression of retinopathy ({chi}2 = 59.4, P < 0.0001) and nephropathy ({chi}2 = 18.2, P = 0.0001), even after adjustment for mean HbA1c (A1C) ({chi}2 = 32.7, P < 0.0001 for retinopathy) and ({chi}2 = 12.8, P = 0.0016 for nephropathy). The predictive effect of A1C vanished after adjustment for furosine and CML ({chi}2 = 0.0002, P = 0.987 for retinopathy and {chi}2 = 0.0002, P = 0.964 for nephropathy). Furosine explained more of the variation in the 10-year progression of retinopathy and nephropathy than did CML. These results strengthen the role of glycation of proteins and AGE formation in the pathogenesis of retinopathy and nephropathy. Glycation and subsequent AGE formation may explain the risk of these complications associated with prior A1C and provide a rational basis for the phenomenon of "metabolic memory" in the pathogenesis of these diabetes complications.

Address correspondence and reprint requests to Saul Genuth, MD, Case Western Reserve University, Cleveland, OH 44106. E-mail: smg15{at}cwru.edu

Abbreviations: AER, albumin excretion rate; AGE, advanced glycation end product; CML, N{varepsilon}-(carboxymethyl)-lysine; DCCT, Diabetes Control and Complications Trial; EDIC, Epidemiology of Diabetes Interventions and Complications


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Diabetes Diabetes Care Clinical Diabetes Diabetes Spectrum
Copyright © 2005 by the American Diabetes Association.