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. 2005 Nov;54(11):3103-11.
doi: 10.2337/diabetes.54.11.3103.

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 Genuth  1 , Wanjie Sun, Patricia Cleary, David R Sell, William Dahms, John Malone, William Sivitz, Vincent M Monnier; DCCT Skin Collagen Ancillary Study Group
Affiliations

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 Genuth et al. Diabetes. 2005 Nov.

Abstract

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 (chi2 = 59.4, P < 0.0001) and nephropathy (chi2 = 18.2, P = 0.0001), even after adjustment for mean HbA(1c) (A1C) (chi2 = 32.7, P < 0.0001 for retinopathy) and (chi2 = 12.8, P = 0.0016 for nephropathy). The predictive effect of A1C vanished after adjustment for furosine and CML (chi2 = 0.0002, P = 0.987 for retinopathy and chi2 = 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.

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Figures

FIG. 1
FIG. 1
Distribution of skin collagens by retinopathy progression status. The mean and SD of each skin collagen parameter are compared in those participants whose retinopathy progressed (red bars) three or more steps on the Early Treatment of Diabetic Retinopathy Scale scale and/or required retinal photocoagulation between the end of the DCCT and year 10 of EDIC versus those whose retinopathy did not progress (formula image). All values are adjusted for age and diabetes duration at the time of the biopsy.
FIG. 2
FIG. 2
Risk of retinopathy progression by DCCT mean A1C and furosine. Shown is the risk of progression of retinopathy in the upper quartile of skin collagen furosine (>Q3) (blue bars) compared with the progression in the lower three quartiles of furosine (Q3) and lower three (P value is from a between-group furosine (>Q3 vs. <Q3) comparison within each A1C (HBA1c) strata using the χ2 test. The greatest risk of progression occurs when both furosine and A1C are >Q3, but the dominance of furosine over A1C as a risk factor is evident.
FIG. 3
FIG. 3
Distribution of skin collagens by nephropathy progression status. The mean and SD of each skin collagen parameter are compared in those participants who developed microalbuminuria or worse (red bars) between the end of the DCCT and EDIC year 9–10 versus those who did not develop microalbuminuria (formula image). All values are adjusted for age and diabetes duration at the time of the biopsy.
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