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

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 ( 2 ‫؍‬ 59.4, P < 0.0001) and nephropathy ( 2 ‫؍‬ 18.2, P ‫؍‬ 0.0001), even after adjustment for mean HbA 1c (A1C) ( 2 ‫؍‬ 32.7, P < 0.0001 for retinopathy) and ( 2 ‫؍‬ 12.8, P ‫؍‬ 0.0016 for nephropathy). The predictive effect of A1C vanished after adjustment for furosine and CML ( 2 ‫؍‬ 0.0002, P ‫؍‬ 0.987 for retinopathy and 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. Diabetes 54:3103-3111, 2005 N onenzymatic glycation of proteins and subsequent formation of advanced glycation end products (AGEs) is one of the pathogenetic mechanisms thought to link hyperglycemia to diabetic retinopathy and nephropathy (1,2). Inhibitors of AGE formation (3-8) and breakers of AGE-protein crosslinks (9,10) reduce both microvascular complications in experimental diabetic models. The relationship of longterm intensive control of glycemia and its effect on these complications with indicators of skin collagen glycation (furosine), glycoxidation and AGE formation (pentosidine and carboxymethyllysine [CML]), and cross-linking (acid and pepsin solubility) were previously examined in 215 patients with type 1 diabetes from the Diabetes Control and Complications Trial (DCCT) (11) who underwent a skin biopsy ϳ1 year before the close of the trial. Compared with conventional treatment, intensive treatment was associated with significantly lower levels of furosine, pentosidine, CML, and relative fluorescence and with higher levels of acid-and pepsin-soluble collagen (11). Age-and duration-adjusted collagen variables were significantly associated with the A1C value closest in time to the biopsy and with mean DCCT A1C. Retinopathy, nephropathy, and neuropathy outcomes as dependent variables were sign...

Advanced glycation end-products and methionine sulphoxide in skin collagen of patients with type 1 diabetes

“…The data support the assumption that the formation of collagen FL is in equilibrium with ambient glucose concentrations [5]. Glycation alone may have a pathogenic role in the development of diabetic complications, and collagen FL is a predictor of complications in DCCT subjects [21,22].…”

“…The data support the contention that 4 years is a sufficient period of time for equilibration even of the end-products. Given that the recent DCCT report shows that the skin collagen FL and CML levels measured earlier (in 1991-1992) predict the 10-year incidence of retinopathy and nephropathy during EDIC [22], the combination of observations adds further support to the idea that damage resulting from glycation and CML formation may have long-term downstream effects that may explain the 'memory effect' of intensive treatment found during the DCCT.…”

Increased serum levels of advanced glycation endproducts predict total, cardiovascular and coronary mortality in women with type 2 diabetes: a population-based 18 year follow-up study

“…An increase in skin AGEs can predict progression of diabetic retinopathy and nephropathy in type 1 diabetes [28]. Compared with the use of samples from skin biopsies for measurement of AGEs, serum samples are simple, and with standardisation they could become a useful clinical tool.…”

Association Between p.Leu54Met Polymorphism at the Paraoxonase-1 Gene and Plantar Fascia Thickness in Young Subjects With Type 1 Diabetes

“…Tissue glycation and/or oxidation via intra-and extracellular generation of AGEs may promote diabetes complications. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/ EDIC) demonstrated in skin biopsies that collagen AGEs predict microvascular disease (12). Skin collagen methionine sulfoxide, a marker of oxidative damage independent of glycemia, has also been associated with type 1 diabetes complications (13).…”