Elevated serum levels of N?-carboxymethyl-lysine, an advanced glycation end product, are associated with proliferative diabetic retinopathy and macular oedema

Abstract

Aims/hypothesis. Diabetic retinopathy is a frequent microvascular complication. In search of novel risk markers, we analysed the association between serum levels of the major advanced glycation end product N ε -carboxymethyl-lysine (CML) and prevalence of advanced stages of retinopathy in Type 2 diabetic patients without nephropathy. Methods. We carried out a case-control study of Type 2 diabetic patients with and without advanced stages of diabetic retinopathy. Retinopathy and macular oedema were defined according to standard criteria. Serum levels of CML were estimated by means of a novel competition-based ELISA assay. Results. Serum levels of CML were significantly different between age-matched controls (n=792; mean value ± SD: 521±134 ng/ml), Type 2 diabetic patients without severe retinopathy (821±141 ng/ml; p<0.0001) and Type 2 diabetic patients with proliferative retinopathy (1182±346 ng/ml; p<0.0001). Levels of CML greater than 1000 ng/ml represented a 25-fold increase in risk of proliferative retinopathy. Receiver operating characteristics analysis revealed a CML threshold of 1087 ng/ml (100% sensitivity, 93% specificity) for clinically significant macular oedema. Conclusions/interpretation. High serum levels of CML were associated with advanced stages of retinopathy. Serum levels were shown to be a progressive risk marker, whereby a level of more than 1000 ng/ml induced a 25-fold increase in risk of proliferative retinopathy and clinically significant macular oedema. Our data suggest that serum levels of CML provide a novel risk marker for advanced stages of diabetic retinopathy in Type 2 diabetic patients.

Evaluation of N ε-(3-formyl-3,4-dehydropiperidino)lysine as a novel biomarker for the severity of diabetic retinopathy

“…Recent work has suggested that monitoring oxidative stress in parallel with hyperglycaemia may help to identify subsets of patients at high risk of advancement of diabetic retinopathy [19][20][21]. Carboxymethyl-lysine (CML), a product of glycooxidation and lipoxidation reactions, is often regarded as a general marker of oxidative stress [42] and a number of studies have shown cross-sectional associations between serum CML levels and the severity of diabetic retinopathy [43][44][45]. In most cases, however, serum CML levels strongly correlate with HbA 1c [46], suggesting that serum CML may not provide any additional risk information beyond that provided by monitoring mean levels of glycaemia.…”

Serum carboxymethyl-lysine, a dominant advanced glycation end product, is increased in women with gestational diabetes mellitus

“…CML is routinely used as a proxy of a total load of AGEs in various pathological situations and increased CML levels have been repeatedly reported in patients with T2DM and related complications [5][6][7] . To date, there are only very limited clinical data about AGE levels in GDM.…”

Gluco-Oxidation of Proteins in Etiology of Diabetic Retinopathy

“…Gluco-oxidation of proteins forms complex and irreversible molecules, which accumulate in the retinal vasculature of patients with diabetes and streptozotocin-induced diabetic rats (Hammes et al, 1999;Stitt et al, 1997) and have been implicated in the development of diabetic retinopathy (Boehm et al, 2004Genuth et al, 2005. Chronic exposure of the endothelium to AGEs has been shown to increase retinal vascular permeability in vivo (Stitt et al, 2000) and ex vivo (Leto et al, 2001).…”