Increased Nε-(carboxymethyl)-lysine levels in cerebral blood vessels of diabetic patients and in a (streptozotocin-treated) rat model of diabetes mellitus

Abstract

ObjectiveNon-enzymatic glycation of proteins and their end products (advanced glycation end products, AGE) have been implicated in the pathogenesis of diabetic complications. Our aim was to evaluate the association between diabetes mellitus (DM) and the accumulation of one of the most abundant AGEs, Nε-(carboxymethyl)-lysine (CML), in cerebral vessels.Research design and methodsBrain tissue samples were obtained by autopsy from 20 DM patients and 13 age-matched controls. In addition, we investigated brain tissue samples of seven rats after induction of diabetes with streptozotocin (STZ) and six non-diabetic control rats. We used an immunohistochemical staining method to examine the CML immunoreactivity in the cerebral vessels.ResultsStaining intensity of CML was significantly higher in cerebral vessels of diabetic patients than in non-diabetic subjects (median of the immunohistochemical intensity score/cm2 in the diabetic group of 0.85 (interquartile range (IQR) 0.66–1.52) vs 0.63 in the control group (IQR 0.44–0.70); P=0.002). Furthermore, there was a similar significant difference in CML staining intensity of cerebral vessels between STZ diabetic rats and non-diabetic control rats (median of the immunohistochemical intensity score/cm2 in the diabetic group of 1.08 (IQR 0.73–1.43) vs 0.23 in the control group (IQR 0.12–0.43); P=0.003).ConclusionsAccumulation of CML-modified proteins is significantly greater in the cerebral vessels of the diabetic patients than their age-matched controls. This association has been confirmed in the insulin-deficient diabetic rat model. It may be possible that the excessive accumulation of AGE-modified proteins in the cerebral vasculature alters the local environment and microcirculation and thereby contributes to the development of cognitive impairments in diabetes. Therefore, additional study on the causal link between AGE accumulation and cognitive dysfunction and the potential benefits of AGE-blocking and/or breaking compounds is indicated.