Early and intermediate Amadori glycosylation adducts, oxidative stress, and endothelial dysfunction in the streptozotocin-induced diabetic rats vasculature

Abstract

Aims/hypothesis. In a model of streptozotocin-induced Type 1 diabetes mellitus in rats of 9 weeks duration, we analysed time associations between the development of hyperglycaemia, early and intermediate glycosylation Amadori adducts, or AGE compared with enhancement of oxidative stress and endothelial dysfunction.Methods. Endothelial function was tested at several stages of streptozotocin-induced diabetes and after treatment with insulin, resulting in different concentrations of blood glucose, glycosylated haemoglobin (an Amadori adduct), and AGE. Other animals were studied antagonising the formation of AGE with aminoguanidine. Results. Relaxation in response to acetylcholine (1 nmol/l to 10 µmol/l) was tested in isolated segments from aorta or mesenteric microvessels. Impairment of endothelium-dependent relaxations occurred after 2 weeks of untreated diabetes. Preincubation of vessels affected with 100 U/ml superoxide dismutase improved the relaxations to acetylcholine, along the time-course of the endothelial impairment. This indicates the participation of reactive oxygen species on diabetic endothelial dysfunction. The impairment of endothelium-dependent relaxations was recovered after 3 more weeks of insulin treatment. Aminoguanidine treatment did not modify this pattern of development. The time course of the rise and disappearance of endothelial dysfunction showed a higher correlation with glycosylated haemoglobin concentrations than with blood glucose or serum AGE. Conclusion/interpretation. Enhancement of early and intermediate Amadori adducts of protein glycosylation was the factor showing a better relation with the development of endothelium impairment. These results are consistent with a role for these products in the development of diabetic vasculopathy. [Diabetologia (2003) 46:556-566] Keywords Diabetes mellitus, endothelial dysfunction, nitric oxide, superoxide anions, hyperglycaemia, Amadori adducts, advanced glycosylation end-products. Endothelial dysfunction seems to be a key factor in the development of diabetic vascular complications. The impairment of endothelium-dependent vasodilatations is an early event occurring in diabetic patients [1,2,3] and animal diabetic models [4,5,6, 7]. Enhanced oxidative stress in diabetes mellitus has been also shown [8,9], which can be detected by peroxidation products [10] or by increased generation of reactive oxygen species (ROS), mainly superoxide anions [11]. Indeed, enhanced oxidative stress is proposed to be a major cause of diabetic endothelial dysfunction [12,13].There is also increasing evidence that diabetic endothelial dysfunction and oxidative stress are a conse-

Lycopene attenuates endothelial dysfunction in streptozotocin-induced diabetic rats by reducing oxidative stress

“…In the present study, the higher MDA levels and the lower SOD levels in the aorta of the diabetic rats compared with the normal control animals demonstrated the presence oxidative damage and impaired antioxidant capacity. The increased oxidative stress in aorta played a central role in endothelial dysfunction, which has been recognized as a critical and initiating factor in the pathogenesis of diabetic cardiovascular complications (Rodríguez-Mañas et al, 2003). Endothelial dysfunction in experimental animal models is commonly demonstrated by impairment of endothelium-dependent vasorelaxation, which has been shown to be associated with a reduction in the release and/or production or abnormal oxidative metabolism of endothelium-derived NO in the vessel wall (Smith et al, 2007;Jin et al, 2009;Wang et al, 2009).…”

“…Endothelial dysfunction, which results from oxidative stress damage induced by the chronic hyperglycemia of diabetes mellitus (Cai & Harrison, 2000), plays an initiating and critical role in the development of these cardiovascular complications (Rodríguez-Mañas et al, 2003).…”

Biomarkers and potential mechanisms of obesity-induced oxidant stress in humans

“…Activation of these intracellular molecules can produce ROS, as has Obesity-induced oxidant stress HK Vincent and AG Taylor been shown in rodent vessel tissues. 63 Oxidant damage and accelerated monocyte homing to the endothelium are the end results. 49,51 Intracellular glucose elevations stimulate the polyol pathway in which aldose reductase mediates conversion of glucose to sorbitol.…”

Effects of glucose tolerance on the changes provoked by glucose ingestion in microvascular function

“…Experimental evidence indicates that atherogenic mechanisms, such as endothelial dysfunction, oxidative stress and inflammation, may be chronically activated in diabetes [4][5][6][7], at least in part as a consequence of exaggerated postprandial glucose excursions [8][9][10]. The negative impact of hyperglycaemia-induced oxidative stress on endothelial dysfunction has been reported in a number of in vitro and animal studies [11][12][13][14][15]. Most of these studies, however, have applied rather extreme experimental conditions, making it difficult to assess their relevance either to diabetes, or to impaired glucose tolerance (IGT) where glucose excursions are smaller, smoother and associated with various degrees of hyperinsulinaemia.…”