Higher Plasma Levels of Advanced Glycation End Products Are Associated With Incident Cardiovascular Disease and All-Cause Mortality in Type 1 Diabetes

Abstract

OBJECTIVETo investigate the associations of plasma levels of advanced glycation end products (AGEs) with incident cardiovascular disease (CVD) and all-cause mortality in type 1 diabetes and the extent to which any such associations could be explained by endothelial and renal dysfunction, low-grade inflammation, and arterial stiffness.RESEARCH DESIGN AND METHODSWe prospectively followed 169 individuals with diabetic nephropathy and 170 individuals with persistent normoalbuminuria who were free of CVD at study entry and in whom levels of Nε-(carboxymethyl)lysine, Nε-(carboxyethyl)lysine, pentosidine and other biomarkers were measured at baseline. The median follow-up duration was 12.3 (interquartile range 7.6–12.5) years.RESULTSDuring the course of follow-up, 82 individuals (24.2%) died; 85 (25.1%) suffered a fatal (n = 48) and/or nonfatal (n = 53) CVD event. The incidence of fatal and nonfatal CVD and of all-cause mortality increased with higher baseline levels of AGEs independently of traditional CVD risk factors: hazard ratio (HR) = 1.30 (95% CI = 1.03–1.66) and HR = 1.27 (1.00–1.62), respectively. These associations were not attenuated after further adjustments for markers of renal or endothelial dysfunction, low-grade inflammation, or arterial stiffness.CONCLUSIONSHigher levels of AGEs are associated with incident fatal and nonfatal CVD as well as all-cause mortality in individuals with type 1 diabetes, independently of other risk factors and of several potential AGEs-related pathophysiological mechanisms. Thus, AGEs may explain, in part, the increased cardiovascular disease and mortality attributable to type 1 diabetes and constitute a specific target for treatment in these patients.

Glyoxalase-1 overexpression reduces endothelial dysfunction and attenuates early renal impairment in a rat model of diabetes

“…In line with this observation, our experiments in cultured endothelial cells showed that GLO-I is an important regulator in the prevention of endothelial inflammation and activation. These results confirmed the link between markers of endothelial function and AGEs [27,28].…”

Serum high-mobility group box-1 levels are positively associated with micro- and macroalbuminuria but not with cardiovascular disease in type 1 diabetes: the EURODIAB Prospective Complications Study

“…One of the proposed mechanisms involves advanced glycation end products (AGEs) and the receptor for AGEs (RAGE) (1,2,3,4). Besides AGEs, RAGE can also be activated by other ligands such as high-mobility group box-1 (HMGB1) (5).…”

Plasma advanced glycation end products (AGEs) and NF-κB activity are independent determinants of diastolic and pulse pressure

“…Advanced glycation end products (AGEs) may play an important role in the development and/or progression of CVD and specifically hypertension [2][3][4][5][6][7]. AGEs are a heterogeneous group of compounds that are formed by non-enzymatic glycation of proteins, lipids and nucleic acids.…”

“…Experimental evidence has shown that AGE accumulation affords structural and functional changes in the cardiovascular system and results in myocardial relaxation abnormalities, atherosclerotic plaque formation, large artery stiffening and endothelial dysfunction [4,[19][20][21][22]. In the vessel wall, AGEs form covalent crosslinks with matrix proteins, which increases vessel rigidity, trap lipoproteins within the arterial wall and disrupts their clearance [23][24][25].…”