Abstract
Aims/hypothesisThis study aimed to investigate the associations of plasma levels of the pro-inflammatory cytokine high-mobility group box 1 (HMGB1) with incident cardiovascular disease (CVD) and all-cause mortality in patients with type 1 diabetes.MethodsWe prospectively followed 165 individuals with diabetic nephropathy and 168 individuals with persistent normoalbuminuria who were free of CVD at study entry and in whom levels of HMGB1 and other cardiovascular risk factors were measured at baseline.ResultsDuring the course of follow-up (median, 12.3 years [interquartile range, 7.8–12.5]), 80 patients died, 82 suffered a fatal (n = 46) and/or non-fatal (n = 53) CVD event. After adjustment for age, sex, case–control status and other risk factors, patients with higher levels of loge HMGB1 had a higher incidence of fatal and non-fatal CVD and all-cause mortality: HR 1.55 (95% CI 0.94, 2.48) and HR 1.86 (95% CI 1.18, 2.93), respectively. Further adjustments for differences in markers of low-grade inflammation, endothelial and renal dysfunction and arterial stiffness did not attenuate these associations because plasma levels of HMGB1 were not independently associated with these variables.Conclusions/interpretationIn patients with type 1 diabetes, higher levels of plasma HMGB1 are independently associated with a higher risk of all-cause mortality and, to a lesser extent, with a higher incidence of CVD. Larger studies are needed to ascertain more definitely the role of HMGB1 in the development of vascular complications in diabetes.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-012-2622-1) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
Highlights
The pathophysiological mechanisms linking hyperglycaemia to the development of cardiovascular complications in patients with diabetes mellitus are not completely clear
Besides AGEs, receptor for AGEs (RAGE) can be activated by high-mobility group box 1 (HMGB1) [2]
The extracellular effects of HMGB1 are mediated by its binding to RAGE, and by its binding to the receptors of the tolllike receptor family [2]
Summary
The pathophysiological mechanisms linking hyperglycaemia to the development of cardiovascular complications in patients with diabetes mellitus are not completely clear. Besides AGEs, RAGE can be activated by high-mobility group box 1 (HMGB1) [2]. Extracellular HMGB1 released from necrotic cells and/or from immune cells upon inflammatory stimulation functions as a pro-inflammatory cytokine, which elicits pro-inflammatory responses from macrophages and endothelial cells [2]. The extracellular effects of HMGB1 are mediated by its binding to RAGE, and by its binding to the receptors of the tolllike receptor family [2]. HMGB1-induced production of inflammatory cytokines and adhesion molecules could contribute to low-grade inflammation (LGI), endothelial and renal dysfunction and arterial stiffening, all of which may partially explain the increased incidence of cardiovascular disease (CVD) in individuals with diabetes
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