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

Abstract

Context and objective: High-mobility group box-1 (HMGB1) is a pro-inflammatory cytokine that may contribute to the pathogenesis of micro-and macrovascular complications commonly observed in diabetes. We investigated whether HMGB1 is associated with: i) markers of low-grade inflammation (LGI) and endothelial dysfunction (ED) and pulse pressure (PP, a marker of arterial stiffness); ii) prevalent nephropathy, retinopathy and cardiovascular disease (CVD) in type 1 diabetes; and iii) the potential mediating roles of LGI, ED and PP therein. Design and methods: This was a cross-sectional nested case-control study of 463 patients (226 women; mean age 40G10 years) with type 1 diabetes from the EURODIAB Prospective Complications Study. We used linear and binary or multinomial logistic regression analyses adjusted for traditional risk factors. Results: Serum Ln-HMGB1 levels were positively associated with LGI and ED (standardised bZ0.07 (95% confidence interval (CI): 0.02-0.12) and bZ0.08 (95% CI: 0.02-0.14) respectively), but not with PP. Higher Ln-HMGB1 (per unit) was associated with greater odds of micro-and macroalbuminuria: odds ratio (OR)Z1.24 (95% CI: 0.90-1.71) and ORZ1.61 (95% CI: 1.15-2.25) respectively, P for trendZ0.004. Further adjustments for LGI or ED did not attenuate these associations. No such associations were found between Ln-HMGB1 and estimated glomerular filtration rate (eGFR), retinopathy or CVD, however. Conclusions: In type 1 diabetes, higher serum HMGB1 levels are associated with greater prevalence and severity of albuminuria, though not with eGFR, retinopathy and CVD. Prospective studies are needed to clarify the causal role of HMGB1, if any, in the pathogenesis of vascular complications in type 1 diabetes.

Higher plasma high-mobility group box 1 levels are associated with incident cardiovascular disease and all-cause mortality in type 1 diabetes: a 12 year follow-up study

“…Second, an inter-assay variation lower than 11%, as obtained in our HMGB1 measures, may enable more precise estimates of the associations examined. Third, we have recently shown that in patients with type 1 diabetes (EURODIAB study) serum HMGB1 was not associated with prevalent CVD [10]. Apart from the difference in study design (cross-sectional vs prospective), the apparent discrepancy with the positive association between plasma HMGB1 and incident CVD observed in the present study raises the possibility that measures obtained in serum vs plasma may not represent the same pool of HMGB1.…”

Toll-Like Receptor 4 Activation Contributes to Diabetic Bladder Dysfunction in a Murine Model of Type 1 Diabetes

“…Although it was originally believed that the innate immune system is activated only in response to pathogens like bacteria and viruses, it is now widely accepted that endogenous molecules generated during sterile injury have equal capacities in activating immunity, which actually evolved to react to danger and not just to non–self-threats (9,20,21). Thus, activation of TLRs is a process that has now been documented as initiating or perpetuating the chronic low-level systemic inflammation that characterizes chronic sterile conditions, such as diabetes (9,14,19,22–24). …”

High-Mobility Group Box-1 and Endothelial Cell Angiogenic Markers in the Vitreous from Patients with Proliferative Diabetic Retinopathy

“…In patients with type 1 diabetes, serum HMGB1 levels were positively associated with markers of low-grade inflammation and endothelial dysfunction. In addition, higher serum HMGB1 levels were associated with greater prevalence and severity of albuminuria [40]. Activation of HMGB1/RAGE signaling axis is important in promoting proinflammatory pathways considered to play an important role in diabetes-induced retinal vascular inflammation.…”