Soluble receptor for AGE (RAGE) is a novel independent predictor of all-cause and cardiovascular mortality in type 1 diabetes

Abstract

Aims/hypothesis Activation of the receptor for AGE (RAGE) is implicated in the development and progression of vascular complications of diabetes. In this study, we explore factors and mortality outcomes associated with soluble RAGE (sRAGE) in a multicentre nationwide cohort of Finnish adults with type 1 diabetes. Methods Baseline sRAGE concentrations were estimated in 3,100 adults with type 1 diabetes. Clinical and biological variables independently associated with sRAGE were identified using multivariate regression analysis. Independent predictors of mortality were determined using Cox and FineGray proportional-hazards models. Results The main independent determinants of sRAGE concentrations were estimated glomerular filtration rate, albuminuria, body mass index, age, duration of diabetes, HbA 1c and insulin dose (all p<0.05). During a median of 9.1 years of follow-up there were 202 deaths (7.4 per 1,000 patient years). sRAGE was independently associated with all-cause (Cox model: HR 1.03) and cardiovascular mortality (Fine-Gray competing risks model: HR 1.06) such that patients with the highest sRAGE concentrations had the greatest risk of mortality, after adjusting for age, sex, macrovascular disease, HDL-cholesterol, HbA 1c , triacylglycerol, high-sensitivity C-reactive protein (hsCRP) and the presence and severity of chronic kidney disease. Although polymorphisms in the gene coding for RAGE were significantly associated with sRAGE concentrations, none were associated with mortality outcomes. Conclusions/interpretation Increased concentrations of sRAGE are associated with increased all-cause and cardiovascular mortality in type 1 diabetes, potentially reflecting the activation and production of RAGE in the context of accelerated vascular disease. These novel findings highlight the importance of the RAGE activation in the prevention and management of diabetic complications.

Relationship Between Levels of Advanced Glycation End Products and Their Soluble Receptor and Adverse Outcomes in Adults With Type 2 Diabetes

“…sRAGE levels were log-transformed to remove the effects of skewness. Because our data tended to have relatively high levels of sRAGE compared with earlier studies in diabetes (13)(14)(15), a sensitivity analysis was run repeating the main analyses of association in a restricted population including only those below the second tertile of sRAGE or AGE, as appropriate.…”

“…Tissue RAGE and circulating sRAGE are both increased in individuals with diabetes, paralleling increased levels of circulating AGEs and other RAGE ligands, including S100a8/9 and high-mobility group protein box-1, whose actions lead not only to RAGE activation but also to the autoinduction of RAGE expression (10)(11)(12). We and others have previously shown that sRAGE is independently associated with the development of cardiovascular complications and mortality in adults with type 1 diabetes (13,14). Similar findings have been reported in patients in type 2 diabetes without prior cardiovascular disease from the Collaborative Atorvastatin Diabetes Study (CARDS), although microvascular outcomes were not described in that report (15).…”

Decrease in Circulating Concentrations of Soluble Receptors for Advanced Glycation End Products at the Time of Seroconversion to Autoantibody Positivity in Children With Prediabetes

“…However, the complex equilibrium of membrane-bound RAGE, sRAGE, esRAGE, and RAGE ligands is anything but deciphered. Some investigators have reported a direct correlation between sRAGE concentrations and risk of diabetic and cardiovascular complications (16,17), while in a somewhat different population, decreased concentrations were associated with increased risk (18).…”

Immunogene Zelltodmarker HMGB1 und sRAGE als neue prädiktive und prognostische Serum Biomarker bei Tumorerkrankungen/Immunogenic cell death markers HMGB1 and sRAGE as new predictive and prognostic serum biomarkers in cancer disease

“…Allerdings gibt es auch Studien, die erh ö hte sRAGEWerte mit einem h ö heren Mortalit ä tsrisiko bei Diabetes Typ I in Verbindung bringen [155] . Au ß erdem sind bei akuten entz ü ndlichen Erkrankungen wie Sepsis, akute Pankreatitis oder unmittelbar nach einem Trauma die sRAGE-Werte z.T.…”