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

Abstract

OBJECTIVEThis study explored whether activation of the receptor for advanced glycation end products (RAGE) is implicated in the development of diabetes complications. RESEARCH DESIGN AND METHODSA case-cohort study was performed in 3,763 participants with prevalent diabetes in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. The hazard ratios (HRs) for death, major cardiovascular events, and new or worsening nephropathy were derived using Cox regression models, and the ability of sRAGE and AGE levels to reclassify the risk of nephropathy was assessed. RESULTSAfter adjustment for a range of possible confounders and other risk factors, sRAGE levels were associated with all-cause mortality (HR 1.11 for a 1-SD increase of log sRAGE [95% CI 1.00-1.22]; P = 0.045) and new or worsening nephropathy (HR 1.20 for a 1-SD increase of log sRAGE [95% CI 1.02-1.41]; P = 0.032). Circulating AGE levels were also independently associated with new or worsening nephropathy (HR 1.21 for a 1-SD increase [95% CI 1.08-1.36]; P = 0.001). Both markers also significantly improved the accuracy with which the 5-year risk of new or worsening nephropathy could be predicted (net reclassification index in continuous model, 0.25 for sRAGE and 0.24 for AGE levels). CONCLUSIONSIn adults with type 2 diabetes, increased levels of sRAGE are independently associated with new or worsening kidney disease and mortality over the next 5 years. Higher levels of AGE are also associated with an increased risk of adverse renal outcomes. The AGE/RAGE axis may be of importance in the prevention and management of diabetes complications.Diabetes is associated with an increased risk of adverse renal and cardiovascular outcomes, which are only partially reduced by intensive glycemic control. This may be because of the long-lasting (legacy) effects of poor glycemic control over many years (1). Potential mediators of this "metabolic karma" include the long-lasting posttranslational molecular modifications induced by hyperglycemia, known as advanced

New Horizons in Diabetic Neuropathy: Mechanisms, Bioenergetics, and Pain

“…In a rodent model of diabetes and DN, aminoguanidine prevented the formation of AGE and had robust pre-clinical promise (Miyauchi et al, 1996), but in humans, the side effects of the drug prohibited its therapeutic development (Thornalley, 2003). A soluble extracellular domain of RAGE, sRAGE, blocks RAGE, and serum levels of sRAGE are strongly associated in man with both cardiovascular disease and diabetic nephropathy, but not as of yet in human DN (Humpert et al, 2007; Thomas et al, 2015). More detailed studies, similar to what has been done for diabetic nephropathy, are proposed to determine if RAGE activation is a meaningful therapeutic target in DN (Zochodne, 2014).…”

Role of Glycated Proteins in the Diagnosis and Management of Diabetes: Research Gaps and Future Directions

“…There is evidence of clinical value of sRAGE. In a case-cohort study of 3,763 patients with type 2 diabetes, both AGE and sRAGE plasma values predicted decreasing renal function and all-cause mortality, but hazard ratios were only 1.1 to 1.2 (88). There is, however, controversy over the associations between sRAGE concentrations and diabetes complications; some studies show a positive association (89) and others an inverse one (90).…”

Histones and heart failure in diabetes

“…Because they are stable and long lasting, AGEs have been implicated in the development and progression of many of the long-term complications of diabetes [137], including heart failure [132]. AGEs may directly modify histone proteins, and this may directly affect chromatin structure and gene expression [138, 139].…”