Relationship between levels of advanced glycation end products and their soluble receptor and adverse outcomes in adults with type 2 diabetes.

Abstract

OBJECTIVE:

This study explored whether activation of the receptor for advanced glycation end products (RAGE) is implicated in the development of diabetes complications.

RESEARCH DESIGN AND METHODS:

A 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.

RESULTS:

After 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).

CONCLUSIONS:

In 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.

• Authors: Merlin C Thomas, Mark Woodward, Bruce Neal, Qiang Li, Raelene Pickering, Michel Marre, Bryan Williams, Vlado Perkovic, Mark E Cooper, Sophia Zoungas, John Chalmers, Graham S Hillis, ADVANCE Collaborative Group
• Journal: Diabetes care (Diabetes Care) Vol. 38 Issue 10 Pg. 1891-7 (Oct 2015) ISSN: 1935-5548 [Electronic] United States
• PMID: 26253728 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Chemical References

• Biomarkers
• Glycation End Products, Advanced
• Hypoglycemic Agents
• Receptor for Advanced Glycation End Products
• Receptors, Immunologic

Topics

• Aged
• Biomarkers (metabolism)
• Diabetes Mellitus, Type 2 (metabolism, prevention & control)
• Diabetic Angiopathies (metabolism, prevention & control)
• Diabetic Nephropathies (metabolism, prevention & control)
• Double-Blind Method
• Drug Therapy, Combination
• Epidemiologic Methods
• Female
• Glycation End Products, Advanced (metabolism)
• Humans
• Hypoglycemic Agents (administration & dosage)
• Male
• Receptor for Advanced Glycation End Products (metabolism)
• Receptors, Immunologic
• Treatment Outcome