Circulating levels of AGEs and soluble RAGE isoforms are associated with all-cause mortality and development of cardiovascular complications in type 2 diabetes: a retrospective cohort study

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Jacopo Sabbatinelli1, Stefania Castiglione2, Federica Macrì2, Angelica Giuliani1, Deborah Ramini3, Maria Vinci4, Elena Tortato5, Anna Rita Bonfigli6, Fabiola Olivieri3, Angela Raucci2
1Department of Clinical and Molecular Sciences, Università Politecnica Delle Marche, Via Tronto 10/A, 60126, Ancona, Italy
2Experimental Cardio-Oncology and Cardiovascular Aging Unit, Centro Cardiologico Monzino-IRCCS, Milan, Italy
3Clinical Laboratory and Molecular Diagnostic, IRCCS INRCA, Ancona, Italy
4Unit of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino-IRCCS, Milan, Italy
5Metabolic Diseases and Diabetology Department, IRCCS INRCA, Ancona, Italy
6Scientific Direction, IRCCS INRCA, Ancona, Italy

Tóm tắt

Abstract Background Advanced glycation end-products (AGEs) and their interaction with the receptor for advanced glycation end-products (RAGE) play a pivotal role in the development and progression of type 2 diabetes. In this retrospective cohort study, we explored the association of circulating levels of soluble RAGE (sRAGE) isoforms, i.e., endogenous secretory esRAGE and cleaved cRAGE, AGEs and their respective ratios with 15-year all-cause mortality in type 2 diabetes. Methods Baseline AGEs and sRAGE isoforms concentration were measured by ELISA in 362 patients with type 2 diabetes and in 125 age- and gender-matched healthy control subjects (CTR). Independent predictors of mortality were determined using Cox proportional-hazards models and used to build and validate a nomogram for all-cause mortality prediction in type 2 diabetes. Results AGEs, total sRAGE, cRAGE and the AGEs/sRAGE and AGEs/esRAGE ratios were significantly increased in patients with type 2 diabetes compared to CTR (p < 0.001). In CTR subjects, but not in type 2 diabetes patients, a significant negative correlation between cRAGE and age was confirmed (p = 0.003), whereas the AGEs/sRAGE (p = 0.032) and AGEs/cRAGE (p = 0.006) ratios were positively associated with age. At an average follow-up of 15 years (4,982 person-years), 130 deaths were observed. The increase in the AGEs/cRAGE ratio was accompanied by a higher risk of all-cause mortality in patients with type 2 diabetes (HR per each SD increment = 1.30, 95% CI 1.15–1.47; p < 0.001). Moreover, sRAGE was associated with the development of major adverse cardiovascular events (MACE) in type 2 diabetes patients without previous MACE (OR for each SD increase: 1.48, 95% CI 1.11–1.89). A nomogram based on age, sex, HbA1c, systolic blood pressure, and the AGEs/cRAGE ratio was built to predict 5-, 10- and 15-year survival in type 2 diabetes. Patients were categorized into quartiles of the monogram scores and Kaplan-Meier survival curves confirmed the prognostic accuracy of the model (log-rank p = 6.5 × 10− 13). Conclusions The ratio between AGEs and the cRAGE isoform is predictive of 15-year survival in patients with type 2 diabetes. Our data support the assessment of circulating AGEs and soluble RAGE isoforms in patients with type 2 diabetes as predictors of MACE and all-cause mortality.

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