Prognostic Values of Inflammation and Oxidative Stress Biomarkers on the Risk of Peripheral Arterial Disease in Type 2 Diabetes
Authors: NATIVEL MATHILDE , SCHNEIDER FABRICE , SAULNIER PIERRE , MEILHAC OLIVIER , RONDEAU PHILIPPE , COURNOT MAXIME , POTIER LOUIS , VELHO GILBERTO , MARRE MICHEL , ROUSSEL RONAN , RIGALLEAU VINCENT , MOHAMMEDI KAMEL , HADJADJ SAMY 
Published: June 2018

Aim: We tested whether inflammation and oxidative stress biomarkers may predict the risk of peripheral arterial disease (PAD) in the SURDIAGENE (SURvie, DIAbete de type 2 et GENEtique) type 2 diabetes cohort.
Methods: plasma concentrations of angiopoietin like 2 (ANGPTL2), TNF receptor 1 (TNFR1), fluorescent advanced glycation end products (F-AGE), advanced oxidation protein products (AOPP), protein carbonyl, ischemia-modified albumin (IMA), total reductive capacity of plasma (TRCP) and oxidative hemolysis inhibition assay (OxHLIA) were measured at baseline using ELISA, spectrofluorimetry, spectrophotometry and Folin-Ciocalteu methods. Cox model was fitted to assess the risk of severe PAD, requiring aortic or lower limb revascularization, by increasing tertiles of each biomarker at baseline adjusting for confounding variables. C-statistic was used to test PAD discrimination.
Results: Among 1395 participants free for PAD at baseline (men 57%, mean±SD age 65±11 years, diabetes duration 14±10 years), aortic or lower limb revascularization was performed in 66 (4.7%) patients during 5.8±3.2 years of follow-up. The rate of revascularisation was higher in the upper tertiles (T2, T3) compared to the lower one (T1): TNFR1 (HR [95% CI] T2 vs. T1, 1.15 [1.01-1.32]; T3 vs. T1, 1.59 [1.34-1.88], trend p&lt;0.0001), F-AGE (1.43 [1.25-1.64]; 2.[1.76-2.38], trend p&lt;0.0001), and TRCP (1.00 [0.88-1.15]; 1.25 [1.09-1.44], trend p=0.002). Similar results were observed when the 3 markers were included together in the same model. TNFR1 (change in c-statistic 0.010 [0.004-0.015], p=0.001), F-AGE (0.026 [0.014-0.039], p&lt;0.0001) and TRCP (0.017 [0.009-0.024], p&lt;0.0001), considered individually or together (0.052 [0.038-0.065], &lt;0.0001), improved PAD discrimination.
Conclusion: Our results suggest that TNFR1, F-AGE, and TRCP can be used to screen severe PAD in type 2 diabetes, and support the role of inflammation and oxidative stress on the pathogenesis of PAD.

Disclosure
M. Nativel: None. F. Schneider: None. P. Saulnier: None. O. Meilhac: None. P. Rondeau: None. M. Cournot: None. L. Potier: Consultant; Self; Sanofi, Novo Nordisk A/S, Eli Lilly and Company. Board Member; Self; Merck Sharp & Dohme Corp.. G. Velho: None. M. Marre: Board Member; Self; Abbott. Consultant; Self; AstraZeneca. Board Member; Self; Intarcia Therapeutics, Inc.. Consultant; Self; Eli Lilly and Company. Board Member; Self; Merck Sharp & Dohme Corp., Novo Nordisk A/S. Research Support; Self; Sanofi. Board Member; Self; Servier. R. Roussel: Advisory Panel; Self; AbbVie Inc., Abbott, Eli Lilly and Company, Sanofi, Novo Nordisk A/S, AstraZeneca. Speaker's Bureau; Self; Servier. Consultant; Self; Bayer AG. Advisory Panel; Self; Merck Sharp & Dohme Corp.. Research Support; Self; Amgen Inc., Sanofi, Novo Nordisk A/S, Danone Research. Stock/Shareholder; Self; Iriade. Advisory Panel; Self; Physiogenex S.A.S.. V. Rigalleau: None. K. Mohammedi: Speaker's Bureau; Self; Novo Nordisk Inc.. Other Relationship; Self; Novo Nordisk Inc.. Speaker's Bureau; Self; Sanofi. Other Relationship; Self; Sanofi, Takeda Development Centre Europe Ltd., Boehringer Ingelheim Pharmaceuticals, Inc. S. Hadjadj: Consultant; Self; Abbott, Novo Nordisk A/S, Servier, AstraZeneca, Merck Sharp & Dohme Corp.. Board Member; Self; Valbiotis. Consultant; Self; Sanofi, Eli Lilly and Company.