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Markers of Endothelial Dysfunction and Inflammation in Type 1 Diabetic Patients With or Without Diabetic Nephropathy Followed for 10 Years

Association with mortality and decline of glomerular filtration rate

¹ Steno Diabetes Center, Gentofte, Denmark
² Department of Internal Medicine, Academic Hospital Maastricht, the Netherlands
³ Faculty of Health Science, Aarhus University, Aarhus, Denmark
⁴ Department of Medical Endocrinology, Rigshospitalet, Copenhagen, Denmark

Corresponding author: Anne Sofie Astrup, MD, Steno Diabetes Center, Niels Steensens Vej 2, DK-2820 Gentofte, Denmark. E-mail: ansa{at}steno.dk

OBJECTIVE—We evaluated the association of biomarkers of endothelial dysfunction and inflammation with all-cause mortality and cardiovascular mortality and morbidity and decline in glomerular filtration rate (GFR) in type 1 diabetic patients.

RESEARCH DESIGN AND METHODS—We prospectively followed 199 type 1 diabetic patients with diabetic nephropathy and 192 patients with persistent normoalbuminuria. Biomarkers were measured at baseline.

RESULTS—We constructed two Z scores: the mean inflammatory Z score combined C-reactive protein, interleukin-6, soluble intercellular adhesion molecule (sICAM-1), and secreted phospholipase A2 and the mean Z score for endothelial dysfunction combined soluble vascular cell adhesion molecule 1, plasminogen activator inhibitor-1, and sICAM-1. The mean Z score of inflammatory biomarkers was associated with mortality and the combined end point in patients with diabetic nephropathy after multivariate adjustment (hazard ratio 1.7 [95% CI 1.1–2.6]; P = 0.025 and 1.5 [1.1–2.2]; P = 0.017). The mean Z score for endothelial dysfunction biomarkers was associated with mortality in a model adjusting for age and sex in patients with diabetic nephropathy (1.6 [1.0–2.3]; P = 0.031). The mean Z score for endothelial dysfunction correlated with decline in GFR (r = –0.243; P = 0.001); the correlation persisted after multivariate adjustment (coefficient –1.38 [95% CI –2.27 to –0.50]; P = 0.002).

CONCLUSIONS—Mean Z scores of inflammatory biomarkers are significantly associated with all-cause mortality and cardiovascular morbidity and mortality in patients with nephropathy after multivariate adjustment. These data suggest that the high risk of cardiovascular disease in type 1 diabetes may be explained in part by inflammatory activity. Mean Z score of endothelial dysfunction correlated after multivariate adjustment with the rate of decline in GFR.

Abbreviations: AUC, area under the receiver operating characteristic curve • GFR, glomerular filtration rate • hsCRP, high-sensitivity C-reactive protein • IL-6, interleukin-6 • PAI-1, plasminogen activator inhibitor-1 • sICAM-1, soluble intercellular adhesion molecule-1 • sPLA2, secreted phospholipase A2 • sVCAM-1, soluble vascular cell adhesion molecule-1 • TGF-β, transforming growth factor-β

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