High Concentrations of AGE-LDL and Oxidized LDL in Circulating Immune Complexes Are Associated With Progression of Retinopathy in Type 1 Diabetes

  1. the DCCT/EDIC Study Group*
  1. 1Department of Medicine, Medical University of South Carolina, Charleston, South Carolina
  2. 2Ralph H. Johnson VA Medical Center, Charleston, South Carolina
  3. 3Harold Hamm Oklahoma Diabetes Center and Section of Endocrinology and Diabetes, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
  4. 4Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina
  1. Corresponding author: Maria F. Lopes-Virella, virellam{at}musc.edu.

Abstract

OBJECTIVE To determine whether immunocomplexes (ICs) containing advanced glycation end product (AGE)–LDL (AGE-LDL) and oxidized LDL (oxLDL) contribute to the development of retinopathy over a 16-year period in subjects with type 1 diabetes.

RESEARCH DESIGN AND METHODS Levels of AGE-LDL and oxLDL in ICs were measured in 517 patients of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort. Retinopathy was assessed by stereoscopic fundus photography. Cox proportional hazards models were used to assess the effect of AGE-LDL-ICs and oxLDL-ICs on retinopathy progression.

RESULTS In unadjusted models, higher baseline levels of AGE-LDL-ICs and oxLDL-ICs significantly predicted progression of diabetic retinopathy outcomes. After adjustment by study-design variables (treatment group, retinopathy cohort, duration of type 1 diabetes, and baseline albumin excretion rate [AER], hemoglobin A1c (HbA1c), and Early Treatment Diabetic Retinopathy Study [ETDRS] score), one SD increase in IC levels was associated with 47% (hazard ratio [HR] 1.47 [95% CI 1.19–1.81]; AGE-LDL-IC) and 45% (1.45 [1.17–1.80]; oxLDL-IC) increased risk of developing proliferative diabetic retinopathy (PDR) and 37% (1.37 [1.12–1.66]; to both ICs) increased risk of progressing to severe nonproliferative retinopathy. Analyses were stratified by retinopathy cohort because results differed between primary and secondary cohorts. For AGE-LDL-ICs, HR for progression to PDR was 2.38 (95% CI 1.30–4.34) in the primary cohort and attenuated in the secondary cohort (1.29 [1.03–1.62]). Similar results were observed for oxLDL-ICs.

CONCLUSIONS Increased levels of AGE-LDL and oxLDL in ICs are associated with increased risk for progression to advanced retinopathy in patients with type 1 diabetes, indicating that the antibody response to modified LDL plays a significant role in retinopathy progression.

  • Received October 19, 2011.
  • Accepted March 10, 2012.

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