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

• DOI: 10.2337/dc11-2040
• Publication Date: 2012-04-18T20:13:52Z
• Authors: Maria F. Lopes-Vi...; Nathaniel L. Baker; Kelly J. Hunt; Timothy J. Lyons; Alicia J. Jenkins; Gabriel Virella
• Keywords: Adult; Glycation End Products, Advanced; Male; Lipoproteins; Glycosylated; 610; LDL; 03 medical and health sciences; Risk Factors; Diabetes Mellitus; Glycosylation End Products; 617; Albuminuria; Humans; Original Research; Proportional Hazards Models; Glycated Hemoglobin; 0303 health sciences; Diabetic Retinopathy; Hemoglobin A; Cholesterol, LDL; name=SDG 3 - Good Health and Well-being; 3. Good health; Lipoproteins, LDL; Cholesterol; Diabetes Mellitus, Type 1; Disease Progression; /dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being; Biological Markers; Advanced; Female; Biomarkers; Type 1

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.