Levels of Oxidized LDL and Advanced Glycation End Products-modified LDL in Circulating Immune Complexes Are Strongly Associated with Increased Levels of Carotid Intima-media Thickness and Its Progression in Type 1 Diabetes

Overview

Journal Diabetes

Specialty Endocrinology

Date 2010 Oct 29

PMID 20980456

Citations 42

Authors

Maria F Lopes-Virella

Kelly J Hunt

Nathaniel L Baker

John Lachin

David M Nathan

G Virella

Affiliations

Soon will be listed here.

Abstract

Objective: High cholesterol levels in circulating immune complexes (IC), surrogate markers of modified LDL, are associated with increased carotid intima-media thickness (IMT) and cardiovascular events in type 1 diabetes. Different modifications of LDL are involved in IC formation, but which of these are predictive of vascular events is not known. Therefore, we measured oxidized LDL (oxLDL), advanced glycation end products-modified LDL (AGE-LDL), and malondialdehyde-modified LDL (MDA-LDL) in IC and determined their relationship with increased carotid IMT and compared the strength of the association with that observed with conventional risk factors.

Research Design And Methods: Levels of oxLDL, AGE-LDL, and MDA-LDL were measured in circulating IC isolated from sera of 479 patients of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort, collected at baseline. Internal and common carotid IMT were measured 8 and 14 years later by DCCT/EDIC.

Results: OxLDL, AGE-LDL, and MDA-LDL levels in circulating IC were significantly correlated with diabetes duration, BMI, and lipid and blood pressure, but not with age. Multivariate logistic regression models indicated that individuals in the highest versus lowest quartile of oxLDL and AGE-LDL in IC had a 6.11-fold [confidence interval (CI) 2.51-14.8] and a 6.4-fold (CI 2.53-16.2) increase in the odds of having high carotid IMT, respectively, after adjusting for conventional risk factors. Parallel analyses resulted in odds ratios of 2.62 (CI 1.24, 5.55) for LDL-C, 1.45 (CI 0.69, 3.03) for diastolic blood pressure, and 2.33 (CI 1.09, 4.99) for A1C.

Conclusions: OxLDL and AGE-LDL in circulating IC were significantly associated with progression and increased levels of carotid IMT in type 1 diabetes.

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References

Nathan D, Genuth S, Lachin J, Cleary P, Crofford O, Davis M . The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993; 329(14):977-86. DOI: 10.1056/NEJM199309303291401. View

Virella G, Lopes-Virella M . Lipoprotein autoantibodies: measurement and significance. Clin Diagn Lab Immunol. 2003; 10(4):499-505. PMC: 164259. DOI: 10.1128/cdli.10.4.499-505.2003. View

Virella G, Thorpe S, Alderson N, Derrick M, Chassereau C, Rhett J . Definition of the immunogenic forms of modified human LDL recognized by human autoantibodies and by rabbit hyperimmune antibodies. J Lipid Res. 2004; 45(10):1859-67. DOI: 10.1194/jlr.M400095-JLR200. View

Steinberg D . Atherogenesis in perspective: hypercholesterolemia and inflammation as partners in crime. Nat Med. 2002; 8(11):1211-7. DOI: 10.1038/nm1102-1211. View

Nathan D, Lachin J, Cleary P, Orchard T, Brillon D, Backlund J . Intensive diabetes therapy and carotid intima-media thickness in type 1 diabetes mellitus. N Engl J Med. 2003; 348(23):2294-303. PMC: 2701300. DOI: 10.1056/NEJMoa022314. View

Libby P . Inflammation in atherosclerosis. Nature. 2002; 420(6917):868-74. DOI: 10.1038/nature01323. View

Virella G, Carter R, Saad A, Crosswell E, Game B, Lopes-Virella M . Distribution of IgM and IgG antibodies to oxidized LDL in immune complexes isolated from patients with type 1 diabetes and its relationship with nephropathy. Clin Immunol. 2008; 127(3):394-400. PMC: 2601558. DOI: 10.1016/j.clim.2008.02.005. View

Hazen S . Oxidized phospholipids as endogenous pattern recognition ligands in innate immunity. J Biol Chem. 2008; 283(23):15527-31. PMC: 2414290. DOI: 10.1074/jbc.R700054200. View

Orchard T, Virella G, Forrest K, Evans R, Becker D, Lopes-Virella M . Antibodies to oxidized LDL predict coronary artery disease in type 1 diabetes: a nested case-control study from the Pittsburgh Epidemiology of Diabetes Complications Study. Diabetes. 1999; 48(7):1454-8. DOI: 10.2337/diabetes.48.7.1454. View

10.

. Feasibility of centralized measurements of glycated hemoglobin in the Diabetes Control and Complications Trial: a multicenter study. The DCCT Research Group. Clin Chem. 1987; 33(12):2267-71. View

11.

Virella G, Koskinen S, Krings G, Onorato J, Thorpe S, Lopes-Virella M . Immunochemical characterization of purified human oxidized low-density lipoprotein antibodies. Clin Immunol. 2000; 95(2):135-44. DOI: 10.1006/clim.2000.4857. View

12.

Lopes-Virella M, Virella G, Orchard T, Koskinen S, Evans R, Becker D . Antibodies to oxidized LDL and LDL-containing immune complexes as risk factors for coronary artery disease in diabetes mellitus. Clin Immunol. 1999; 90(2):165-72. DOI: 10.1006/clim.1998.4631. View

13.

Terkeltaub R, Banka C, Solan J, Santoro D, Brand K, Curtiss L . Oxidized LDL induces monocytic cell expression of interleukin-8, a chemokine with T-lymphocyte chemotactic activity. Arterioscler Thromb. 1994; 14(1):47-53. DOI: 10.1161/01.atv.14.1.47. View

14.

Burton D, Woof J . Human antibody effector function. Adv Immunol. 1992; 51:1-84. DOI: 10.1016/s0065-2776(08)60486-1. View

15.

Yla-Herttuala S, Palinski W, Rosenfeld M, Parthasarathy S, Carew T, Butler S . Evidence for the presence of oxidatively modified low density lipoprotein in atherosclerotic lesions of rabbit and man. J Clin Invest. 1989; 84(4):1086-95. PMC: 329764. DOI: 10.1172/JCI114271. View

16.

. Fundus photographic risk factors for progression of diabetic retinopathy. ETDRS report number 12. Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology. 1991; 98(5 Suppl):823-33. View

17.

Andersson J, Libby P, Hansson G . Adaptive immunity and atherosclerosis. Clin Immunol. 2009; 134(1):33-46. DOI: 10.1016/j.clim.2009.07.002. View

18.

Yla-Herttuala S, Palinski W, Butler S, Picard S, Steinberg D, Witztum J . Rabbit and human atherosclerotic lesions contain IgG that recognizes epitopes of oxidized LDL. Arterioscler Thromb. 1994; 14(1):32-40. DOI: 10.1161/01.atv.14.1.32. View

19.

Michaelsen T, Sandlie I, Bratlie D, Sandin R, Ihle O . Structural difference in the complement activation site of human IgG1 and IgG3. Scand J Immunol. 2009; 70(6):553-64. DOI: 10.1111/j.1365-3083.2009.02338.x. View

20.

Virella G, Thorpe S, Alderson N, Stephan E, Atchley D, Wagner F . Autoimmune response to advanced glycosylation end-products of human LDL. J Lipid Res. 2003; 44(3):487-93. DOI: 10.1194/jlr.M200370-JLR200. View