This application is responsive to PAR-09-247: Ancillary Studies to Major Ongoing Clinical Research Studies to Advance Areas of Scientific Interest within the Mission of the NIDDK (R01). Moreover, the proposed study not only capitalizes on the established infrastructure of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study, but builds of off a previously supported NIH funded Program Project Grant (P01 HL55782) entitled """"""""Markers and Mechanisms of Vascular Disease in Diabetes"""""""" that terminated in 2008. In brief, we propose to complete secondary data analysis to study the epidemiology of LDL immune complex (IC) measurements in relation to micro- and macro-vascular complications in 520 DCCT/EDIC participants with these biomarkers measured at four time points spanning 22 years. Preliminary data suggest that oxLDL-IC and AGE-LDL-IC are stronger predictors of atherosclerosis in type 1 diabetes than established risk factors including LDL cholesterol levels, hemoglobin A1c and albumin excretion rate. However, proper analysis of the longitudinal data is essential. The longitudinal studies proposed will allow us to determine which LDL-IC modifications are the most important in predicting development of complications in diabetes and may allow us to uncover possible mechanisms through which the development of complications could be prevented.
Aim 1 of the proposed study is to determine whether glucose control, lipid lowering therapy or treatment with angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), which are known to decrease lipids and/or oxidative stress, leads to a decrease in LDL-IC levels.
Aim 2 of the proposed study is to test the hypothesis that ox-LDL, AGE-LDL and MDA-LDL immune complexes predict micro- and macro-vascular disease outcomes in individuals with type 1 diabetes;to determine the discriminatory power of these novel risk factors relative to established risk factors;to identify biomarker panels able to predict outcomes of interest;and to determine whether tight glucose control, lipid lowering therapy or treatment with ACE inhibitors or ARBs modifies the relationship between baseline LDL-IC levels and disease outcomes. Type 1 diabetes is a chronic debilitating disease which ultimately results in complications which cause major morbidity and mortality. If specific LDL-IC are playing a critical role in the development of type 1 diabetes complications, not only could specific LDL-IC serve as biomarkers of future disease risk, but knowledge of their role on the disease pathway may provide a mechanism to target for therapy development.
LDL immune complexes (IC) are new biomarkers which may predict complications in patients with type 1 diabetes. Therefore, using data on these biomarkers previously collected as part of a large ongoing study on individuals with type 1 diabetes we propose to determine whether specific LDL immune complexes are associated with common complications in individuals with type 1 diabetes including heart disease, peripheral vascular disease, renal disease and eye disease. If LDL-IC are playing a critical role in the development of type 1 diabetes complications, not only could specific LDL-IC serve as biomarkers of future disease risk, but knowledge of their role on the disease pathway may provide a mechanism to target for therapy development.
