The overall goal of this project is to determine the role of oxidative stress with associated inflammation and abnormalities in nitric oxide synthase (NOS) in the pathogenesis of clinical cardiovascular disease (CVD), carotid IMT, cardiac MRI and microvascular (retinopathy and nephropathy) complications of diabetes. Specific biomarkers arising from the molecular footprints of currently identified pathways producing oxidative stress from carbohydrate and lipid metabolism will be measured in samples obtained at baseline and frequent intervals thereafter in a large cohort of patients (DCCT/EDIC) with type 1 diabetes (T1DM). This cohort and their level of glycemic control has been exceedingly well characterized and examined frequently and rigorously for diabetic complications and their known risk factors over a 25 year period with little loss to follow-up. The identification of key biomarkers and their relationship CVD as determined by clinical events, carotid IMT and cardiac MRI as well as, nephropathy and retinopathy as well as possible relationships of these biomarkers to glycemic control should lead to new and more specific therapeutic methods and guidelines for reducing the risk of diabetic complications. These goals will be accomplished through 2 specific aims:
Aim 1 To test the hypothesis that specific oxidative pathways are associated with increased risk for clinical CVD, carotid IMT, cardiac MRI and microvascular complications in the DCCT/EDIC cohort.
Aim 2. To determine the effect of intensive versus conventional treatment during the DCCT on measures of oxidative stress and whether this effect is related to chronic glycemic control (HbA1c). Biomarkers for analysis will include measures of oxidation (Isoprostanes, myeloperoxidase and downstream products including nitrotyrosine) as well as modifications of HDL that may alter its functional characteristics in atherosclerosis protection. Modulators of NOS including ADMA, SDMA will also be measured. The relationship of each of these markers to cardiovascular disease (CVD) events (primary analyses for power calculations) in all DCCT/EDIC subjects who have had an event compared to DCCT/EDIC controls. In related analyses, the effects of these markers on other measures of CVD (carotid intimal medial thickness and cardiac MRI) as well as on microvascular complications (diabetic retinopathy and overt nephropathy). Related analyses will evaluate whether intensive vs. conventional glycemic control (and associated levels of HgbA1c) affect the levels of the biomarkers. These analyses may give insights into whether the effects of glycemic control on the complications of diabetes are mediated through any of the proposed biomarkers.
The Diabetes Control and Complications Trial (DCCT) and its follow up study called Epidemiology of Diabetes Interventions and Complications (EDIC) have a well-characterized cohort of type 1 diabetic subjects in whom the benefits of intensive glycemic control to reduce the risks for onset and progression of retinopathy, onset and progression of nephropathy and reduction in CVD risk have been demonstrated. Mechanisms by which the complications of diabetes mellitus may occur are not yet well understood. The current proposal seeks to determine whether specific measures of oxidation predict the risk to develop microvascular and macrovascular complications of type 1 DM (Aim 1) and whether any observed relationships of oxidation to complications may be modified by intensive glycemic control (Aim 2).
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