Determinants of Accelerated CVD in Type 1 Diabetes

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DESCRIPTION (provided by applicant): Prevention and treatment of cardiovascular disease remains to be a critical problem in the management of type 1 diabetes (T1D). Since 1999, Coronary Artery Calcification in Type 1 Diabetes (CACTI) study (R01 HL61753) has studied development and progression of coronary atherosclerosis in 654 T1D patients and 766 non-diabetic controls (age 20-55). This cohort has been examined using the electron beam tomography (EBT) and a battery of classical and novel cardiovascular risk factors during the baseline (4/00-3/02) and 3-year follow-up examination (1/03-5/04). Here, we are proposing to investigate mechanisms of cardiovascular complications using stored samples from this large cohort study and to include well-characterized study participants in two substudies utilizing novel techniques to: Disentangle the role of inflammation, immune response and diabetes-related metabolic factors in progression of coronary artery calcification. These processes will be characterized, usingCACTI baseline and 3-year follow-up samples, in 200 subject whose coronary atherosclerosis progressed significantly and 200 control subjects. Prospectively collect peripheral blood samples for measurement of inflammatory (CRP, MMP-9, WBC, MPO, fibrinogen, PAI-1) and immune response factors involved in atherosclerosis, such as SIL-2R, CD40/CD40L, cytokine panel as well as autoantibodies to oxidized LDL. To further our understanding of the role of insulin resistance in accelerated atherosclerosis among T1D patients by studying 48 T1 DM patients and 48 non-diabetic controls using euglycemic hyperinsulinemic clamps. To characterize T1D-specific morphology of coronary plaque and functional corollaries through indepth examination of T1D and non-diabetic subjectes identified with significant plaque burden. Re-analyze jointly already collected prospective data from the CACTI Study the Epidemiology of Diabetes Complications Study (T. Orchard, PI) and the EURODIAB study (J. Fuller, PI), to develop more generalizable estimates of the incidence of clinical CAD in T1D patients, defined by fatal and non-fatal Ml, revascularization or angina, as well as stroke, peripheral artery disease and cause-specific mortality and the incidence and progression rate of subclinical coronary atherosclerosis, characterized by coronary artery calcification.