Determinants of Accelerated CVD in Type 1 Diabetes

描述（由申请人提供）：心血管疾病的预防和治疗仍然是1型糖尿病（T1D）管理的关键问题。自1999年以来，1型糖尿病冠状动脉钙化（CACTI）研究（R01 HL61753）研究了654例T1D患者和766例非糖尿病对照组（20-55岁）冠状动脉粥样硬化的发生和进展。该队列在基线（4/00-3/02）和3年随访检查（1/03-5/04）期间使用电子束断层扫描（EBT）和一系列经典和新型心血管危险因素进行检查。在这里，我们建议利用这项大型队列研究中储存的样本来研究心血管并发症的机制，并利用新技术在两个亚研究中纳入特征明确的研究参与者：解开炎症、免疫反应和糖尿病相关代谢因素在冠状动脉钙化进展中的作用。这些过程将在200名冠状动脉粥样硬化进展明显的受试者和200名对照组中使用cacti基线和3年随访样本进行表征。前瞻性采集外周血样本，检测炎症（CRP、MMP-9、WBC、MPO、纤维蛋白原、PAI-1）和与动脉粥样硬化相关的免疫反应因子，如SIL-2R、CD40/CD40L、细胞因子面板以及氧化LDL自身抗体。为了进一步了解胰岛素抵抗在T1D患者动脉粥样硬化加速中的作用，我们研究了48例T1 DM患者和48例非糖尿病对照，使用了正糖高胰岛素钳。通过对具有明显斑块负担的T1D和非糖尿病受试者进行深入检查，表征T1D特异性冠状动脉斑块形态和功能推论。联合重新分析CACTI研究、糖尿病并发症流行病学研究（T. Orchard， PI）和EURODIAB研究（J. Fuller， PI）已经收集的前瞻性数据，以对T1D患者的临床CAD发病率进行更普遍的估计，T1D患者的发病率由致死性和非致死性Ml、血运重建术或心绞痛、中风、外周动脉疾病和病因特异性死亡率以及亚临床冠状动脉粥样硬化的发病率和进展率定义。以冠状动脉钙化为特征。

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.