Complications and Comorbidities of Type 1 Diabetes

描述(由申请人提供)：与普通人群相比，当今1型糖尿病(T1D)并发症的关键挑战之一是冠状动脉疾病(CAD)风险的极大增加。虽然更严格的血糖、血压和血脂控制降低了肾病和视网膜病变的发生率，但T1D患者和非糖尿病患者之间的CAD风险差距一直存在，无法用传统的危险因素解释。这项拟议的研究将检验新因素在T1D血管并发症中的作用，这些因素不是直接的 目前的预防指南涉及：胰岛素抵抗、AGEs、氧化应激和内皮功能障碍。预期的结果将为预防T1D患者过早冠心病和进一步延迟微血管并发症的试验设计提供参考。2000年至2002年，1型糖尿病患者的冠状动脉钙化(CACTI)研究跟踪调查了1416名成年人(652名T1D患者，764名非糖尿病对照组)，年龄在19-56岁之间，并在3年和6年后复查。这个队列的独特特征包括：T1D和非糖尿病(非DM)受试者的群体代表性，体型大，以及可获得前瞻性定义的心肾表型。我们建议对这一队列进行为期12年的后续检查。冠状动脉钙化(CAC)是研究的主要结果，在普通人群中是冠心病风险的一个很好的标志。这项拟议的研究将极大地扩展我们关于CAC与T1D宏微血管并发症之间的关系的知识，并将有助于开发不涉及辐射的替代生物标记物，并且可以在护理点应用以识别高危T1D患者。具体目标1：评估这些特征良好的T1D患者和非DM对照组人群中12年来亚临床冠状动脉粥样硬化的发展和进展，以：i)确定是否有证据表明这些组的亚临床动脉粥样硬化的进展继续存在差异；ii)评估新的危险因素；以及iii)探索其他非侵入性测量CAD的方法。继续每年确定所有研究对象的冠心病事件(包括血管重建)和死亡率。具体目标2：在所有受试者中，继续对肾功能进行前瞻性评估，并：i)确定肾脏并发症是否可独立预测CAC的进展，以及T1D无肾脏并发症的患者是否增加了CAC II的风险；ii)评估额外的新型微血管并发症，以估计全球微血管并发症的负担及其与CAC的相关性；iii)评估新的危险标志物(胰岛素抵抗、年龄、血糖控制和变异性)作为所有并发症的共同因素。具体目标3：在有并发症和无并发症的研究队列中确定的T1D和非DM受试者的子组中，检测微血管和大血管并发症的内皮特异性机制。

DESCRIPTION (provided by applicant): One of the key challenges in type 1 diabetes (T1D) complications today is the vastly increased risk of coronary artery disease (CAD), compared to the general population. While more intensive glycemic, blood pressure and lipid control has decreased the rates of nephropathy and retinopathy, the gap in CAD risk between T1D and non-diabetic persons has persisted, unexplained by conventional risk factors. This proposed study will examine the role of novel factors in vascular complications of T1D that are not directly addressed by current preventive guidelines: insulin resistance, AGEs, oxidative stress, and endothelial dysfunction. Anticipated results will inform the design of trials to prevent premature CAD and further delay microvascular complications in patients with T1D. The Coronary Artery Calcification in Type 1 Diabetes (CACTI) study has followed 1416 adults (652 with T1D, 764 non-diabetic controls) aged 19-56 years at the baseline examination in 2000-2002, and re-examined after 3 and 6 years. The unique features of this cohort include: population-representativeness of the T1D and non- diabetic (Non-DM) subjects, large size, and availability of prospectively defined cardio-renal phenotypes. We are proposing a 12-year follow-up examination of this cohort. Coronary artery calcification (CAC), the main study outcome, is an excellent marker of CAD risk in the general population. This proposed study will significantly expand our knowledge concerning CAC associations with macro- and micro-vascular complications of T1D, and will help to develop alternative biomarkers that do not involve radiation and can be administered at point of care to identify those T1D patients at high risk. Specific Aim 1: Evaluate development and progression of subclinical coronary atherosclerosis over 12 years in these well characterized cohorts of T1D patients and Non-DM controls to: i) Determine if there is evidence for continued divergence of progression of subclinical atherosclerosis in these groups; ii) Evaluate novel risk factors; and iii) Explore additional non-invasive measurements of CAD. iv) Continue annual ascertainment of CAD events (including revascularization) and mortality in all study subjects. Specific Aim 2: In all subjects, continue prospective assessment of renal function, and: i) Determine whether renal complications independently predict CAC progression, and whether T1D patients without renal complications have increased risk of CAC ii) Assess additional, novel microvascular complications to estimate the global burden of microvascular complications and their association with CAC; iii) Evaluate novel risk markers (insulin resistance, AGEs, glycemic control and variability) as factors common to all complications. Specific Aim 3: Examine endothelium-specific mechanisms of micro and macrovascular complications in a subgroup of T1D and Non-DM subjects identified from the study cohorts with complications vs. without.