Characterization of cardiovascular diseases (CVD) in people with long duration Type 1 diabetes

摘要 心血管疾病（CVD）是1型糖尿病（T1 D）死亡的主要原因。一些CVD危险因素 2型糖尿病（T2 D）的发病率是多少？然而，血脂异常的差异， 胰岛素抵抗的严重程度、疾病发作、对血糖控制的反应和自身免疫的存在 提示CVD的发病机制在T1 D和T2 D之间可能不同。糖尿病肾病（DN）是一种严重的 T1 D中CVD的危险因素;但尽管它发生在40%的T1 D患者中，CVD仍然是T1 D的主要原因。 无DN的患者死亡率。自身免疫也可能导致CVD，因为动脉粥样硬化的风险是 在几种自身免疫性疾病中升高。理解TID中CVD的发病机制也受到以下因素的阻碍： 缺乏T1 D与T2 D老年人冠状动脉血管的比较病理学研究， 非糖尿病患者。来自Medalist研究的初步研究，一个大型队列（n=1019）， 胰岛素依赖性T1 D显示，虽然只有13%的人患有DN，但40%的人表现出显著的CVD病史， 与CT冠状动脉钙化（CAC）评分和心脏MRI心肌功能不全相关 （CMR）。虽然>90%的奖牌获得者具有典型自身免疫性T1 D的高风险HLA等位基因，但8%的人也具有高风险HLA等位基因。 单基因糖尿病的已知基因Medalist生物库包括血浆/血清样本和尸检样本。 器官标本（带冠状血管的心脏、心脏、肾脏、胰腺等）。试点研究， Medalists提供了T1 D的炎症和代谢组学特征的第一个广泛特征， 它们与CAC评分和CMR参数的相关性，这可能表明与已发表数据的差异 关于T2 D对奖牌获得者冠状血管的初步形态学研究清楚地发现了免疫细胞浸润， 包括CD 3 + T细胞。自身免疫在动脉粥样硬化恶化中的作用已被清楚地证实， 使用新创建的ApoE-/-/NOD小鼠进行的研究， 显示出显著更多的动脉粥样硬化斑块，其中含有升高的促炎性T细胞亚群 和比非糖尿病ApoE-/-/CongNOD对照小鼠更少的调节性T细胞。在本建议中，我们的目标是 通过临床、生化、成像、代谢组学和病理学研究表征T1 D中的CVD， 通过对T2 D、单基因糖尿病的Medalist队列的比较研究， 和非糖尿病受试者。我们的具体目标如下：Sp.目标1：表征动脉粥样硬化和 根据CVD病史对长期1型糖尿病患者心肌结构和功能的研究（Joslin Medalist研究） 和成像，自身免疫的存在，β细胞功能，炎症和代谢组学标志物，代谢 控制和微血管疾病。目的2：比较两组患者的菌斑特征和组成， 免疫细胞，包括单核细胞、巨噬细胞、B细胞和T细胞（CD 3+、CD 4+和CD 8 + T细胞），以及 冠状动脉粥样硬化斑块中的T细胞亚型（Treg、Tfh、Th 1和Th 17）， T1 D、T2 D、单基因糖尿病和非DM患者的外周动脉。

Abstract Cardiovascular disease (CVD) is the major cause of mortality in Type 1 diabetes (T1D). Some CVD risk factors are shared between people with T1D and Type 2 diabetes (T2D). However, differences in dyslipidemia, severity of insulin resistance, disease onset, responses to glycemic control, and presence of autoimmunity suggest that the pathogenesis of CVD may differ between T1D and T2D. Diabetic nephropathy (DN) is a major risk factor for CVD in T1D; but while it occurs in 40% of those with T1D, CVD is still the major cause of mortality in those without DN. Autoimmunity may also contribute to CVD, since the risks of atherosclerosis are elevated in several autoimmune diseases. Understanding the pathogenesis of CVD in TID is hampered also by the lack of comparative pathological studies of coronary vessels of aging people with T1D versus T2D and non-diabetic subjects. Preliminary studies from the Medalist Study, a large cohort (n=1019) with >50 years of insulin-dependent T1D, showed that while only 13% have DN, 40% exhibited significant CVD history, which correlated with coronary artery calcium (CAC) scores by CT and myocardial dysfunction by cardiac MRI (CMR). While >90% of Medalists possess high-risk HLA alleles for classic autoimmune T1D, 8% also have known genes for monogenic diabetes. The Medalist biobank includes plasma/serum samples and postmortem organ specimens (hearts with coronary vessels, aortae, kidney, pancreases and others). Pilot studies in Medalists provide the first extensive characterizations of inflammatory and metabolomics profiles of T1D and their associations with CAC scores and CMR parameters, which may indicate differences with published data on T2D. Pilot morphological studies of Medalists’ coronary vessels clearly identified immune cell infiltrates, including CD3+ T-cells. The role of autoimmunity in exacerbating atherosclerosis is clearly demonstrated by studies using newly-created ApoE-/-/NOD mice with autoimmune diabetes closely mimicking T1D, which exhibited significantly more atherosclerotic plaques containing elevated subsets of pro-inflammatory T-cells and less regulatory T-cells than in non-diabetic ApoE-/-/CongNOD control mice. In this proposal, we aim to characterize CVD in T1D by clinical, biochemical, imaging, metabolomic and pathological studies, and their associations with autoimmunity, via comparative studies of the Medalist cohort with T2D, monogenic diabetes and non-diabetic subjects. Our specific aims are as follows: Sp. Aim 1: To characterize atherosclerosis and myocardial structure and function in type 1 diabetes of long duration (Joslin Medalist Study) by CVD history and imaging, presence of autoimmunity, beta cell function, inflammatory and metabolomics markers, metabolic control and microvascular diseases. Sp. Aim 2: To compare the plaque characteristics and composition of immune cells, including monocytes, macrophages, B-cells and T-cells (CD3+, CD4+ and CD8+ T cells) and subtypes of T-cells (Treg, Tfh, Th1 and Th17) in the atherosclerotic plaques of the coronary vessels and peripheral arteries from patients with T1D, T2D, monogenic diabetes and no DM.