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(T1D)死亡的主要原因。一些心血管疾病的危险因素 在患有T1D和2型糖尿病(T2D)的人之间共享。然而，血脂异常的差异， 胰岛素抵抗的严重程度、疾病的发病、对血糖控制的反应以及自身免疫的存在 提示T1D和T2D的CVD发病机制可能不同。糖尿病肾病(DN)是一种 T1D时发生心血管疾病的危险因素；但虽然40%的T1D患者会发生CVD，但CVD仍然是 无糖尿病肾病患者的死亡率。自身免疫也可能导致心血管疾病，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。TID中CVD的发病机制也受到以下因素的阻碍 老年人T1D、T2D和T2D型冠脉病变的对比病理研究 非糖尿病受试者。来自奖牌获得者研究的初步研究，一个具有50年历史的大队列(n=1019) 胰岛素依赖型T1D显示，虽然只有13%的人有糖尿病肾病，但40%的人有明显的心血管病史， CT冠状动脉钙化(CAC)积分与心脏MRI心肌功能不全的相关性 (CMR)。90%的奖牌获得者具有典型自身免疫性T1D的高危HLA等位基因，8%的获奖者也有 已知的单基因糖尿病基因。奖牌获得者生物库包括血浆/血清样本和尸检 器官标本(有冠状动脉、主动脉、肾脏、胰腺等的心脏)。中国的试点研究 获奖者首次对T1D和T1D的炎症和代谢组学特征进行了广泛的描述 它们与CAC分数和CMR参数的关联，这可能表明与已发布数据的差异 在T2D上。对奖牌获得者冠状动脉的初步形态研究清楚地发现了免疫细胞的渗透， 包括CD3+T细胞。自身免疫在加剧动脉粥样硬化中的作用清楚地表明 研究使用新创建的患有自身免疫性糖尿病的ApoE-/-/NOD小鼠来模拟T1D，这是 显示明显更多的动脉粥样硬化斑块，其中含有升高的促炎T细胞亚群 与非糖尿病ApoE-/-/CongNOD对照组小鼠相比，调节性T细胞减少。在这项建议中，我们的目标是 通过临床、生化、影像、代谢组学和病理学研究来确定T1D的CVD特征及其临床意义 通过对奖牌获得者与T2D、单基因糖尿病队列的比较研究，与自身免疫的相关性 和非糖尿病受试者。我们的具体目标是：SP。目的1：研究动脉粥样硬化的特征和 心血管病史对长期1型糖尿病患者心肌结构和功能的影响 和成像，自身免疫的存在，β细胞功能，炎症和代谢组学标记物，代谢 控制和微血管疾病。SP.目的2：比较斑块的特征和组成。 免疫细胞，包括单核细胞、巨噬细胞、B细胞和T细胞(CD3+、CD4+和CD8+T细胞)和 冠状动脉和冠状动脉粥样硬化斑块中T细胞亚型(Treg、Tfh、Th1和Th17) T1D、T2D、单基因糖尿病和非糖尿病患者的外周动脉。

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.