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

长期 1 型糖尿病患者心血管疾病 (CVD) 的特征

• 批准号: 10543994
• 负责人: GEORGE L KING
• 金额: $ 77.58万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-24 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10543994
• 关键词: Acceleration; Affect; Aging; Alleles; Animal Model; Antihypertensive Agents; Apolipoprotein E; Apoptotic; Area; Arterial Fatty Streak; Arteries; Atherosclerosis; Autoantibodies; Autoimmune; Autoimmune Diabetes; Autoimmune Diseases; Autoimmunity; Autopsy; B-Lymphocytes; Beta Cell; Biochemical; C-Peptide; CD3 Antigens; CD8-Positive T-Lymphocytes; CRISPR/Cas technology; Calcium; Cardiac Myosins; Cardiovascular Diseases; Caring; Cell physiology; Cells; Characteristics; Clinical; Comparative Study; Coronary Vessels; Coronary artery; Data; Development; Diabetes Mellitus; Diabetic Nephropathy; Disease Progression; Dyslipidemias; Electrocardiogram; Exhibits; Future; Gender; Genes; Heart; Heart failure; High Density Lipoproteins; High Fat Diet; Human; Hyperglycemia; Hyperlipidemia; Hypertension; Image; Immune; Inbred NOD Mice; Inflammation; Inflammatory; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Islet Cell; Kidney; Kidney Diseases; Knowledge; Laboratories; Lipids; Macrophage; Medical; Metabolic Control; Metabolic Pathway; Microvascular Dysfunction; Mononuclear; Morphology; Mus; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardial dysfunction; Necrosis; Non-Insulin-Dependent Diabetes Mellitus; Onset of illness; Organ; Pathogenesis; Pathologic; Pathology; Patient Self-Report; Patients; Peripheral; Persons; Pilot Projects; Plasma; Population; Prediabetes syndrome; Property; Publishing; Recording of previous events; Regulatory T-Lymphocyte; Reporting; Retinal Diseases; Risk Factors; Role; Sampling; Senile Plaques; Serum; Severities; Specimen; Stains; Structure; T-Lymphocyte; T-Lymphocyte Subsets; Tibial Arteries; atherosclerosis risk; biobank; calcification; cardiac magnetic resonance imaging; cardiovascular disorder risk; cardiovascular risk factor; clinical risk; cohort; comparative; contrast enhanced; coronary calcium scoring; cytokine; design; disease phenotype; experience; genome editing; glycemic control; heart imaging; high risk; illness length; immune cell infiltrate; improved; inflammatory marker; insulitis; male; metabolomics; monocyte; mortality; myocardial damage; non-diabetic; novel; research clinical testing; response; risk variant; type I and type II diabetes

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.

抽象的 心血管疾病 (CVD) 是 1 型糖尿病 (T1D) 死亡的主要原因。一些 CVD 危险因素 T1D 和 2 型糖尿病 (T2D) 患者共有此症状。但血脂异常的差异， 胰岛素抵抗的严重程度、疾病发作、对血糖控制的反应以及自身免疫的存在 表明 CVD 的发病机制在 T1D 和 T2D 之间可能有所不同。糖尿病肾病（DN）是一种主要的 T1D 中 CVD 的危险因素；虽然 40% 的 T1D 患者会出现这种情况，但 CVD 仍然是导致 1D 病的主要原因 无 DN 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 在多种自身免疫性疾病中升高。了解 TID 中 CVD 的发病机制还受到以下因素的阻碍： 缺乏对患有 T1D 和 T2D 的老年人冠状血管的比较病理学研究 非糖尿病受试者。 Medalist 研究的初步研究是一个大型队列 (n=1019)，研究年限超过 50 年 胰岛素依赖性 T1D 表明，虽然只有 13% 患有 DN，但 40% 的人表现出明显的 CVD 病史，这 与 CT 得出的冠状动脉钙 (CAC) 评分和心脏 MRI 得出的心肌功能障碍相关 （CMR）。虽然 >90% 的获奖者拥有经典自身免疫性 T1D 的高风险 HLA 等位基因，但 8% 的获奖者还拥有 已知的单基因糖尿病基因。 Medalist 生物库包括血浆/血清样本和尸检样本 器官标本（心脏、冠状血管、主动脉、肾脏、胰腺等）。试点研究 奖牌获得者首次提供了 T1D 和 T1D 炎症和代谢组学特征的广泛表征 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。对奖牌获得者冠状血管的初步形态学研究清楚地发现了免疫细胞浸润， 包括 CD3+ T 细胞。自身免疫在加剧动脉粥样硬化中的作用被清楚地证明 使用新创建的 ApoE-/-/NOD 小鼠进行的研究，该小鼠患有与 T1D 非常相似的自身免疫性糖尿病， 表现出明显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 与非糖尿病 ApoE-/-/CongNOD 对照小鼠相比，调节性 T 细胞较少。在本提案中，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描述 T1D CVD 的特征及其 通过对 Medalist 队列与 T2D、单基因糖尿病的比较研究，发现与自身免疫的关联 和非糖尿病受试者。我们的具体目标如下：目标 1：表征动脉粥样硬化和 长期 1 型糖尿病患者的心肌结构和功能（Joslin Medalist 研究）（根据 CVD 病史） 和成像、自身免疫的存在、β细胞功能、炎症和代谢组学标记、代谢 控制和微血管疾病。 Sp。目标 2：比较斑块特征和组成 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）以及 冠状动脉粥样硬化斑块中的 T 细胞亚型（Treg、Tfh、Th1 和 Th17） 来自 T1D、T2D、单基因糖尿病和非 DM 患者的外周动脉。