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

基本信息

批准号：
10372462
负责人：
GEORGE L KING
金额：
$ 85.09万
依托单位：
JOSLIN DIABETES CENTER
依托单位国家：
美国
项目类别：
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/10372462
关键词：
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 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 Insulin Resistance Insulin-Dependent Diabetes Mellitus Islet Cell Kidney Kidney Diseases Knowledge Laboratories Lip structure Lipids Medical Metabolic Control Metabolic Pathway Microvascular Dysfunction Mononuclear Morphology Mus Myocardial Myocardial Infarction Myocardial Ischemia Myocardial dysfunction Necrosis Non obese Non-Insulin-Dependent Diabetes Mellitus Onset of illness Organ Pancreas 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 Severities Specimen Stains Structure T-Lymphocyte T-Lymphocyte Subsets Tibial Arteries Tumor-infiltrating immune cells atherosclerosis risk biobank calcification cardiac magnetic resonance imaging cardiovascular disorder risk cardiovascular risk factor clinical risk cohort comparative contrast enhanced coronary artery calcium coronary calcium scoring cytokine design diabetic disease phenotype experience genome editing glycemic control heart imaging high risk illness length inflammatory marker insulitis macrophage male metabolomics monocyte mortality myocardial damage non-diabetic novel research clinical testing response risk variant type I and type II diabetes

项目摘要

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。 1 型糖尿病 (T1D) 和 2 型糖尿病 (T2D) 患者都有相同的症状，但血脂异常存在差异。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提示 CVD 的发病机制在 T1D 和 T2D 之间可能有所不同，糖尿病肾病 (DN) 是主要的疾病。 T1D 中 CVD 的危险因素；尽管 40% 的 T1D 患者发生 CVD，但 CVD 仍然是其主要原因没有 DN 的患者的死亡率也可能导致 CVD，因为动脉粥样硬化的风险是在几种自身免疫性疾病中，该值升高。了解 TID 中 CVD 的发病机制也受到阻碍。缺乏对患有 T1D 和 T2D 的老年人冠状血管的比较病理学研究来自奖章获得者研究的非糖尿病受试者的初步研究，这是一个超过 50 年的大型队列（n = 1019）。胰岛素依赖性 T1D 表明，虽然只有 13% 患有 DN，但 40% 的人明显表现出 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% 的获奖者也有 Medalist 生物库包括血浆/血清样本和死后样本。器官标本（心脏、冠状血管、主动脉、肾脏、胰腺等）。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对 T2D 获奖者冠状动脉的初步形态学研究清楚地发现了免疫细胞浸润，包括 CD3+ T 细胞在内的自身免疫在加剧动脉粥样硬化中的作用已被清楚地证明。使用新创建的 ApoE-/-/NOD 小鼠进行研究，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 细胞更少。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我们的具体目标如下：目标 1：描述动脉粥样硬化和非糖尿病受试者的特征。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。