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：
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
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/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

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

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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）死亡率的主要原因。一些CVD风险因素在患有T1D和2型糖尿病（T2D）的人之间共享。但是，血脂异常的差异，胰岛素抵抗的严重性，疾病发作，对血糖控制的反应以及自身免疫性的存在表明CVD的发病机理在T1D和T2D之间可能有所不同。糖尿病性肾病（DN）是主要的 T1D中CVD的危险因素；但是，尽管它发生在40％的T1D的人中，但CVD仍然是没有DN的人的死亡率。自身免疫力也可能导致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。了解TID中CVD的发病机理也受到了阻碍缺乏对T1D与T2D和T2D和T2D衰老的冠状动脉血管的比较病理研究非糖尿病主体。奖牌研究的初步研究，一项大型队列（n = 1019），> 50年胰岛素依赖性T1D表明，虽然只有13％的DN，但40％暴露了重要的CVD史，这通过CT和心肌功能障碍与心脏MRI相关，与心肌功能障碍相关（CMR）。 > 90％的奖牌获得者拥有经典自身免疫性T1D的高风险HLA等位基因，而8％也有已知的单基因糖尿病基因。奖章的生物库包括等离子体/血清样品和验尸器官标本（带有冠状动脉，主动脉，肾脏，胰腺等的心脏）。试点研究奖章者提供了T1D和它们与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。奖章冠状动脉血管的试验形态学研究清楚地鉴定出免疫细胞浸润，包括CD3+ T细胞。自身免疫在加剧动脉粥样硬化中的作用清楚地证明了使用新创建的APOE-/ - /NOD小鼠与自身免疫性糖尿病的研究非常模仿T1D 表现出更多的动脉粥样硬化斑块，其中包含促炎性T细胞的升高与非糖尿病的APOE - / - /Congnod Control小鼠相比，调节T细胞少。在此提案中，我们的目标是通过临床，生化，成像，代谢组学和病理研究来表征T1D中CVD的表征通过与T2D，单基因糖尿病的奖章同类队列的比较研究，与自身免疫性的关联和非糖尿病学科。我们的具体目的如下：sp。目标1：表征动脉粥样硬化和 CVD历史记录的长时间1型糖尿病（乔斯林奖章研究）中的心肌结构和功能以及成像，自身免疫性的存在，β细胞功能，炎症和代谢标记，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）和 T细胞（Treg，TFH，Th1和Th17）的亚型在冠状血管的动脉粥样硬化斑块中 T1D，T2D，单基因糖尿病和无DM的患者的外周动脉。