Circulating hydrogen sulfide, diabetes and diabetes-related cardiovascular disease

循环硫化氢、糖尿病和糖尿病相关的心血管疾病

基本信息

批准号：
10700816
负责人：
Rozenn Lemaitre
金额：
$ 65.53万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-15 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10700816
关键词：
Affect Age Anabolism Apoptosis Atherosclerosis Beta Cell Bioinformatics Blood Cardiac Cardiac Myocytes Cardiovascular Diseases Cardiovascular system Cell Line Cell physiology Cells Clinical Clinical Trials Cohort Studies Cross-Sectional Studies Cytoprotection Data Development Diabetes Mellitus Diabetes prevention Disease Epidemic Event Experimental Animal Model Family Study Fasting Functional disorder Future Glucose Heart Heart Hypertrophy Heart Injuries Heart failure HepG2 Hepatic Human Hydrogen Sulfide Incidence Inhibition of Apoptosis Insulin Insulin Resistance Ischemic Stroke Islets of Langerhans Japanese Link Liver Longitudinal Studies Mass Spectrum Analysis Measures Mediating Metabolic Metabolic Marker Methylation Modeling Molecular Morbidity - disease rate Mus Muscle Fibers Myocardial Infarction Non-Insulin-Dependent Diabetes Mellitus Observational Study Organ Oxidative Stress Palmitic Acids Pancreas Participant Pathway interactions Patients Persons Plasma Play Proliferating Prospective Studies Prospective cohort Public Health Reactive Oxygen Species Risk Risk Factors Rodent Model Role Sampling Signal Transduction Small Interfering RNA Testing Toxic effect Vasodilator Agents Ventricular cardiovascular health cohort diabetes risk endothelial dysfunction enzyme biosynthesis experimental study glucose uptake heart function improved innovation insight insulin secretion macrovascular disease mortality myocardial injury novel population based preclinical study prevent prospective protective pathway response secondary analysis transcriptomics

项目摘要

Project Summary/Abstract Type 2 diabetes affects over 30 million people in the US and carries a high burden of cardiovascular morbidity and mortality. Identifying new, modifiable mechanisms that may influence the development and macrovascular complications of this multifactorial disease will make a substantial public health impact. This application will investigate the associations of hydrogen sulfide (H2S) with risks of incident diabetes and diabetes-associated cardiovascular disease (CVD). H2S is a gasotransmitter that is crucial for cell signaling and cell function. In addition, H2S appears to play an important role in the development of diabetes and mitigating the related toxicities. In the pancreas, H2S regulates insulin secretion and protects beta cells from apoptosis. In the liver, the main organ for the synthesis and storage of glucose, H2S reduces insulin resistance and improves glucose uptake. In preclinical studies, compounds that release H2S, and therefore increase systemic concentrations, protect from endothelial dysfunction, cardiac hypertrophy, myocardial injury and atherosclerosis in rodent models of diabetes. Studies in humans are limited to cross-sectional studies showing a reduction in plasma H2S in patients with type 2 diabetes. Prospective studies are needed to bridge the gap between pre-clinical studies and future clinical trials. Therefore we propose to conduct efficient case-cohort and longitudinal studies of H2S, diabetes and CVD. We hypothesize that higher levels of H2S in plasma are associated with lower risks of incident diabetes and diabetes-associated CVD; and we hypothesize that cellular H2S levels protects human hepatic and cardiomyocyte from insulin resistance and the resulting cellular dysfunction. To test these hypotheses, we will measure circulating H2S levels in existing samples from two prospective cohorts and examine H2S associations with type 2 diabetes and diabetes-associated CVD (Aim 1). Importantly, in Aim 2, we supplement these observational studies with functional experimental studies in human derived cell lines to investigate the molecular mechanism of H2S hepatic and cardiac protection in insulin resistance, and to discover novel H2S-regulated pathways that may lead to future targets for the prevention of diabetes and CVD.

项目概要/摘要 2 型糖尿病影响美国超过 3000 万人，并带来沉重的心血管疾病负担和死亡率。识别可能影响发育和大血管的新的、可修改的机制这种多因素疾病的并发症将对公众健康产生重大影响。该应用程序将研究硫化氢 (H2S) 与糖尿病发生风险和糖尿病相关疾病的关系心血管疾病（CVD）。 H2S 是一种气体递质，对细胞信号传导和细胞功能至关重要。在此外，H2S 似乎在糖尿病的发展和减轻相关的糖尿病中发挥着重要作用。毒性。在胰腺中，H2S 调节胰岛素分泌并保护 β 细胞免于凋亡。在肝脏中， H2S是合成和储存葡萄糖的主要器官，可降低胰岛素抵抗，改善血糖吸收。在临床前研究中，释放 H2S 并因此增加全身浓度的化合物，保护啮齿动物免受内皮功能障碍、心脏肥大、心肌损伤和动脉粥样硬化糖尿病模型。人类研究仅限于显示血浆减少的横断面研究 2 型糖尿病患者体内的 H2S。需要进行前瞻性研究来弥合临床前研究之间的差距研究和未来的临床试验。因此，我们建议进行有效的病例队列和纵向研究 H2S、糖尿病和 CVD。我们假设血浆中较高水平的 H2S 与较低的风险相关糖尿病和糖尿病相关心血管疾病的发生率；我们假设细胞 H2S 水平可以保护人类肝脏和心肌细胞免受胰岛素抵抗以及由此产生的细胞功能障碍。为了测试这些假设，我们将测量两个前瞻性队列的现有样本中的循环 H2S 水平，检查 H2S 与 2 型糖尿病和糖尿病相关 CVD 的关联（目标 1）。重要的是，在目标 2 中，我们通过人源细胞系的功能实验研究来补充这些观察性研究研究H2S在胰岛素抵抗中保护肝脏和心脏的分子机制，并发现新的 H2S 调节途径，可能导致未来预防糖尿病的目标化学气相沉积。