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

• 批准号: 10420827
• 负责人: Rozenn Lemaitre
• 金额: $ 67.31万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 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/10420827
• 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; 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; Insulin; Insulin Resistance; Ischemic Stroke; Islets of Langerhans; Japanese; Lead; Link; Liver; Longitudinal Studies; Mass Spectrum Analysis; Measures; Mediating; Metabolic; Metabolic Marker; 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; Prospective Studies; Prospective cohort; Public Health; Reactive Oxygen Species; Risk; Risk Factors; Rodent Model; Role; Sampling; Signal Transduction; Small Interfering RNA; Suggestion; 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; response; secondary analysis; transcriptomics

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.

项目摘要/摘要 2型糖尿病在美国影响超过3000万人，并承担着高负担心血管发病率的负担 和死亡率。确定可能影响发展和大血管的新的，可修改的机制 这种多因素疾病的并发症将对公共卫生产生重大影响。此应用程序将 研究硫化氢（H2S）与出现糖尿病和糖尿病相关的风险的关联 心血管疾病（CVD）。 H2S是一种对细胞信号传导和细胞功能至关重要的增发剂。在 此外，H2S似乎在糖尿病的发展中起着重要作用并减轻相关的作用 毒性。在胰腺中，H2S调节胰岛素分泌并保护β细胞免受凋亡。在肝脏中， 葡萄糖合成和储存的主要器官，H2S降低了胰岛素耐药性并改善了葡萄糖 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， 防止啮齿动物的内皮功能障碍，心脏肥大，心肌损伤和动脉粥样硬化 糖尿病的模型。人类的研究仅限于横断面研究表明血浆的减少 2型糖尿病患者的H2S。需要前瞻性研究来弥合临床前之间的差距 研究和未来的临床试验。因此，我们建议进行有效的病例 - 霍特和纵向研究 H2S，糖尿病和CVD的。我们假设血浆中较高的H2s与较低的风险有关 入射糖尿病和与糖尿病相关的CVD的；我们假设细胞H2S水平保护人类 胰岛素耐药性以及由此产生的细胞功能障碍产生的肝和心肌细胞。测试这些 假设，我们将测量来自两个前瞻性队列的现有样本中的循环H2S水平， 检查与2型糖尿病和糖尿病相关CVD的H2S关联（AIM 1）。重要的是，在AIM 2中， 我们通过人类衍生细胞系中的功能实验研究来补充这些观察性研究 研究胰岛素抵抗中H2S肝和心脏保护的分子机制，以及 发现新型H2S调节的途径，可能导致预防糖尿病和预防的未来目标 CVD。