Circulating hydrogen sulfide, diabetes and diabetes-related cardiovascular disease

项目摘要/摘要 在美国，2型糖尿病影响着3000多万人，并带来了很高的心血管发病率负担 和死亡率。确定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共卫生产生重大影响。此应用程序将 研究硫化氢(H_2S)与糖尿病发病风险及糖尿病相关风险的关系 心血管疾病(CVD)。硫化氢是一种气体递质，对细胞信号和细胞功能至关重要。在……里面 此外，硫化氢似乎在糖尿病的发生和缓解相关疾病方面发挥了重要作用 毒物。在胰腺中，硫化氢调节胰岛素的分泌，保护胰岛细胞免于凋亡。在肝脏中， 作为葡萄糖合成和储存的主要器官，硫化氢可降低胰岛素抵抗并改善血糖 领悟。在临床前研究中，释放硫化氢的化合物会增加全身的浓度， 对啮齿动物内皮功能障碍、心肌肥大、心肌损伤和动脉粥样硬化的保护作用 糖尿病模型。对人类的研究仅限于显示血浆减少的横断面研究 2型糖尿病患者的硫化氢水平。需要前瞻性研究来弥合临床前和临床前之间的差距 研究和未来的临床试验。因此，我们建议进行有效的病例队列和纵向研究。 硫化氢、糖尿病和心血管疾病。我们假设血浆中较高的硫化氢水平与较低的风险相关 糖尿病和糖尿病相关心血管疾病的发生；我们假设细胞内的硫化氢水平保护人类 肝脏和心肌细胞因胰岛素抵抗而导致的细胞功能障碍。为了测试这些 假设，我们将测量现有样本中循环的硫化氢水平，来自两个预期的队列和 检查硫化氢与2型糖尿病和糖尿病相关心血管疾病的关系(目标1)。重要的是，在目标2中， 我们用人类衍生细胞系的功能实验研究来补充这些观察性研究 探讨硫化氢在胰岛素抵抗中保护肝脏和心脏的分子机制 发现新的硫化氢调控途径，可能导致未来预防糖尿病和 心血管疾病。

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.