Circulating hydrogen sulfide, diabetes and diabetes-related cardiovascular disease

项目总结/摘要 2型糖尿病影响着美国超过3000万人，并带来了心血管发病率的高负担 and mortality.识别可能影响发育和大血管的新的、可改变的机制 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）与糖尿病发病风险及糖尿病相关风险的关系。 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疾病中起重要作用。 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， 作为合成和储存葡萄糖的主要器官，H2S可降低胰岛素抵抗并改善葡萄糖 摄取。在临床前研究中，释放H2S并因此增加全身浓度的化合物， 保护内皮功能障碍、心肌肥大、心肌损伤和动脉粥样硬化 糖尿病模型人体研究仅限于显示血浆中 2型糖尿病患者中的硫化氢。需要前瞻性研究来弥合临床差距 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水平的H2S与较低的风险相关， 糖尿病和糖尿病相关CVD的发病率;我们假设细胞H2S水平保护人类 肝脏和心肌细胞的胰岛素抵抗和由此产生的细胞功能障碍。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H2S与2型糖尿病和糖尿病相关CVD的关系（目的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补充了这些观察性研究， 探讨H2S对胰岛素抵抗大鼠肝脏和心脏保护作用的分子机制， 发现新的H2S调节途径，可能导致未来预防糖尿病的目标， CVD。

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.