我们前期课题发现脂蛋白脂酶基因敲除杂合子（LPL+/-）小鼠通过脂毒性直接诱发了糖代谢异常。随后在机制研究中发现LPL+/-小鼠在胰腺通过脂毒性诱发了胰岛β细胞功能障碍，为了探讨其分子机制，通过基因芯片筛选和体外研究，我们首次发现Gremlin-1蛋白及其下游骨形态形成蛋白（BMPs）信号通路参与了脂毒性介导的β细胞功能障碍的发生发展；同时还发现脂毒性引起的Gremlin-1下调还通过非BMPs信号通路激活β细胞炎症反应，进而导致其功能紊乱。因此本课题将围绕Gremlin-1蛋白更加深入地阐明脂毒性如何导致胰岛β细胞功能受损以及Gremlin-1/BMPs信号通路在该过程中的调控机制，并进一步探索免疫炎症及其他如血管生成等通路如何参与Gremlin-1介导的β细胞功能障碍。本项目的开展不仅为2型糖尿病分子病因学研究提供了新的视角，同时也为将来针对糖尿病开展β细胞靶向治疗提供了新的依据。

We have shown in our previous studies that heterozygous lipoprotein lipase (LPL) knockout mice (LPL+/-) develop lipotoxicity-induced glucose intolerance and islet β cell dysfunction. However, the underlying molecular basis for the β cell dysfunction is unclear. By gene chip screening and in vitro study, we have firstly found the Gremlin-1 protein and its downstream BMPs signaling pathway may be involved. We also discovered that lipotoxicity-induced Gremlin-1 down-regulation may activate islet β cell inflammation through non-BMPs signaling pathways, leading to its dysfunction. In this study, we will further elucidate the role of Gremlin-1 protein and its downstream BMPs/Smad signaling pathway, immune inflammatory response and also angiogenesis pathway in β-cell dysfunction. This project will provide novel information on the molecular etiology of type 2 diabetes mellitus (T2DM). Such knowledge may provide a new basis for pancreatic β cell-targeted therapy of T2DM in the future.