胰岛beta细胞功能障碍是2型糖尿病发生发展过程中至关重要的环节。申请人课题组通过基因测序和功能验证，创新性发现转录因子YY1在调控胰岛beta细胞功能方面可能发挥着重要作用，目前YY1对胰岛beta细胞功能的影响及潜在机制尚无报道。我们的研究初步发现了令人振奋的结果：胰岛beta细胞特异性敲除YY1小鼠出现糖耐量受损、葡萄糖刺激胰岛素分泌能力下降、胰岛中胰岛素含量减少，提示YY1可能参与调控胰岛beta细胞功能及糖代谢。本项目将在前期研究基础上，利用已构建的基因修饰小鼠模型并结合现代分子生物学和细胞生物学研究方法，首次阐明YY1在胰岛beta细胞中的功能，创新性证实YY1通过线粒体能量代谢途径影响beta细胞功能的机制，并在已建立队列中明确YY1相关基因对胰岛beta细胞功能及糖尿病预后的影响，证实YY1作为精准干预靶点的潜力，阐释调控胰岛beta细胞功能的新机制和糖尿病干预新靶点。

Beta cell dysfunction is a key pathological state in the pathogenesis of type 2 diabetes. Through gene sequencing and functional verification, our research group has found that transcription factor YY1 may play an important role in the regulation of pancreatic beta cell function. Until now, the effects of YY1 on pancreatic beta cell function and its underlying mechanism have remained largely unknown. Our preliminary study have found exciting results: islet beta cell-specific knockout YY1 mice exhibited impaired glucose tolerance, decreased insulin secretion, and reduced insulin content in islets, suggesting that YY1 may be involved in the regulation of pancreatic beta cell function and blood glucose metabolism. This grant proposal builds on our previous findings and will use tissue-specific knockout mice, together with modern techniques of molecular and cellular biology to elucidate the mechanisms of YY1 in the regulation of beta cell function, and its regulation of nuclear-encoded mitochondrial genes contributing to the maintenance of beta cell function. Furthermore, we will take advantage of our established cohorts to investigate the relation between YY1-related genes and type 2 diabetes and confirm the potential of YY1 as a target for precision prevention. This proposed study has great potential to shed light on the new mechanisms for the regulation of beta cell function and to identify novel targets for the prevention of type 2 diabetes.