我国2型糖尿病(T2DM)的患病率逐年攀升。近年来的研究表明，除了传统的危险因素如遗传易感性、生活方式改变外，跨代遗传效应亦参与到T2DM的发病过程。申请人在前期工作中，利用C57BL/6小鼠模型，首次发现：父亲应激后(Psychological Stress)，精子发生特定的表观遗传学改变，导致子代小鼠(Stress-F1)肝脏糖异生能力的增加(Cell Metabolism，2016)。在近期工作中，我们发现：Stress-F1小鼠在老龄时，表现为葡萄糖耐量异常和胰岛素敏感性的下降。在分子水平上，我们进一步检测到：Stress-F1肝脏中MicroRNA-194表达下调，导致mTORC1信号通路增强。因此，本项目将在这些发现的基础上，继续探讨父代应激通过精子的表观遗传学改变，导致子代糖代谢紊乱的作用和机制，从而为阐明跨代遗传理论在2型糖尿病中的作用提供坚实的基础。

The prevalence of type 2 diabetes mellitus (T2DM) has been increasing year by year in China. Recent studies have shown that, in addition to the traditional risk factors including genetic susceptibility and lifestyle changes, transgenerational effects are also involved in the pathogenesis of T2DM. In our previous study, using a C57BL/6 mouse model of psychological stress, we showed that offspring of stressed fathers (Stress-F1) exhibited enhanced hepatic gluconeogenesis due to epigenetic changes in spermatozoon (Cell Metabolism, 2016). Here, we further found that aged Stress-F1 mice exhibited glucose intolerance and insulin resistance. At the molecular level, MicroRNA-194 was down-regulated in livers of Stress-F1 mice, which might promote the activation of mTORC1 signaling pathway. Therefore, this project will continue to explore the roles and mechanisms of paternal stress in the regulation of offspring's glucose metabolism, which might help to clarify the functions of transgeneration effects in the pathogenesis of T2DM.