State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
Proc Natl Acad Sci U S A. 2014 Feb 4;111(5):1873-8. doi: 10.1073/pnas.1321195111. Epub 2014 Jan 21.
The global prevalence of prediabetes and type 2 diabetes (T2D) is increasing, and it is contributing to the susceptibility to diabetes and its related epidemic in offspring. Although the impacts of paternal impaired fasting blood glucose and glucose intolerance on the metabolism of offspring have been well established, the exact molecular and mechanistic basis that mediates these impacts remains largely unclear. Here we show that paternal prediabetes increases the susceptibility to diabetes in offspring through gametic epigenetic alterations. In our findings, paternal prediabetes led to glucose intolerance and insulin resistance in offspring. Relative to controls, offspring of prediabetic fathers exhibited altered gene expression patterns in the pancreatic islets, with down-regulation of several genes involved in glucose metabolism and insulin signaling pathways. Epigenomic profiling of offspring pancreatic islets revealed numerous changes in cytosine methylation depending on paternal prediabetes, including reproducible changes in methylation over several insulin signaling genes. Paternal prediabetes altered overall methylome patterns in sperm, with a large portion of differentially methylated genes overlapping with that of pancreatic islets in offspring. Our study uniquely revealed that prediabetes can be inherited transgenerationally through the mammalian germ line by an epigenetic mechanism.
全球范围内，糖尿病前期和 2 型糖尿病（T2D）的患病率正在上升，这导致了糖尿病及其相关流行在后代中的易感性。尽管已经证实了父系空腹血糖受损和葡萄糖耐量异常对后代代谢的影响，但介导这些影响的确切分子和机制基础在很大程度上仍不清楚。在这里，我们显示父系糖尿病前期通过配子表观遗传改变增加了后代患糖尿病的易感性。在我们的研究结果中，父系糖尿病前期导致后代出现葡萄糖不耐受和胰岛素抵抗。与对照组相比，糖尿病前期父亲的后代胰岛中出现了基因表达模式的改变，涉及葡萄糖代谢和胰岛素信号通路的几个基因下调。对后代胰岛的表观基因组分析显示，根据父系糖尿病前期，胞嘧啶甲基化发生了许多变化，包括胰岛素信号基因的多个甲基化可重复性变化。父系糖尿病前期改变了精子的整体甲基组模式，其中很大一部分差异甲基化基因与后代胰岛中的基因重叠。我们的研究独特地揭示了糖尿病前期可以通过表观遗传机制在哺乳动物种系中跨代遗传。
