胰岛素抵抗与不足是妊娠期糖尿病（GDM）发病的基础。胰岛素信号通路重要蛋白-SIRT1启动子中含有C/EBP家族位点，当C/EBPβ与其他蛋白形成复合物时，负向调节SIRT1。而SIRT1的表达及其活性下降可介导胰岛素抵抗及相对不足的发生。我们前期发现GDM与高脂饮食、血清脂多糖（LPS）增高相关；小鼠模型中胰岛素外周靶器官炎性因子被异常活化；肝细胞GDM模型在LPS刺激下核内NAD+减少，C/EBPβ蛋白复合物合成增加。故推测：高脂血症及高脂饮食协同导致肠道G-菌异常繁殖，LPS入血增加，进而胰岛素外周靶器官炎性因子表达上调，细胞内NAD+区域化合成异常，致C/EBPβ活性增强，C/EBPβ-HDAC1复合物增多，抑制SIRT1启动子活性，最终引起胰岛素敏感性下降，GDM发生。项目拟用分子生物学、宏基因组学及代谢组学等方法，以全新角度诠释GDM的病生过程，为研究其发病机制提供新思路。

Insulin resistance and deficiency are the etiology basis of gestational diabetes mellitus (GDM). SIRT1 is an important regulating protein in insulin signaling pathway and its promoter contains binding sites for C/EBP family. When C/EBPβ forms a complex with other proteins, it downregulates SIRT1, which in term, the reduced expression/activity of SIRT1 lead to insulin hypersensitivity. Our previous studies found that GDM was associated with high-fat diet and increased serum lipopolysaccharide (LPS); the inflammatory factors of insulin peripheral target organ were abnormally activated in a mouse model; the LPS-induced GDM hepatocyte model decreased nucleus NAD+ and stimulated the synthesis of C/EBPβ complex. Therefore, we speculated that the combination of hyperlipidemia and high-fat diet leads to abnormal intestinal gram-negative (g) bacterial growth, increases circulating LPS that stimulates the expression of inflammatory factors in peripheral insulin-targeted organs. This causes the abnormal synthesis of cytoplasmic NAD+ and subsequently elevates the formation of C/EBPΒ-HDAC1 complex via C/EBPβ activation. As a result, the inhibition of SIRT1 promoter activity eventually advances to the insulin insensitivity of GDM. Our project aims to implicate molecular biology, macrogenomics, and metabolomics to elucidate the underlying pathophysiology of GDM from a new perspective, and provide a novel strategy to study its pathogenic mechanism.