二甲双胍是以肝脏糖异生为主要作用靶点的一线用药，但其作用机制尚不够清晰。PTG为蛋白磷酸酶1的一种调节亚基，是本课题组应用基因芯片技术筛选到的肝糖异生相关基因。前期研究发现：db/db鼠肝脏PTG表达显著增加。在原代培养的小鼠肝脏细胞，cAMP干预显著促进糖异生，同时PTG表达明显升高；将PTG基因沉默后糖异生受抑制，而过表达PTG后糖异生增多。二甲双胍则以剂量依赖方式抑制肝细胞PTG基因的表达，但其对过表达PTG的肝细胞糖异生无明显影响。以上研究表明，PTG可能介导了二甲双胍对肝脏糖异生的作用。本研究拟进一步从细胞和整体水平阐明PTG在二甲双胍干预肝脏糖异生中的作用；并从转录调控等方面入手，探明二甲双胍通过PTG调控肝脏糖异生的分子机制。该课题具有源头创新性，通过本项目的实施，有望加深人们对PTG基因功能和作用的理解，丰富肝脏糖异生的调控机制学说，对胰岛素抵抗、2型糖尿病的防治提供帮助。

Metformin is recommended as the first-line agent in the management of type 2 diabetes mellitus for its main target on hepatic gluconeogenesis, but its mechanism remains only partially understood and controversial. PTG, a regulatory subunit of protein phosphatase 1, is a gene related to hepatic gluconeogenesis which was screened by our team using gene chip technology. Our previous study found that the expression of PTG was significantly increased in the liver of db/db mice. We also demonstrated that, in cultured primary liver cells of mice, cAMP significantly promoted gluconegenesis and increased the mRNA expression levels of PTG. When the expression of PTG gene was blocked by RNAi in liver cells, gluconegenesis was inhibited, while overexpression of PTG gene increased gluconegenesis. Metformin inhibited the expression of PTG gene in hepatocytes in a dose-dependent manner, but it had no significant effect on hepatic gluconegenesis in PTG overexpressed liver cells. Based on the findings mentioned above, it suggested that metformin might inhibit hepatic gluconeogenesis via reducing the activity of PTG. In the present study, we aim to comprehensively study the effects of PTG on metformin-intervented hepatic gluconeogenesis in vivo and vitro, and further clarify the molecular mechanisim of metformin regulating hepatic gluconegenesis via PTG. This study will provide strong evidence for the new role of PTG in regulating hepatic gluconeogenesis, and PTG may serve as a potential therapeutic target for the treatment of insulin resistance and type 2 diabetes.