肝脏胰岛素抵抗是2型糖尿病发病机制的主要环节，有效抑制肝脏过度糖异生, 减少内源性葡萄糖生成, 是治疗2型糖尿病的重要靶标之一。Betatrophin，近年来新发现的一种分泌蛋白，主要由肝脏组织表达。本课题组前期动物及临床研究发现，在胰岛素抵抗状态，Betatrophin表达显著增高；在原代培养的小鼠肝脏细胞，cAMP、地塞米松促进糖异生，Betatrophin重组蛋白则明显减弱此作用，同时发现其能抑制糖异生途径限速酶PEPCK等基因的表达；以上研究表明，Betatrophin可能直接调控肝脏糖异生。本研究拟进一步从细胞和整体水平观察Betatrophin对肝脏糖异生的影响，并从信号通路、转录调控等方面入手，探明其调控机制。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Betatrophin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。

Hepatic insulin resistance is a key contributor to the pathogenesis of type 2 diabetes. Inhibition of overactivated hepatic gluconeogenesis is a important therapeutic target for the treatment of type 2 diabetes. Betatrophin, a newly identified secreted protein of 198 amino acids, is enriched in the liver and fat of mice. Recently, it has been showed that insulin receptor antagonist S961 caused dramatic insulin resistance in mice, and S961 infusion-mediated insulin resistance was accompanied with a surge in betatrophin mRNA in liver and fat. Our previous study discovered that betatrophin mRNA expression was significantly up-regulated in the livers of ob/ob and db/db mice. We have demonstrated for the first time that serum betatrophin concentrations were significantly increased in newly diagnosed and untreated type 2 diabetes patients compared with the controls, and serum betatrophin was negatively associated with 1/HOMA-IR (insulin sensitivity index) in type 2 diabetes group. In cultured primary liver cells of mice, cAMP and hexadecadrol induced PEPCK and G6Pase genes transcription to initiate gluconeogenesis, while recombinant betatrophin protein inhibited expression of both genes. Based on the findings metioned above, it showed that betatrophin may improve glycemia by direct inhibition of overactivated gluconeogenesis in liver. In the present study, we aim to comprehensively study the effects of betetrophin on hepatic gluconeogenesis in vivo and vitro, and further clarify the molecular mechanisim of betetrophin regulating gluconeogenesis. This study will provide strong evidence for the new role of betatrophin in regulating hepatic gluconeogenesis, and betatrophin may serve as a potential therapeutic target for the treatment of insulin resistance and type 2 diabetes.