肝糖异生升高是2型糖尿病（T2DM）发生与发展的重要因素之一，而抑制肝糖异生是治疗T2DM的有效策略。TAK1是一种蛋白激酶，属于MAP3K家族。丙酮酸激酶（PKM）是细胞糖酵解系统中的一种酶，包括PKM1和PKM2。前人研究结果表明，PKM2活性升高可导致细胞进行有氧糖酵解，最终引起丙酮酸和乳酸的积聚（这两类物质是肝糖异生作用底物）。并且，磷酸化修饰可导致PKM2活性降低。我们初步研究发现，上调TAK1可抑制肝糖异生，而下调TAK1则可激活肝糖异生。免疫共沉淀及蛋白质谱结果表明，TAK1与PKM2存在物理结合作用。综上所述，我们推测，TAK1与PKM2结合并磷酸化修饰PKM2，导致其活性降低，肝糖异生底物丙酮酸及乳酸含量下降，肝糖异生作用受到抵制，最终导致T2DM小鼠血糖下降，缓解高糖血症。本项目的开展，有望揭示TAK1在调控肝糖异生中的生理作用，并为治疗T2DM药物筛选提供可能的靶点。

Ectopic increase in hepatic gluconeogenesis is an important factor for progression of type 2 diabetes. Inhibition of hepatic gluconeogenesis is considered as a useful strategy for combating type 2 diabetes. TAK1 belongs to mitogen-activated protein kinase kinase kinase (MAP3K) family, which plays a key role in cell survival, immunity responses and the process of metabolism. It has been shown that PKM2 activation tends to favor metabolism via aerobic glycolysis rather than the much more efficient oxidative phosphorylation pathway. As a consequence, there are more pyruvate and lactate accumulated in cells, which will stimulates hepatic gluconeogenesis since these chemicals are substrates of gluconeogenesis. Moreover, one study showed that phosphorylation of PKM2 greatly inhibits its enzyme activity. Our preliminary results showed that TAK1 over-expression repressed hepatic gluconeogenesis and knockdown of TAK1 activated hepatic gluconeogenesis. Furthermore, our data revealed that PKM2 physically interacted with TAK1 in hepatocytes. Taken together, we predict that TAK1 interacts with PKM2 and phosphorylates PKM2, leading to a reduction in PKM2 activity. Thus, pyruvate and lactate were decreased, which inhibits hepatic gluconeogenesis and eventually alleviates hyperglycemia. Our data will reveal a new aspect of TAK1 and might provide a drug target for developing novel drugs for treating type 2 diabetes.