我们发现肝移植术后新发糖尿病(NODALT)在中国人群中发病率高且预后差。免疫抑制剂tacrolimus(TAC)被认为是NODALT的重要诱因，但机制未明，目前研究集中于其胰岛损伤作用。我们前期研究表明移植肝在NODALT发病中起重要作用，TAC能抑制肝钙调磷酸酶(CaN)活性，诱发肝糖代谢稳态失衡。新近发现的CRTC2受CaN调控，是肝脏糖脂代谢重要调节子。因此我们提出“TAC介导CaN/CRTC2通路调控移植肝糖代谢稳态”这一科学假设，拟从细胞和动物模型层面观察TAC对肝CRTC2转录、翻译、磷酸化水平及其下游分子(PEPCK、IRS2、SREBP1等)表达的影响，评估肝CaN/CRTC2通路在TAC诱发糖代谢稳态失衡中的作用，利用小鼠肝移植模型探索移植手术和TAC双重打击对肝糖代谢稳态的影响。本研究将从新的视角阐述TAC诱发NODALT的可能机制，为疾病防治提供分子靶点。

We have demonstrated that new-onset diabetes after liver transplantation (NODALT) is a very common complication in Chinese liver transplant population and is closely associated with poor prognosis. Tacrolimus (TAC) is the most widely used immunosuppressive agent after liver transplantation and has been considered as the predominant risk factor for NODALT. However, the underlying mechanism of TAC-induced imbalance of glucose metabolism homeostasis has not been clearly elucidated yet. The current studies mainly focused on its toxicity in pancreatic beta cells. In our previous reports, we have revealed that donor liver plays a central role in the glucose metabolism homeostasis. We proposed that donor liver may act as a possible origin of NODALT. Furthermore, we found that TAC could target donor liver calcineurin (CaN) and induce imbalanced hepatic glucose metabolism homeostasis. The newly identified CREB regulated transcription coactivator 2 (CRTC2) is regulated by CaN and plays a key role in hepatic glucose and lipid metabolism. Therefore, we hypothesize that "TAC may regulate hepatic glucose metabolism homeostasis through the CaN/CRTC2 signaling pathway in liver transplantation". We plan to conduct in vitro and in vivo studies to observe the impact of TAC on CRTC2 transcription, translation, phosphorylation and targets expression (e.g. PEPCK, IRS2, SREBP1); to evaluate the role of hepatic CaN/CRTC2 signaling pathway in TAC-induced imbalance of glucose metabolism homeostasis; to investigate the effect of "dual strike" from both transplant surgical stress and TAC on hepatic glucose metabolism. The study will clarify the underlying mechanism of TAC-induced NODALT from the view of donor liver, and provide molecular targets for disease prevention and treatment.