胰岛素抵抗是2型糖尿病、代谢综合征等多种病症的基本病理机制。氧化应激是胰岛素抵抗的关键诱因，然而具体的分子机制还不明确。我们的前期研究发现，肝细胞核因子1b（HNF1b）表达降低与氧化应激、糖异生增加、胰岛素抵抗易感性密切相关，提示HNF1b可能是联系ROS和糖代谢的关键枢纽。基于前期研究及文献进展，我们提出科学假说：在遗传背景下，氧化应激抑制HNF1b表达，HNF1b缺陷诱导/加重氧化应激，形成恶性循环，扰乱胰岛素信号，促进糖异生，抑制糖原合成，最终导致胰岛素抵抗。为证明该假说，本项目拟从HNF1b在氧化应激和胰岛素抵抗状态下的变化特点入手，利用敲减/过表达HNF1b的细胞、动物模型，研究HNF1b对胰岛素敏感性和氧化还原平衡的影响及机制，并深入研究HNF1b的靶点及转录调控机制。有望明确HNF1b功能缺陷在胰岛素抵抗中的关键作用和机制，为认识其发病机制及提出防治策略提供理论和实验依据。

Insulin resistance is the hallmark of type 2 diabetes mellitus and metabolic syndrome. Although oxidative stress plays a key role in the pathogenesis of insulin resistance, the molecular mechanism is still not clear. Our previous results demonstrated that (1) Down-regulation of hepatocyte nuclear factor 1b (HNF1b) mRNA was closely related with oxidative stress, enhanced gluconeogenesisthe and genetic sensitivity of oxidative stress-induced insulin resistance, indicating the key role of HNF1b in the interation of ROS and glucose metabolism. Based our previous results and literature, we propose a scientific hypothesis: in the background of genetic sensitivity, oxidative stress inhibits the function of HNF1b, and deficiency of HNF1b function induces or aggravates oxidative stress, resulting in vicious cycle, leading to the promotion of gluconeogenesis, inhibition of glycogen synthesis, disturbance of insulin signal, and insulin resistance. To verify the hypothesis, in the present project, we will (1) firstly clarify the characteristics of the expression of HNF1b under the condition of insulin resistance; (2) secondly establish the cell and animal model of HNF1b knock down/up, and study the effect of HNF1b deficiency on insulin sensitivity and redox balance and possible mechanisms; (3) further study the targets of HNF1b and its transcriptionally regulatory mechanisms. After all these experiments, we are able to elucidate the key role of HNF1b deficiency in insulin resistance and provide theoretical and practical evidence for the insight into the pathogenesis and preventive strategy of insulin resistance.