Periostin调控外周组织胰岛素敏感性及其机制研究

Insulin resistance is the most powerful predictor of type 2 diabetes, and it plays an important role in the whole course of the disease, yet the molecular mechanism of insulin resistance remains elusive. Periostin could act as a hepatokine. In animal models of insulin resistance like db/db mice、ob/ob mice and high fat diet feeding mice, we observed an elevated expression of periostin in the liver. We also found that insulin resistance improved and plasma glucose decreased after knocking down of periostin in db/db mice with adenoviral shRNAs targeting postn. Activation of JNK pathway was also blocked with periostin being knocked down. So we proposed that periostin caused insulin resistance through activation of JNK pathway. To confirm it, we will further focus on: 1) The role of periostin in regulating insulin sensitivity and interaction of it with insulin signal pathway in animal models or cell with periostin overexpressed/knocked-down. 2) The molecular mechanisms of how periostin interacts with insulin signal pathway. This study will lead to a better understand of the pathogenesis of insulin resistance and function of hepatokines. Periostin may also provide a promising target for the treatment of insulin resistance.

胰岛素抵抗是2型糖尿病发病的重要基础，然而目前其产生机制尚不清楚。Periostin是肝脏产生的细胞因子，我们在胰岛素抵抗动物模型db/db、ob/ob以及高脂喂养小鼠中观察到肝脏Periostin表达增多，而利用腺病毒包被的shRNA干扰db/db小鼠肝脏Periostin表达后，周围组织胰岛素敏感性增强，血糖下降，并且发现干扰Periostin表达后JNK通路的激活受抑制。在上述工作基础上我们提出假设：Periostin通过激活JNK通路引起周围组织胰岛素抵抗。为进一步证实，本项目拟开展以下工作:1）运用多种过表达与干扰表达的小鼠、细胞模型，明确Periostin对于外周组织胰岛素敏感性与胰岛素信号通路的调控作用；2）阐明Periostin调控胰岛素信号通路的分子机制。本项目将不仅加深对胰岛素抵抗发病机制以及肝脏细胞因子功能的认识，也为胰岛素抵抗的治疗提供新的靶点。

胰岛素抵抗是2型糖尿病发病的重要发病机制之一，也是重要的治疗靶点，然而对于胰岛素抵抗产生的机制并不十分明确，本研究在db/db，ob/ob等遗传性胰岛素抵抗模型和高脂饮食诱导的胰岛素抵抗模型中，均观察到肝脏Periostin表达上调；与对照小鼠相比，过表达Periostin小鼠高脂喂养后肝脏胰岛素抵抗更明显，糖代谢紊乱更加严重。干扰db/db小鼠肝脏Periostin表达后，周围组织胰岛素敏感性增强，血糖下降。在机制刚面，我们发现Periostin通过调节JNK信号通路调控肝脏胰岛素敏感性。.本项目将不仅加深对胰岛素抵抗发病机制以及肝脏细胞因子功能的认识，也为胰岛素抵抗的治疗提供新的靶点。Periostin是分泌蛋白，开发针对 Periostin中和抗体，阻断血清中Periostin蛋白的生物学作用，将可能成为治疗糖尿病和代谢综合征的新型靶标。