应用子宫特异Akt2基因敲除小鼠探讨启宫丸改善PCOS子宫胰岛素抵抗的机制

PCOS patients often manifest insulin resistance, which results in metabolic dysfunction. Previous clinical studies indicated that these patients suffered not only peripheral but also local tissue insulin resistance. Recently, we showed that inactivation of PI3K/Akt signaling pathway contributes to uterine insulin resistance in PCOS-like rats. Akt2 plays a key role in the PI3K/Akt signaling. Female mice lacking Akt2 exhibit peripheral insulin resistance as same as in PCOS patients. Our preliminary results indicated that the expression of uterine Akt2 protein was decreased in PCOS patients and PCOS-like rats. Interestingly, Qi Gong Wan was shown to ameliorate PCOS-induced reproductive dysfunction by increasing the peripheral insulin sensitivity. Based on the results from these clinical and animal studies, we hypothesized that Qi Gong Wan might improve the uterine function via Akt2 activation to increase uterine cell insulin sensitivity and suppress NF-kappa B-mediated inflammatory progression under PCOS conditions. In this proposal, we will generate and use uterine Akt2 knockout mice to investigate the effect of Qi Gong Wan on insulin resistance, abnormal inflammation and implantation failure under PCOS conditions. This study will provide the molecular evidence for the clinical application of Qi Gong Wan in PCOS patients with uterine insulin resistance.

胰岛素抵抗是PCOS主要病理特征和发病的中心环节之一。研究发现PCOS子宫局部同样存在胰岛素抵抗，胰岛素信号通路PI3K/Akt失调是其主要机制。Akt2为PI3K/Akt通路的关键分子，Akt2基因敲除小鼠呈现了与人PCOS相类似的外周胰岛素抵抗，我们前期研究证实了PCOS大鼠模型和患者子宫内膜Akt2的蛋白表达均明显下降。临床研究表明启宫丸可以调节PCOS胰岛素敏感性，改善生殖功能。因此提出“启宫丸可以通过激活子宫内膜细胞Akt2的表达，增强胰岛素敏感性，同时降调Akt2/NF-κB介导的炎症因子的表达，促进子宫生殖功能恢复”的假说。本研究以启宫丸为干预手段，应用子宫特异Akt2基因敲除小鼠模型，探讨中药对PCOS子宫胰岛素敏感性、异常炎症及胚胎着床的影响，为启宫丸的临床应用和推广提供科学依据，同时为子宫胰岛素抵抗的治疗明确干预靶点，具有重要的研究意义。

胰岛素抵抗是PCOS主要病理特征和发病的中心环节之一。研究发现PCOS子宫局部同样存在胰岛素抵抗，胰岛素信号通路PI3K/Akt失调是其主要机制。Akt2为PI3K/Akt通路的关键分子，Akt2基因敲除小鼠呈现了与人PCOS相类似的外周胰岛素抵抗，前期研究证实了PCOS大鼠模型和患者子宫内膜Akt2的蛋白表达均明显下降。临床研究表明启宫丸可以调节PCOS胰岛素敏感性，改善生殖功能。为此我们提出“启宫丸可以通过激活子宫内膜细胞Akt2的表达，增强胰岛素敏感性，同时降调Akt2/NF-κB介导的炎症因子的表达，促进子宫生殖功能恢复”的假说。本研究以启宫丸为干预手段，从体内研究证实了子宫 Akt2 异常表达可能为诱导子宫胰岛素抵抗的关键因素，子宫胰岛素抵抗与卵巢糖代谢及外周组织胰岛素抵抗在 PCOS 发病中可能具有不同的作用和独特性，证实了启宫丸具有改善PCOS子宫胰岛素抵抗，促进子宫生殖功能恢复的作用，并应用Akt2基因敲除小鼠，验证了Akt2可能为启宫丸改善PCOS子宫胰岛素抵抗，促进子宫生殖功能恢复的主要作用靶点，为启宫丸的临床应用和推广提供了科学依据。