Provincial Key Laboratory for Developmental Biology and Neurosciences, College of Life Sciences, Fujian Normal University, Fuzhou, Fujian 350007, P.R. China.
State Key Laboratory for Evaluation of Exercise Physiological Functions from General Administration of Sport of China, School of Physical Education and Sport Sciences, Fujian Normal University, Fuzhou, Fujian 350007, P.R. China.
Mol Med Rep. 2017 Dec;16(6):8164-8170. doi: 10.3892/mmr.2017.7678. Epub 2017 Sep 29.
It is established that the physiological effects of insulin are primarily mediated by the insulin signaling pathway. However, a defective insulin signaling is closely associated with the clinical manifestations of polycystic ovary syndrome (PCOS), which include excess androgen levels, insulin resistance and anovulation, and is involved in the pathophysiology of PCOS at the molecular level. Dimethyldiguanide (DMBG) has been widely employed to alleviate reproduction dysfunction in women with PCOS, however, the exact mechanism of this effect remains unclear. The objective of the present study was to investigate the effects of DMBG on the expression of the insulin signaling pathway in the ovaries of rats with PCOS, and to identify the potential underlying molecular mechanisms of these effects in PCOS. In the present study, a PCOS rat model was induced by letrozole, and successful establishment of the model was confirmed by examining ovarian histology and determining serum testosterone levels, by hematoxylin and eosin staining and ELISA, respectively. Subsequently, the expression of two key elements of insulin signaling, insulin receptor substrate (IRS)‑2 and phosphatidylinositol 3‑kinase (PI3K), was determined by immunohistochemistry and western blot analysis. The results demonstrated that IRS‑2 and PI3K expression was markedly decreased in PCOS ovaries, which was rescued by DMBG treatment. These results indicate that IRS‑2/PI3K signaling may be involved in the development of PCOS and the therapeutic effects of DMBG on PCOS. To further confirm the effects of DMBG on insulin signaling expression during this process, the expression of an additional two downstream proteins, phosphoinositide‑dependent kinase‑1 (PDK‑1) and the mammalian target of rapamycin (mTOR), was also investigated in the present study, and the results demonstrated that the expression of PDK‑1 and mTOR was significantly reduced in PCOS ovaries and increased following DMBG treatment, further indicating that altered insulin signaling may have an important role in the development and treatment of PCOS. In conclusion, the results of the present study indicate that the reduced expression of proteins involved in insulin signaling may contribute to the development of the clinical features of PCOS, and DMBG reverses reduced expression of insulin signaling components, by a mechanism that is yet to be determined, to attenuate certain symptoms of PCOS, such as obesity. To the best of our knowledge, the present study is the first to provide data regarding the detailed changes of insulin signaling during the development and treatment of PCOS, and may provide an important reference for clinical PCOS treatment.
已经确定胰岛素的生理作用主要是通过胰岛素信号通路介导的。然而，胰岛素信号的缺陷与多囊卵巢综合征（PCOS）的临床表现密切相关，其临床表现包括雄激素水平过高、胰岛素抵抗和排卵障碍，并且在分子水平上参与 PCOS 的病理生理学过程。二甲双胍（DMBG）已被广泛用于缓解 PCOS 女性的生殖功能障碍，然而，其确切作用机制尚不清楚。本研究的目的是探讨 DMBG 对 PCOS 大鼠卵巢中胰岛素信号通路表达的影响，并确定 DMBG 在 PCOS 中发挥这种作用的潜在分子机制。在本研究中，通过使用来曲唑诱导 PCOS 大鼠模型，并通过卵巢组织学检查和酶联免疫吸附试验（ELISA）分别检测血清睾酮水平来确认模型的成功建立。随后，通过免疫组织化学和 Western blot 分析检测胰岛素信号的两个关键元素胰岛素受体底物（IRS）-2 和磷脂酰肌醇 3-激酶（PI3K）的表达。结果表明，IRS-2 和 PI3K 的表达在 PCOS 卵巢中明显降低，而 DMBG 治疗可挽救这种降低。这些结果表明 IRS-2/PI3K 信号可能参与 PCOS 的发生发展，DMBG 对 PCOS 的治疗作用。为了进一步证实 DMBG 在这一过程中对胰岛素信号表达的影响，本研究还研究了另外两个下游蛋白，磷酸肌醇依赖性激酶-1（PDK-1）和哺乳动物雷帕霉素靶蛋白（mTOR）的表达，结果表明，PDK-1 和 mTOR 的表达在 PCOS 卵巢中显著降低，而在 DMBG 治疗后增加，进一步表明改变的胰岛素信号可能在 PCOS 的发生发展和治疗中发挥重要作用。综上所述，本研究结果表明，参与胰岛素信号的蛋白表达减少可能导致 PCOS 临床特征的发生发展，DMBG 通过尚未确定的机制逆转胰岛素信号成分的表达减少，从而减轻 PCOS 的某些症状，如肥胖。据我们所知，本研究首次提供了关于胰岛素信号在 PCOS 发生发展和治疗过程中详细变化的数据，可能为临床 PCOS 治疗提供重要参考。
