Elevated insulin levels compromise endometrial decidualization in mice with decrease in uterine apoptosis in early-stage pregnancy
Elevated insulin levels compromise endometrial decidualization in mice with decrease in uterine apoptosis in early-stage pregnancy
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胰岛素水平升高会损害小鼠子宫内膜蜕膜化，从而减少妊娠早期子宫细胞凋亡
DOI：
10.1007/s00204-019-02601-8
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发表时间：
2019-10
影响因子：
6.1
通讯作者：
Gao Rufei
中科院分区：
文献类型：
--
作者：
Zhang Chen;Yang Chengshun;Li Na;Liu Xueqing;He Junlin;Chen Xuemei;Ding Yubin;Tong Chao;Peng Chuan;Yin Hubin;Wang Yingxiong;Gao Rufei
患有高胰岛素血症和胰岛素抵抗的女性生育力下降，但其潜在机制仍不清楚。妊娠早期子宫内膜蜕膜异常与妊娠并发症有关。在这项研究中，我们的目标是测试升高的胰岛素水平是否会影响怀孕早期蜕膜的形成。高胰岛素暴露组C57BL/6J小鼠皮下注射重组胰岛素，剂量为0.05IU/d。在妊娠早期蜕膜化过程中，高胰岛素水平的小鼠血清胰岛素、雌二醇、孕酮、黄体生成素、卵泡刺激素和血糖水平均发生显著变化。体内高胰岛素水平显著降低胚胎着床部位数和子宫内膜蜕膜标志物BMP2、ER、PR。100nmol/L胰岛素水平对原代小鼠子宫内膜间质细胞和永生化人子宫内膜间质细胞系的人工蜕膜诱导均有抑制作用。流式细胞仪、透射电子显微镜和Western blotting检测结果显示，蜕膜细胞凋亡率显著降低。线粒体跨膜电位也受到高胰岛素水平的影响而显著增加。PI3K和p-Akt在胰岛素暴露后显著升高，PI3K/Akt抑制剂LY294002在体内和体外均可挽救因高胰岛素治疗而受损的蜕膜形成。综上所述，我们证明了高胰岛素水平会损害小鼠在妊娠早期的蜕膜形成，而PI3K/p-Akt调节的细胞凋亡在这一作用中是必不可少的。为今后高胰岛素血症妇女生殖功能障碍的研究提供线索。
Women with hyperinsulinism and insulin resistance have reduced fertility, but the underlying mechanism is still poorly understood. Aberrant endometrial decidualization in early pregnancy was linked to pregnancy complications. In this study, we aimed to test whether elevated insulin levels compromise decidualization in early-stage pregnancy. C57BL/6J mice in high insulin-exposed group were given a subcutaneous injection of recombinant insulin at a concentration of 0.05 IU daily. During decidualization in early pregnancy, serum levels of insulin, E2, P4, LH, FSH and blood glucose were significantly altered in mice treated with high insulin levels. The number of embryo implantation sites and endometrial decidual markers BMP2, ER, PR was significantly decreased by high insulin levels in vivo. Artificial decidual induction in primary mouse endometrial stromal cells and immortal human endometrial stromal cells line were all compromised after treated with 100 nmol/L insulin levels. All these results on flow cytometry, transmission electron microscopy and western blotting of Bax, Bcl2, cleaved Caspase3, cleaved PARP proteins level showed that decidual cells apoptosis was significantly decreased. Mitochondrial transmembrane potential also significantly increased by the influence of high insulin levels. PI3K and p-Akt were much higher after insulin exposure and the compromised decidualization by high insulin treatment was rescued by PI3K/Akt inhibitor LY294002 both in vitro and in vivo. In conclusion, we demonstrated that elevated insulin levels could compromise mice decidualization in early-stage pregnancy and PI3K/p-Akt-regulated apoptosis was essential for this role. It provides a clue for future investigation on compromised reproduction in women with hyperinsulinemia.
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影响因子：
82.9
作者：
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通讯作者：
Dey SK
影响因子：
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作者：
Liao XG;Li YL;Gao RF;Geng YQ;Chen XM;Liu XQ;Ding YB;Mu XY;Wang YX;He JL
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Nie, Guiying
影响因子：
16.2
作者：
Desoye, Gernot;Mouzon, Sylvie Hauguel-De
通讯作者：
Mouzon, Sylvie Hauguel-De
影响因子：
3
作者：
Liu JJ;Druta M;Shibata D;Coppola D;Boler I;Elahi A;Reich RR;Siegel E;Extermann M
通讯作者：
Extermann M