Elevated Insulin Levels Compromise Mouse Decidualization with Decreases on Uterine Endometrial Apoptosis in Early-Stage Pregnancy

Abstract

Objective: Compromised reproduction was a serious problem in women with hyperinsulinism and insulin resistance. However, the mechanism is not clear. Women with hyperinsulinism and insulin resistance have reduced fertility, but the underlying mechanism is still not known. Aberrant endometrial decidualization in early pregnancy has been linked to pregnancy complications, including infertility and recurrent miscarriage. Methods: C57BL/6J mice were randomly divided into normal control group and high insulin-exposed group. High insulin-exposed group were given a subcutaneous injection of human recombinant insulin. After insulin treatment, mice were sacrificed in early pregnancy. Serum and uterine tissues were collected for analysis. ELISA were used to evaluate changes in blood glucose and various hormones. Western blotting, immunohistochemical staining and quantitative measurement were used to evaluate the uterine decidualization and endometrial apoptosis in early pregnancy mice. For in vitro studies, decidualization was induced in mESCs and T-HESCs from control and high-insulin-exposed group. Western blotting was used to examine the protein expressions of apoptosis and PI3K/Akt signalling pathway related proteins. Results: Serum levels of insulin, E2, P4, LH, FSH and blood glucose were significantly altered in mice treated with insulin. Endometrial decidualization in early pregnancy was impaired by high insulin levels. Furthermore, endometrial apoptosis which is essential for decidualization was also markedly decreased. Suppression of insulin signaling by blocking insulin receptor reverses these alterations. Importantly, activated PI3K/Akt was found to have associated with decreased apoptosis during compromised decidualization by high insulin levels in vitro and in vivo. Conclusion: High insulin levels suppress endometrial apoptosis by PI3K/Akt signaling pathway, which further impairs decidualization in early pregnancy. Funding Statement: This work was supported by the National Natural Science Foundation of China (No. 81300486, No.81801482, No.31571190), the Natural Science Foundation of Chongqing (No. cstc2015jcyjA10013), Scientific Research Program of Science and Technology Commission of Yuzhong District of Chongqing (No.20150104). Declaration of Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Ethics Approval Statement: Eight-week-old KUNMING mice, approved by the Laboratory Animal Centre of Chongqing Medical University (No. 20110016), were supplied with regular life condition.