High insulin impaired ovarian function in early pregnant mice and the role of autophagy in this process

• Published in: Endocrine Journal Vol. 64; no. 6; pp. 613 - 621
• Main Authors: Su, Yan, Wu, Juan, He, Junlin, Liu, Xueqing, Chen, Xuemei, Ding, Yubin, Zhang, Chen, Chen, Wenqi, Wang, Yingxiong, Gao, Rufei
• Format: Journal Article
• Language: English
• Published: Japan The Japan Endocrine Society 2017; Japan Science and Technology Agency
• Subjects: Animals; Animals, Outbred Strains; Anovulation - etiology; Autophagy; Autophagy-Related Protein-1 Homolog - genetics; Autophagy-Related Protein-1 Homolog - metabolism; Beclin-1 - genetics; Beclin-1 - metabolism; Cathepsin B; Cathepsin B - genetics; Cathepsin B - metabolism; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Disease Models, Animal; Embryo Implantation; Embryo Loss - etiology; Estrogens; Female; Follicle-stimulating hormone; Follicles; Gene Expression Regulation, Developmental; Growth differentiation factor 9; Growth Differentiation Factor 9 - genetics; Growth Differentiation Factor 9 - metabolism; Hyperinsulinemia; Hyperinsulinism - metabolism; Hyperinsulinism - pathology; Hyperinsulinism - physiopathology; Implantation; Infertility; Insulin; Insulin Glargine; Luteinizing hormone; Menstruation; Metabolic disorders; Mice; Microtubule-associated protein 1; mRNA; Ovaries; Ovary; Ovary - metabolism; Ovary - pathology; Ovary - physiopathology; Phagocytosis; Polycystic ovary syndrome; Pregnancy; Progesterone; Random Allocation; Reproductive status; Sequestosome-1 Protein - genetics; Sequestosome-1 Protein - metabolism; Serum levels; Embryo implantation; Hyperinsulinemia; Ovary; Autophagy; Insulin
• ISSN: 0918-8959; 1348-4540
• DOI: 10.1507/endocrj.EJ16-0494

Metabolic disorders, such as PCOS (polycystic ovarian syndrome) and T2DM (type 2 diabetes mellitus), are associated with menstrual dysfunction, anovulation, infertility, and early pregnancy loss. Ovarian dysfunction is not only related to low pregnancy rates but also to the increased risk of miscarriage. Women with PCOS or T2DM, characterized by hyperinsulinemia, commonly experience ovarian dysfunction. In this study, we first explored whether high insulin levels directly affected ovarian functioning during embryo implantation. Mice in the insulin-treated group were given a subcutaneous injection of human recombinant insulin. After insulin treatment, serum levels of E2 (estrogen), PROG (progesterone), LH (luteinizing hormone), and FSH (follicle-stimulating hormone) were obviously lower, and there was a significant decrement of ovarian GDF9 (growth differentiation factor 9) mRNA. H&E (hematoxylin and eosin) staining showed a greater number of immature follicles and less luteinization in the insulin group. Further autophagy was studied in this process. A significant increase of P62 (SQSTM1/Sequestosome1) and a decrease of Cathepsin B, BECN1 (Beclin 1), and ULK1 (Unc-51-like kinase 1) mRNA in ovary was found in the insulin group. Western blot analysis showed that the expressions of LC3 (microtubule-associated protein 1 light chain 3), BECN1, and Cathepsin B proteins in ovaries from insulin group were obviously reduced, while P62 proteins were significantly increased. All these results illustrated that insulin could directly impair ovarian function during embryo implantation and the imbalance of ovarian autophagy due to insulin. Autophagy could enhance the impaired ovarian function results from insulin.