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

Abstract

METABOLIC DISORDERS, such as PCOS (polycystic ovary syndrome) and T2DM (type 2 diabetes mellitus), are reported to be associated with high miscarriage rates, decreased pregnancy rates, and low live birth rates [1]. PCOS and T2DM are characterized by hyperinsulinemia [2]. PCOS is an endocrine and metabolic disorder with a prevalence ranging from 5 to 13% in women of reproductive age. Moreover, PCOS is often accompanied by menstrual dysfunction, anovulaHigh insulin impaired ovarian function in early pregnant mice and the role of autophagy in this process Abstract. 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.

Protein–Protein Interaction Network Analysis Reveals Several Diseases Highly Associated with Polycystic Ovarian Syndrome

“…Meanwhile, elevated insulin levels and/or insulin resistance are commonly seen in women with PCOS, and this is one of the most important mechanisms in PCOS pathogenesis [31,32]. It was found to be able to impair ovarian autophagy and function in mice [33]. Recently, insulin-sensitizers such as inositol have been used to improve the insulin resistance in PCOS by regulating autophagy [34].…”

Bone Morphogenetic Protein 15 Knockdown Inhibits Porcine Ovarian Follicular Development and Ovulation

“…As shown in Figure 5C, an undetectable level of autophagy-related protein LC3B (microtubule-associated protein 1 light chain 3) (Jiang et al, 2017) was observed in the oocytes of TGFA SFs, whereas the oocytes of WT and TGF normal follicles displayed a normal level of LC3B. This result demonstrates that autophagy activity of the oocytes of TGFA follicles, which is fundamental to the cellular processes of the oocytes, was largely weakened (Su et al, 2017).…”

Essential role of Bone morphogenetic protein 15 in porcine ovarian and follicular development and ovulation

“…5C, an undetectable level of autophagy-related protein LC3B (microtubule-associated protein 1 light chain 3)(Jiang et al, 2017) was shown in oocytes of TGFA SFs, while oocytes of WT and TGF normal follicles displayed a normal level of LC3B. This result demonstrated that autophagy activity of the oocytes of TGFA follicles was largely weakened, which was fundamental to many oocyte cellular processes(Su et al, 2017).…”