Expression and Contribution of Insulin Signaling Pathway to the Development of Polycystic Ovary Syndrome

Abstract

Our previous studies have demonstrated that insulin signaling pathway has an important role in the pathophysiology of polycystic ovary syndrome (PCOS), including phosphatidylinositol 3-kinase and protein kinase B signaling, which is critically implicated in insulin resistance, androgen secretion, obesity, and follicular development. PCOS manifests as defective ovarian steroid biosynthesis and hyperandrogenemia, and 50-70% of women with PCOS exhibit insulin resistance and are hyperinsulinemic, indicating that insulin resistance and hyperinsulinism may have an important role in the pathophysiology of PCOS. Therefore, the present article will review the contribution of insulin signaling pathway to the abnormal regulation of follicular growth and ovulation, which can cause corresponding reproductive endocrine diseases and affect women's reproductive health. Exploring the mechanism of insulin signaling pathway in PCOS will help not only to understand the physiology and pathology of follicular development but also to provide theoretical basis for the treatment of PCOS.

Insulin Metabolism in Polycystic Ovary Syndrome: Secretion, Signaling, and Clearance

“…When looking at the signaling downstream of IRS, IRS-1-associated activation of PI3K was decreased in the skeletal muscles of women with PCOS [ 70 ]. Impaired PI3K activity may lead to a decreased activation of PKB, the main enzyme for propagating the translocation of GLUT4 to the cell membrane, resulting in reduced insulin-induced glucose uptake in target tissues [ 71 ]. Insulin is closely interconnected to the mitochondria, which are involved in regulation of cellular ATP and reactive oxygen species levels [ 72 ].…”

Involvement of Transcription Factor FoxO1 in the Pathogenesis of Polycystic Ovary Syndrome

“…Given the polymorphism of PCOS phenotype, it is considered to be a multi-gene-mediated disease ( Li et al, 2013 ; Barthelmess and Naz, 2014 ; Nandi et al, 2014 ; Wang and Wang, 2017 ). For example, PCOS has previously been related to insulin receptor (INSR) gene with racial differences ( Stewart et al, 2006 ; Wang et al, 2017a ; Lin et al, 2019 ), and the family history might be a potential risk factor for the incidence of PCOS ( Azziz and Kashar-Miller, 2000 ; Wang and Wang, 2017 ). It has been also reported that visceral obesity, proinflammatory factors, hyperinsulinemia, and IR are likely associated with the occurrence of PCOS ( Wang et al, 2015 , 2017b ; Hughan et al, 2016 ; Zhang et al, 2019 ).…”

“…IR is a state of pathological metabolism with decreased ability to use glucose, and thus, insulin secretion is increased to compensate and maintain the normal blood glucose level, thereby leading to hyperinsulinemia. Interestingly, hyperinsulinemia not only increases androgen secretion through selectively increasing the sensitivity of theca cells to luteinizing hormone, but also increases the level of free androgen through inhibiting the synthesis of sex hormone binding globulin in the liver, thereby promoting the occurrence of PCOS ( Bremer and Miller, 2008 ; Wang et al, 2015 , 2017a , b ; Lin et al, 2019 ; Zhang et al, 2019 ).…”

“…FoxO1 is a key downstream molecule of the INS/IGF-1 signaling pathway, regulating the circulatory metabolism and hormone levels in liver, pancreas, hypothalamus-pituitary axis, and adipose tissue through increasing the level of circulating glucose ( Wang et al, 2015 , 2017a , b ; Kamagate and Dong, 2018 ; Lin et al, 2019 ; Zhang et al, 2019 ). For example, FoxO1 elevates the blood glucose levels through acting on the key enzymes, such as glucose-6-phosphatase and phosphoenolpyruvate carboxykinase during the process of gluconeogenesis, and it also affects the apoptosis of beta cells and development of type 2 diabetes mellitus through INS/IGF-1 signaling ( Wang et al, 2015 , 2017a , b ; Kamagate and Dong, 2018 ; Lin et al, 2019 ; Zhang et al, 2019 ). Rosas et al (2010) found that the expression of glucose transporter 4 (GLUT4) related molecules in endometrium during secretory phase of normal menstrual cycle was beneficial for glucose uptake, while some molecules in PCOS patients related with hyperandrogenism decreased, and the exposure of GLUT4 and absorption of glucose reduced, thereby resulting in IR.…”

“…At present, the incidence rate of polycystic ovary syndrome (PCOS) is about 5.6% among women of reproductive age (19–45 years) in Chinese Han population based on a large community-based study ( Li et al, 2013 ), but the specific mechanism underlying the pathogenesis of PCOS is still unclear. Apart from polycystic ovaries, hyperandrogenism, and ovulatory disorders, PCOS is often accompanied by insulin resistance (IR), low-grade chronic inflammatory response, obesity, abnormal lipid metabolism, and long-term complications, such as hypertension, type 2 diabetes, and endometrial cancer ( Li et al, 2013 ; Barthelmess and Naz, 2014 ; Nandi et al, 2014 ; Wang et al, 2015 , 2017a , b ; Wang and Wang, 2017 ; Lin et al, 2019 ; Zhang et al, 2019 ).…”