Ins2 gene dosage in a polycystic ovary syndrome mouse model: Role in pathogenesis and health during pregnancy
Date
2025
Authors
Houston, Emma
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Abstract
Polycystic ovary syndrome (PCOS) is reproductive endocrine disorder with quintessential features of irregular ovulation, hyperandrogenism, polycystic ovarian morphology, pregnancy complications, and metabolic dysfunction. Hyperinsulinemia (i.e., elevated insulin without hypoglycemia) is a common metabolic feature of PCOS that worsens its reproductive symptoms by exacerbating pituitary hormone imbalances and increasing levels of bioactive androgens. In turn, high androgen levels can augment both hyperinsulinemia and insulin resistance, generating a self-perpetuating cycle of reproductive and metabolic dysfunction. In this study, I aimed to assess 1) the precise role of insulin in the pathogenesis of PCOS, and 2) how insulin affects health outcomes during pregnancy with PCOS. Using Ins1-null mice with reduced Ins2 gene dosage and littermate controls with full Ins2 gene dosage, I examined the progression of metabolic and reproductive phenotypes in PCOS-like mice generated via prenatal exposure to anti-Müllerian hormone (AMH). I observed that Ins1-null PCOS-like mice exhibited mild reproductive phenotypes of PCOS, including increased anogenital distance, delayed puberty, and disrupted estrous cycling, without any strong metabolic phenotypes. In the absence of hyperinsulinemia, reduced Ins2 gene dosage did not exert notable changes in glucose tolerance, estrous cycling, or time of vaginal opening, although there were subtle changes in body mass, insulin sensitivity, and anogenital distance that suggest a role for Ins2 in the development of these phenotypes. In PCOS-like pregnant dams exposed to a high-fat, high-sucrose diet for 2.5 months, I observed reduced beta-cell mass and diminished pregnancy induced-elevation of insulin levels, together with improved glucose tolerance at G14.5, which may indicate early metabolic aberrations at this stage of pregnancy. Overall, I observed subtle PCOS-like phenotypes in mice with prenatal-AMH exposure, although no robust changes in reproductive or metabolic phenotypes were observed due to reduced Ins2 gene dosage. The slight responses to prenatal-AMH treatment may suggest a protective effect of Ins1 ablation against androgen-induced hyperinsulinemia. These results help to provide further insight into the role of Ins1 and Ins2 in the pathogenesis of PCOS-like symptoms in murine models, which may contribute to current understanding of the role of insulin within the PCOS pathogenesis paradigm.
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Keywords
Polycystic ovary syndrome, PCOS, Insulin, Insulin resistance, Hyperinsulinemia, Anti Mullerian hormone