Reappraising the relationship between hyperinsulinemia and insulin resistance in PCOS

Abstract

Polycystic ovary syndrome (PCOS), a reproductive endocrine disorder with quintessential features of metabolic dysfunction, affects millions of women worldwide. 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. Hyperinsulinemia in PCOS is often attributed to insulin resistance, based on the concept that impaired insulin-mediated glucose disposal would induce compensatory insulin hypersecretion. However, it is challenging to define the sequential relationship between insulin sensitivity and insulin secretion, as they are tightly interlinked, and evidence suggests that hyperinsulinemia can alternatively precede insulin resistance. Notably, other drivers of hyperinsulinemia (outside of insulin resistance) may be highly relevant in the context of PCOS. For instance, high androgen levels can augment both hyperinsulinemia and insulin resistance, generating a self-perpetuating cycle of reproductive and metabolic dysfunction. In this review, we evaluate the cause-and-effect relationships between insulin resistance and hyperinsulinemia in PCOS. We examine evidence for the prevailing theory of insulin resistance as the primary defect that causes secondary compensatory hyperinsulinemia, and an alternative framework of hyperinsulinemia as the earlier defect that perpetuates reproductive and metabolic features of PCOS. Considering the heterogeneous nature of PCOS, it is improbable that its metabolic characteristics always follow the same progression. Comprehensively examining all mechanistic regulators of hyperinsulinemia and insulin resistance in PCOS might thereby lead to improved prevention and management strategies, and address critical knowledge gaps in the progression of PCOS pathogenesis.

Keywords: androgens; insulin; insulin clearance; insulin hypersecretion; insulin sensitivity; metabolic dysfunction; polycystic ovary syndrome.

Figure 1

Simplified insulin signal transduction cascades. Binding of insulin to the tyrosine kinase receptor (i.e., proximal insulin signaling) induces dimerization and autophosphorylation of the receptor beta subunit, creating docking sites for adapter proteins that initiate the mitogenic MAPK/ERK cascade and/or the metabolic PI3K/Akt cascade. Phosphorylation of Shc by the insulin receptor allows for the binding of Grb2, an adapter protein that complexes with son of sevenless (SOS), a guanylyl exchange factor. SOS promotes GDP/GTP exchange on Ras, a GTPase that activates a serine/threonine kinase cascade, which results in phosphorylation of ERK. Once phosphorylated, ERK can enter the nucleus and activate various transcription factors and mitogen-activated protein kinases, leading to coordination of cell proliferation and differentiation. The PI3K/Akt cascade is initiated by the recruitment and activation of PI3K by IRSs IRS1/2. PI3K phosphorylates phosphatidylinositol 4,5-bisphosphate (PIP₂), producing phosphatidylinositol 3,4,5-triphosphate (PIP₃). Accumulation of PIP₃ creates docking sites for phosphoinositide-dependent kinase 1 (PDK1), which phosphorylates and activates Akt. Akt performs many downstream functions. For instance, Akt activates protein synthesis through phosphorylation of mTORC1/2, glycogen synthesis through phosphorylation of GSK3, lipid synthesis through activation of aPKC and glucose transport by phosphorylating TBC1D1/4, which promote translocation of GLUT4-containing vesicles to the cell membrane, ultimately leading to glucose uptake into the cell. A full color version of this figure is available at https://doi.org/10.1530/JOE-24-0269.

Figure 2

Pathophysiology of PCOS. PCOS is best defined by the presence of ovulatory dysfunction (e.g., oligo/anovulation), hyperandrogenemia, and/or polycystic ovarian morphology (PCOM), symptoms which are induced by alterations of the hypothalamic–pituitary–ovary axis and metabolic dysfunctions. Hyperactive GnRH-releasing neurons lead to hypersecretion of LH and reduced FSH secretion by the anterior pituitary gland. LH signals to ovarian theca cells to increase androgen biosynthesis, while granulosa cell aromatization of androgens is diminished due to relative FSH deficiency, resulting in hyperandrogenemia. Elevated insulin levels due to causes such as compensatory β-cell responses to insulin resistance work synergistically with LH to promote ovarian steroidogenesis and suppress hepatic production of SHBG, thus exacerbating hyperandrogenemia by increasing levels of bioavailable androgens. Simultaneously, androgens can worsen insulin resistance and increase insulin production, creating a self-perpetuating cycle of hyperinsulinemia and hyperandrogenemia. Elevated androgen levels, combined with excessive AMH production by immature follicles, contribute toward arresting follicle development, thus leading to polycystic ovarian morphology and anovulation. A full color version of this figure is available at https://doi.org/10.1530/JOE-24-0269.

Figure 3

Alternative PCOS pathogenesis paradigm. In a subset of patients, hyperinsulinemia may be an early upstream defect that drives insulin resistance and exacerbates hyperandrogenism. Factors such as intrinsic genetic defects or a prenatal hyperandrogenic environment may lead to aberrant β-cell insulin secretion and hepatic insulin clearance, causing persistent hyperinsulinemia. Insulin can promote both ovarian and adrenal steroidogenesis, decrease production of SHBG and increase androgen production in adipose tissue, ultimately increasing levels of bioactive androgens. In turn, testosterone can act directly on β-cells to induce insulin hypersecretion, in addition to reducing hepatic insulin binding and degradation, collectively worsening hyperinsulinemia. Elevated insulin levels can downregulate insulin signaling by inducing receptor degradation and altering phosphorylation patterns of signal effector molecules, resulting in insulin resistance. Advanced stages of insulin resistance could cause compensatory hyperinsulinemia, further increasing insulin levels and its effects on the reproductive and metabolic symptoms of PCOS. A full color version of this figure is available at https://doi.org/10.1530/JOE-24-0269.