Selective insulin resistance is central to the proposed connection. Insulin normally binds a transmembrane receptor tyrosine kinase, recruits insulin receptor substrate proteins and activates the PI3K/Akt pathway. Akt then promotes the translocation of GLUT4 glucose transporters to cell membranes, enabling glucose uptake in skeletal muscle and adipose tissue and supporting glycogen synthesis and the suppression of gluconeogenesis. In insulin-resistant states, receptor-level defects and inhibitory serine phosphorylation of IRS proteins can weaken this cascade. Meanwhile, the MAPK branch, which regulates cell growth and proliferation, may remain comparatively preserved. The review describes this division as selective insulin resistance: metabolic responses to insulin weaken while growth-related signaling remains strong or becomes exaggerated.

This distinction helps connect impaired glucose regulation with ovarian androgen production. In polycystic ovary syndrome, elevated insulin stimulates ovarian theca cells and can increase the expression of steroidogenic enzymes such as CYP17A1. It also potentiates signaling through insulin-like growth factor 1 and works with luteinizing hormone to increase production of testosterone and androstenedione. At the same time, insulin suppresses hepatic production of sex hormone-binding globulin, raising the biological availability of free testosterone. The resulting hyperandrogenism is associated with ovulatory dysfunction, menstrual irregularity, arrested follicular development and the characteristic polycystic ovarian morphology described in the review.

The reproductive effects are also embedded in a wider hypothalamic–pituitary–ovarian network. Increased gonadotropin-releasing hormone pulsatility preferentially stimulates luteinizing hormone over follicle-stimulating hormone, raising theca-cell activity while limiting granulosa-cell aromatization. Follicle-stimulating hormone normally supports granulosa-cell proliferation and the conversion of androgens into estrogens, contributing to the emergence of a dominant follicle. A hormonal pattern dominated by luteinizing hormone and androgens instead can retain follicles at the small antral stage and impede ovulation. Hyperinsulinemia may reinforce this pattern by increasing pituitary luteinizing hormone secretion and making ovarian theca cells more responsive to the hormone, linking metabolic disturbance with abnormal folliculogenesis.

Cellular energy-sensing machinery provides another connection between the disorders. AMP-activated protein kinase, or AMPK, responds to increased cellular energy demand by promoting glucose uptake and fatty-acid oxidation while restraining anabolic growth signaling through mTOR. The review reports reduced or dysregulated AMPK activity alongside excessive mTOR activity in insulin-resistant states. Hyperinsulinemia can contribute to mTOR activation, while mTOR can suppress insulin-receptor substrate function and further impede insulin action. In ovarian tissue, excessive mTOR activity has been associated with abnormal follicular growth, androgen production and follicular arrest. Metformin acts through AMPK-dependent and AMPK-independent mechanisms and can improve insulin sensitivity and several metabolic and reproductive features of polycystic ovary syndrome, although the review does not treat AMPK as the sole explanation for its effects.

Inflammation and oxidative stress can help propagate both metabolic and reproductive abnormalities rather than merely accompanying them. Hyperglycemia, elevated free fatty acids and dysfunctional adipose tissue activate NF-κB, a central regulator of inflammatory gene expression. Adipose-tissue macrophage infiltration and Toll-like receptor 4 signaling add tumor necrosis factor alpha, interleukin-6 and other mediators to this environment. These cytokines can interfere with IRS proteins, reduce GLUT4 expression and stimulate lipolysis, sending more fatty acids into circulation and renewing the inflammatory stimulus. Reactive oxygen species add another layer: excess oxidative stress damages mitochondria, activates JNK, p38 MAPK and NF-κB, and can further inhibit IRS-1. Antioxidant defenses involving catalase, glutathione peroxidase, glutathione and Nrf2 may become overwhelmed under chronic metabolic stress.

WNT/β-catenin signaling is a comparatively less established component of the shared model. Canonical WNT signaling stabilizes beta-catenin, allowing it to enter the nucleus and regulate genes involved in cell proliferation, differentiation, ovarian follicle development and steroidogenesis. Experimental studies summarized in the review have found altered WNT ligands, beta-catenin and glycogen synthase kinase 3 beta in granulosa cells from women with polycystic ovary syndrome. Greater kinase activity can promote beta-catenin degradation and impair transcription needed for follicle maturation, while abnormal signaling may also increase granulosa-cell apoptosis and alter responsiveness to follicle-stimulating hormone. WNT signaling intersects with PI3K/Akt, AMPK, mTOR and adipocyte development, potentially providing a link between ovarian dysfunction and impaired insulin sensitivity.

Adipose tissue functions both as a metabolic organ and as a source of endocrine signals that can reach the reproductive axis. Adiponectin normally improves insulin sensitivity through AMPK activation and fatty-acid oxidation, and reduced concentrations have been associated with polycystic ovary syndrome independently of obesity. Leptin regulates appetite and reproductive neuroendocrine function, but hyperleptinemia in obesity and insulin resistance can occur alongside resistance to its effects, disturbed gonadotropin signaling and increased inflammatory and oxidative stress. Resistin has been linked to inflammatory cytokine production and impaired insulin action. Together, these adipokines can connect adipose dysfunction and inflammation with androgen excess, while impaired WNT-dependent adipocyte differentiation may contribute to hypertrophic, insulin-resistant fat cells and ectopic lipid accumulation.

Human evidence supports an association between the disorders, but it does not by itself establish that one directly causes the other. A meta-analysis of 23 observational studies involving more than 319,000 participants, as cited by the review, estimated approximately 3.5-fold higher risk of type 2 diabetes among women with polycystic ovary syndrome, although overweight and obesity strongly influenced the estimate. Metabolic abnormalities and insulin resistance have also been documented in non-obese women with the condition, supporting an intrinsic contribution beyond adiposity. The reported risk nevertheless varies with ethnicity, obesity and the method used to assess glucose metabolism. The review therefore presents shared pathways as a mechanistic framework and as candidates for further investigation, not as already validated targets for treating both conditions.

The review distinguishes established management from experimental molecular approaches. Lifestyle modification, metformin, combined oral contraceptives, anti-androgen treatment and letrozole for ovulation induction have evidence in appropriate clinical contexts, while glucagon-like peptide 1 receptor agonists and sodium-glucose cotransporter 2 inhibitors are being evaluated for women with polycystic ovary syndrome who have metabolic risk. Direct PI3K/Akt activators, WNT modulators, agents targeting NF-κB or the NLRP3 inflammasome, and treatments aimed at mitochondrial health remain largely experimental. The overall conclusion is bounded: the reviewed evidence describes substantial overlap in insulin resistance, hyperinsulinemia, inflammation, oxidative stress and intracellular signaling, while emphasizing that much of the pathway-level evidence is tissue-specific, preclinical or based on cross-sectional human studies. Establishing which shared mechanisms are most important in people—and which are clinically actionable—will require more direct human research.

Subject of Research: Shared metabolic and reproductive signaling pathways in polycystic ovary syndrome and type 2 diabetes

Article Title: Interconnected metabolic and reproductive signaling axis in type 2 diabetes mellitus and polyendocrine metabolic ovarian syndrome

Article References: Padder, K. A., Ganie, M. A., Jahan, N., Yousuf, M. A., Sehar, T., Bhat, M. A., Buhroo, S. A., Muzaffar, S., Majeed, S., Dar, R. A., & Sheikh, T. (2026). Interconnected metabolic and reproductive signaling axis in type 2 diabetes mellitus and polyendocrine metabolic ovarian syndrome. Frontiers in Endocrinology, 17, Article 1996827. https://doi.org/10.3389/fendo.2026.1996827

Image Credits: AI Generated

DOI: 10.3389/fendo.2026.1996827

Keywords: polycystic ovary syndrome, type 2 diabetes, insulin resistance, hyperinsulinemia, hyperandrogenism, PI3K/Akt signaling, AMPK–mTOR signaling, NF-κB, WNT/β-catenin, oxidative stress, adipokines, narrative review