Hyperinsulinemia and insulin sensitivity in PCOS, the cart or the horse question
- Ladan Kalani
- May 10
- 5 min read
This week’s blog is on the paper
“Reappraising the relationship between hyperinsulinemia and insulin resistance in PCOS”
, published in the journal Society for Endocrinology by Emma J. Houston and Nicole M. Templeman at the Biology department of the University of Victoria, British Columbia, Canada.
For decades, the story of PCOS seemed linear:
Hormonal imbalances resulted in reproductive dysfunction, with insulin resistance being at the epicentre of deviation from a state of homeostasis, which leads to too much insulin in circulation to compensate. End of story.
Except biology rarely follows simple patterns like this. Templeman and Houston offer another perspective, looking at hyperinsulinemia not as a consequence of metabolic dysfunction, but rather as an earlier driver of it. Most people think of insulin as the hormone that lowers blood sugar, but this is only one of the many things it is responsible for. Insulin affects fat storage, protein synthesis, inflammation, cell cycle, and also the ovaries. In many ways, insulin acts as a master regulator of metabolic signalling. As shown in the simplified figure below, adapted from the review paper, there is a feedback loop between insulin resistance and hyperinsulinemia, and any loss-of-function mutation in key proteins involved in insulin results in aberrant signalling, which can drive both insulin resistance and hyperinsulinemia.
Under normal conditions, insulin helps tissues absorb and store nutrients after a meal. Skeletal muscle takes up glucose for energy. Adipose tissue stores excess fuel. The liver reduces glucose production. Everything is designed to be balanced.
But when tissues become less responsive to insulin, the pancreas compensates by producing more of it. Traditionally, this sequence of insulin resistance first, hyperinsulinemia second, has dominated metabolic research. To be fair, there is strong evidence supporting it. With the rise of chronic conditions, such as autoimmune diseases, and obesity, which have tripled since 1975 worldwide, and as interest in white adipocyte tissue (white fat) has increased, it has become ever so clear that adipocyte functionality relates very much to whole body metabolic health (Hagberg & Spalding, 2024).
Obesity-associated inflammation, fat cell dysfunction, and genetic defects in insulin-signalling proteins can all impair glucose handling and lead to secondary hyperinsulinemia. Experimental mouse models with loss-of-function mutations in proteins such as GLUT4 (a glucose transporter) or AKT2 (a kinase involved in insulin signalling, particularly important for activation of Rac-1, important for glucose uptake (Takenaka et al., 2019)) recapitulate this phenomenon remarkably well.
PCOS complicated this further. Researchers noticed that insulin resistance is not limited to obesity-associated PCOS; lean individuals with PCOS also exhibit this feature, and this observation quietly challenged one of the field’s biggest assumptions: if obesity is not always present, obesity is not the root cause.
And the metabolic loops began appearing. Generally, adipose tissue is considered a metabolic organ closely related to energy metabolism by exchanging nutrients and secreting adipose-derived hormones and cytokines, together termed adipokines (Hagberg & Spalding, 2024).
Adipose tissue in PCOS often behaves differently, even at similar BMI. Increased abdominal fat, altered adipokine secretion, chronic low-grade inflammation, and impaired GLUT4 expression all point toward disrupted insulin signalling. Meanwhile, elevated androgens can worsen insulin sensitivity, while elevated insulin itself may stimulate androgen production.
Suddenly, the system no longer looks linear; it becomes circular, stuck in a positive feedback loop. Hyperinsulinemia worsens androgen excess (hyperandrogenism). Hyperandrogenism worsens insulin resistance. Insulin resistance may further elevate insulin levels. The cycle feeds itself. Experiments in cells and in animals have both confirmed that elevated insulin beyond physiological levels causes ovarian hyperandrogenism (Barbieri, 1988). What makes this intriguing is that the field still does not fully agree on where the story begins. Clinical tools often struggle to distinguish hyperinsulinemia from insulin resistance because the two are tightly interconnected. In some individuals, elevated insulin appears before measurable insulin resistance. In others, insulin resistance comes first.
Perhaps the most important message from this review is not that one model is correct and the other is wrong. It is rather that PCOS does not follow a single biological script, and this applies far beyond PCOS itself. The more we study metabolism, the more it becomes clear that chronic disease is rarely driven by isolated pathways. Hormones, immune signals, nutrient sensing, adipose tissue, and stress responses are all participating in the same conversation. The challenge is learning how to listen to this interconnected cell chat (Houston & Templeman, 2025).
Comments and critiques:
This paper does an excellent job of reviewing current research supporting the new perspective on PCOS: that excess insulin itself can have deleterious effects on insulin sensitivity.
Critique of this paper is with regard to the section “Insulin-sensitizing therapies in PCOS” that touches upon available treatments such as metformin and GLP-1 agonists. The authors provide an excellent summary of the detailed biochemistry of how these drugs have a favourable impact in insulin sensitizing; what is missing, however, is the risks associated with these medications. An example is B12 deficiency in people who have been chronically using metformin for years. In a study that tested veterans 50 years or older with type 2 diabetes, with or without metformin treatment, the authors found mean B12 concentration was significantly lower than that of those who were not exposed to metformin (without diabetes), and 7% of people with diabetes were B12-deficient (Kancherla et al., 2017).
Moreover, it is mentioned that lifestyle and diet interventions need to be implemented in addition to these treatments, but they have not elaborated much on what these interventions entail.
Overall, this review provides a compelling synthesis of emerging perspectives on hyperinsulinemia in PCOS. One notable limitation, however, is the limited discussion of the long-term risks of insulin-sensitizing therapies and the lack of detail regarding practical lifestyle and dietary interventions.
References:
Barbieri, R. L., & Hornstein, M. D. (1988). Hyperinsulinemia and Ovarian Hyperandrogenism: Cause and Effect. Endocrinology and Metabolism, 17, 685-703. https://doi.org/doi.org/10.1016/S0889-8529(18)30405-5
Hagberg, C. E., & Spalding, K. L. (2024). White adipocyte dysfunction and obesity-associated pathologies in humans. Nat Rev Mol Cell Biol, 25(4), 270-289. https://doi.org/10.1038/s41580-023-00680-1
Houston, E. J., & Templeman, N. M. (2025). Reappraising the relationship between hyperinsulinemia and insulin resistance in PCOS. J Endocrinol, 265(2). https://doi.org/10.1530/JOE-24-0269
Kancherla, V., Elliott Jr, J. L., Patel, B. B., Holland, N. W., Johnson Ii, T. M., Khakharia, A., Phillips, L. S., Oakley Jr, G. P., & Vaughan, C. P. (2017). Long-term Metformin Therapy and Monitoring for Vitamin B12 Deficiency Among Older Veterans. Journal of the American Geriatrics Society, 65(5), 1061-1066.
Takenaka, N., Araki, N., & Satoh, T. (2019). Involvement of the protein kinase Akt2 in insulin-stimulated Rac1 activation leading to glucose uptake in mouse skeletal muscle. PLoS One, 14(2), e0212219. https://doi.org/10.1371/journal.pone.0212219
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