Molecular Mechanisms of Insulin Resistance in Polycystic Ovary Syndrome: Unraveling the Conundrum in Skeletal Muscle?

Abstract

Context Polycystic ovary syndrome (PCOS) is a common endocrine condition affecting 8% to 13% of women across the lifespan. PCOS affects reproductive, metabolic, and mental health, generating a considerable health burden. Advances in treatment of women with PCOS has been hampered by evolving diagnostic criteria and poor recognition by clinicians. This has resulted in limited clinical and basic research. In this study, we provide insights into the current and future research on the metabolic features of PCOS, specifically as they relate to PCOS-specific insulin resistance (IR), that may affect the most metabolically active tissue, skeletal muscle. Current Knowledge PCOS is a highly heritable condition, yet it is phenotypically heterogeneous in both reproductive and metabolic features. Human studies thus far have not identified molecular mechanisms of PCOS-specific IR in skeletal muscle. However, recent research has provided new insights that implicate energy-sensing pathways regulated via epigenomic and resultant transcriptomic changes. Animal models, while in existence, have been underused in exploring molecular mechanisms of IR in PCOS and specifically in skeletal muscle. Future Directions Based on the latest evidence synthesis and technologies, researchers exploring molecular mechanisms of IR in PCOS, specifically in muscle, will likely need to generate new hypothesis to be tested in human and animal studies. Conclusion Investigations to elucidate the molecular mechanisms driving IR in PCOS are in their early stages, yet remarkable advances have been made in skeletal muscle. Overall, investigations have thus far created more questions than answers, which provide new opportunities to study complex endocrine conditions.

Skeletal Muscle Immunometabolism in Women With Polycystic Ovary Syndrome: A Meta-Analysis

“…Clinical studies and transcriptomics data clearly demonstrate that molecular dysfunction in skeletal muscle contributes to insulin resistance in women with PCOS. Intracellular insulinsignaling pathways, mitochondrial function and fat oxidation, with a possible contribution of reduced adiponectin levels, have all been in focus for the mechanism of insulin resistance in PCOS (Stepto et al, 2019). Here, we identify 99 genes not previously shown to be altered in PCOS muscle, two of them consistently upregulated in all three studies.…”

“…Fibrosis in skeletal muscle can impair muscle function and affect muscle fiber regeneration after injury (Delaney et al, 2017;Mahdy, 2019). Tissue fibrosis is often initiated and maintained through TGF-beta signaling and has been suggested to be associated with insulin resistance and steatosis in PCOS (Petta et al, 2017;Stepto et al, 2019). This association is supported by a recent paper, investigating TGF-beta ligand induced fibrosis in obese women with PCOS (Stepto et al, 2020).…”

Could perturbed fetal development of the ovary contribute to the development of polycystic ovary syndrome in later life?

“…Women with PCOS suffer symptoms of excess androgen (hirsutism, acne, central adiposity), reproductive dysfunction (infertility, menstrual irregularity, miscarriage, pregnancy complications) and metabolic complications [4,5]. Metabolic features include insulin resistance [6], compensatory hyperinsulinaemia and associated risk of obesity [4], gestational diabetes, impaired glucose tolerance, type 2 diabetes, non-alcoholic fatty liver disease, dyslipidaemia, and increased risk factors for cerebro-and cardiovascular disease [4,5,7,8]. Women with PCOS have a four-fold elevated risk of developing type 2 diabetes, irrespective of their BMI, and thus PCOS accounts for a quarter of type 2 diabetes in women of reproductive age [9].…”

Guizhi Fuling Wan, Chinese Herbal Medicine, Ameliorates Insulin Sensitivity in PCOS Model Rats With Insulin Resistance via Remodeling Intestinal Homeostasis

“…Clinical and/or biochemical hyperandrogenemia (HA), oligo-anovulation (OA), and polycystic ovarian morphology (PCOM) are three main characteristics of PCOS, the diagnosis of PCOS, according to the Rotterdam Consensus criteria (2003), requires two of the above (4). In addition to reproductive dysfunction, PCOS patients often have metabolic disturbances characterized by insulin resistance (IR) and display an inflammatory state, with an increased risk of developing type 2 diabetes (T2D), dyslipidemia, hypertension, and cardiovascular disease (5)(6)(7)(8)(9). Besides, PCOS-related insulin resistance and chronic inflammation is independent of obesity (10,11).…”