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.

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Molecular Mechanisms in Skeletal Muscle Underlying Insulin Resistance in Women Who Are Lean With Polycystic Ovary Syndrome

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2018-01771 ◽

2018 ◽

Vol 104 (5) ◽

pp. 1841-1854 ◽

Cited By ~ 11

Author(s):

Solvejg L Hansen ◽

Pernille F Svendsen ◽

Jacob F Jeppesen ◽

Louise D Hoeg ◽

Nicoline R Andersen ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Polycystic Ovary Syndrome ◽

Molecular Mechanisms ◽

Polycystic Ovary ◽

Ovary Syndrome

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Biomediators in Polycystic Ovary Syndrome and Cardiovascular Risk

Biomolecules ◽

10.3390/biom11091350 ◽

2021 ◽

Vol 11 (9) ◽

pp. 1350

Author(s):

Srdan Pandurevic ◽

Djuro Macut ◽

Flaminia Fanelli ◽

Uberto Pagotto ◽

Alessandra Gambineri

Keyword(s):

Insulin Resistance ◽

Polycystic Ovary Syndrome ◽

Molecular Mechanisms ◽

Polycystic Ovary ◽

Clinical Manifestations ◽

Molecular Heterogeneity ◽

Ovary Syndrome ◽

Metabolic Complications ◽

Early Predictors ◽

Cv Disease

Polycystic ovary syndrome (PCOS) is extremely heterogeneous in terms of clinical manifestations. The variability of the syndrome’s phenotype is derived from the genetic and molecular heterogeneity, with a great deal of environmental factors that may have long-term health consequences, such as metabolic and cardiovascular (CV) diseases. There is no doubt that women with PCOS suffer from metabolic complications more than their age-matched counterparts in the general population and at an earlier age. Obesity, low steroid hormone-binding globulin (SHBG), hyperandrogenemia, insulin resistance, and compensatory hyperinsulinemia are biomediators and early predictors of metabolic complications in PCOS. Doubts remain about the real risk of CV diseases in PCOS and the molecular mechanisms at the basis of CV complications. Based on that assumption, this review will present the available evidence on the potential implications of some biomediators, in particular, hyperandrogenism, estrogen-progesterone imbalance, insulin resistance, and low SHBG, in the processes leading to CV disease in PCOS, with the final aim to propose a more accurate CV risk assessment.

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A Narrative Review of Placental Contribution to Adverse Pregnancy Outcomes in Women With Polycystic Ovary Syndrome

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2019-00383 ◽

2019 ◽

Vol 104 (11) ◽

pp. 5299-5315 ◽

Cited By ~ 9

Author(s):

Angela S Kelley ◽

Yolanda R Smith ◽

Vasantha Padmanabhan

Keyword(s):

Insulin Resistance ◽

Polycystic Ovary Syndrome ◽

Pregnancy Complications ◽

Polycystic Ovary ◽

Evidence Synthesis ◽

Developmental Programming ◽

Androgen Excess ◽

Ovary Syndrome ◽

Increased Risk ◽

Adverse Pregnancy

Abstract Context Polycystic ovary syndrome (PCOS) is the most common endocrinopathy of reproductive-aged women. In pregnancy, women with PCOS experience increased risk of miscarriage, gestational diabetes, preeclampsia, and extremes of fetal birth weight, and their offspring are predisposed to reproductive and cardiometabolic dysfunction in adulthood. Pregnancy complications, adverse fetal outcomes, and developmental programming of long-term health risks are known to have placental origins. These findings highlight the plausibility of placental compromise in pregnancies of women with PCOS. Evidence Synthesis A comprehensive PubMed search was performed using terms “polycystic ovary syndrome,” “placenta,” “developmental programming,” “hyperandrogenism,” “androgen excess,” “insulin resistance,” “hyperinsulinemia,” “pregnancy,” and “pregnancy complications” in both human and animal experimental models. Conclusions There is limited human placental research specific to pregnancy of women with PCOS. Gestational androgen excess and insulin resistance are two clinical hallmarks of PCOS that may contribute to placental dysfunction and underlie the higher rates of maternal–fetal complications observed in pregnancies of women with PCOS. Additional research is needed to prevent adverse maternal and developmental outcomes in women with PCOS and their offspring.

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Selenium and Polycystic Ovary Syndrome; Current Knowledge and Future Directions: A Systematic Review

Hormone and Metabolic Research ◽

10.1055/a-0890-6823 ◽

2019 ◽

Vol 51 (05) ◽

pp. 279-287 ◽

Cited By ~ 3

Author(s):

Fatemeh Hajizadeh-Sharafabad ◽

Jalal Moludi ◽

Helda Tutunchi ◽

Ehsaneh Taheri ◽

Azimeh Izadi ◽

...

Keyword(s):

Systematic Review ◽

Insulin Resistance ◽

Polycystic Ovary Syndrome ◽

Current Knowledge ◽

Polycystic Ovary ◽

Therapeutic Effects ◽

Protective Effects ◽

Case Control Studies ◽

Ovary Syndrome ◽

The Impact

AbstractPolycystic ovary syndrome (PCOS), as the most common endocrine disorder in reproductive-aged women, is recognized by hyperandrogenism and insulin resistance. Selenium (Se) potentially possesses therapeutic effects on PCOS due to antioxidant and insulin-like properties. This systematic review evaluates the potential role of Se in the complications of PCOS. A systematic review was performed on published studies reporting the effects of Se on PCOS. Three major databases including PubMed, Scopus, and Google Scholar were searched until December 2018. A total of 7 human studies and two in vitro studies met the inclusion criteria. Two out of three case-control studies showed that serum Se levels tend to decrease in patients with PCOS. Of four studies that evaluated the impact of Se supplementation on insulin resistance, only one study showed protective effects of Se against insulin resistance. Two out of three studies reported the antioxidant effect of Se. Few studies investigating anti-androgenic effect of Se presented controversial results. There were three studies that evaluated the anti-hyperlipidemic effect of Se, of which two surveys indicated the lowering effects of Se on VLDL and LDL-cholesterol. The reviewed studies confirmed inverse relationships between serum Se levels and some androgenic hormones in PCOS. Se is able to attenuate insulin resistance and dyslipidemia. The available data are currently insufficient to support the protective effects of Se on PCOS.

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Insulin resistance in polycystic ovary syndrome is associated with defective regulation of ERK1/2 by insulin in skeletal muscle in vivo

Biochemical Journal ◽

10.1042/bj20082176 ◽

2009 ◽

Vol 418 (3) ◽

pp. 665-671 ◽

Cited By ~ 23

Author(s):

Madhurima Rajkhowa ◽

Sandra Brett ◽

Daniel J. Cuthbertson ◽

Christopher Lipina ◽

Antonio J. Ruiz-Alcaraz ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Insulin Sensitivity ◽

Polycystic Ovary Syndrome ◽

Insulin Signalling ◽

Polycystic Ovary ◽

Insulin Stimulation ◽

Ovary Syndrome ◽

Stimulation Of

Insulin resistance is a recognized feature of PCOS (polycystic ovary syndrome). However, the molecular reason(s) underlying this reduced cellular insulin sensitivity is not clear. The present study compares the major insulin signalling pathways in skeletal muscle isolated from PCOS and controls. We measured whole-body insulin sensitivity and insulin signalling in skeletal muscle biopsies taken before and after acute exposure to hyperinsulinaemia in nine women diagnosed with PCOS and seven controls. We examined the expression, basal activity and response to in vivo insulin stimulation of three signalling molecules within these human muscle samples, namely IRS-1 (insulin receptor substrate-1), PKB (protein kinase B) and ERK (extracellular-signal-regulated kinase) 1/2. There was no significant difference in the expression, basal activity or activation of IRS-1 or PKB between PCOS and control subjects. However, there was a severe attenuation of insulin stimulation of the ERK pathway in muscle from all but two of the women with PCOS (the two most obese), and an accompanying trend towards higher basal phosphorylation of ERK1/2 in PCOS. These results are striking in that the metabolic actions of insulin are widely believed to require the IRS-1/PKB pathway rather than ERK, and the former has been reported as defective in some previous PCOS studies. Most importantly, the molecular defect identified was independent of adiposity. The altered response of ERK to insulin in PCOS was the most obvious signalling defect associated with insulin resistance in muscle from these patients.

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Obesity, but not hyperandrogenism or insulin resistance, predicts skeletal muscle mass in reproductive‐aged women with polycystic ovary syndrome: A systematic review and meta‐analysis of 45 observational studies

Obesity Reviews ◽

10.1111/obr.13255 ◽

2021 ◽

Author(s):

Maryam Kazemi ◽

Roger A. Pierson ◽

Stephen A. Parry ◽

Mojtaba Kaviani ◽

Philip D. Chilibeck

Keyword(s):

Systematic Review ◽

Insulin Resistance ◽

Skeletal Muscle ◽

Polycystic Ovary Syndrome ◽

Observational Studies ◽

Skeletal Muscle Mass ◽

Polycystic Ovary ◽

Meta Analysis ◽

Ovary Syndrome ◽

Reproductive Aged Women

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Molecular Mechanisms of Insulin Resistance in the Polycystic Ovary Syndrome

Contemporary Endocrinology - Androgen Excess Disorders in Women ◽

10.1007/978-1-59745-179-6_26 ◽

2007 ◽

pp. 293-302

Author(s):

Theodore P. Ciaraldi

Keyword(s):

Insulin Resistance ◽

Polycystic Ovary Syndrome ◽

Molecular Mechanisms ◽

Polycystic Ovary ◽

Ovary Syndrome

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Electroacupuncture Mimics Exercise-Induced Changes in Skeletal Muscle Gene Expression in Women With Polycystic Ovary Syndrome

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgaa165 ◽

2020 ◽

Vol 105 (6) ◽

pp. 2027-2041 ◽

Cited By ~ 1

Author(s):

Anna Benrick ◽

Nicolas J Pillon ◽

Emma Nilsson ◽

Eva Lindgren ◽

Anna Krook ◽

...

Keyword(s):

Gene Expression ◽

Skeletal Muscle ◽

Polycystic Ovary Syndrome ◽

Glucose Uptake ◽

Molecular Mechanisms ◽

Polycystic Ovary ◽

Glycogen Synthesis ◽

Whole Body ◽

Ovary Syndrome ◽

Altered Expression

Abstract Context Autonomic nervous system activation mediates the increase in whole-body glucose uptake in response to electroacupuncture but the mechanisms are largely unknown. Objective To identify the molecular mechanisms underlying electroacupuncture-induced glucose uptake in skeletal muscle in insulin-resistant overweight/obese women with and without polycystic ovary syndrome (PCOS). Design/Participants In a case-control study, skeletal muscle biopsies were collected from 15 women with PCOS and 14 controls before and after electroacupuncture. Gene expression and methylation was analyzed using Illumina BeadChips arrays. Results A single bout of electroacupuncture restores metabolic and transcriptional alterations and induces epigenetic changes in skeletal muscle. Transcriptomic analysis revealed 180 unique genes (q < 0.05) whose expression was changed by electroacupuncture, with 95% of the changes towards a healthier phenotype. We identified DNA methylation changes at 304 unique sites (q < 0.20), and these changes correlated with altered expression of 101 genes (P < 0.05). Among the 50 most upregulated genes in response to electroacupuncture, 38% were also upregulated in response to exercise. We identified a subset of genes that were selectively altered by electroacupuncture in women with PCOS. For example, MSX1 and SRNX1 were decreased in muscle tissue of women with PCOS and were increased by electroacupuncture and exercise. siRNA-mediated silencing of these 2 genes in cultured myotubes decreased glycogen synthesis, supporting a role for these genes in glucose homeostasis. Conclusion Our findings provide evidence that electroacupuncture normalizes gene expression in skeletal muscle in a manner similar to acute exercise. Electroacupuncture might therefore be a useful way of assisting those who have difficulties performing exercise.

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