GLUT4 translocation is not impaired after acute exercise in skeletal muscle of women with obesity and polycystic ovary syndrome

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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Mechanisms underlying absent training-induced improvement in insulin action in lean, hyperandrogenic women with polycystic ovary syndrome (PCOS)

10.2337/figshare.12860540 ◽

2020 ◽

Author(s):

Ada Admin ◽

Solvejg L. Hansen ◽

Kirstine N. Bojsen-Møller ◽

Anne-Marie Lundsgaard ◽

Frederikke L. Hendrich ◽

...

Keyword(s):

Skeletal Muscle ◽

Blood Flow ◽

Exercise Training ◽

Polycystic Ovary Syndrome ◽

Glucose Uptake ◽

Insulin Action ◽

Polycystic Ovary ◽

Whole Body ◽

Ovary Syndrome ◽

Leg Blood Flow

Women with polycystic ovary syndrome (PCOS) have been shown to be less insulin sensitive compared with control women, independent of BMI. Training is associated with molecular adaptations in skeletal muscle improving glucose uptake and metabolism in both healthy and type 2 diabetic individuals. In the present study, lean, hyperandrogenic women with PCOS (n=9) and healthy controls (CON, n=9) completed 14 weeks of controlled and supervised exercise training. In CON, the training intervention increased whole body insulin action by 26% and insulin-stimulated leg glucose uptake by 53%, together with increased insulin-stimulated leg blood flow and a more oxidative muscle fiber type distribution. In PCOS, no such changes were found, despite similar training intensity and improvements in maximal oxygen uptake. In skeletal muscle of CON, but not PCOS, training increased GLUT4 and HKII mRNA and protein expressions. These data suggest that the impaired increase in whole body insulin action in women with PCOS with training is caused by an impaired ability to upregulate key glucose handling proteins for insulin-stimulated glucose uptake in skeletal muscle, and insulin-stimulated leg blood flow. Still, other important benefits of exercise training appeared in women with PCOS, including an improvement of the hyperandrogenic state.

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Endothelial dysfunction in hyperandrogenic polycystic ovary syndrome is not explained by either obesity or ectopic fat deposition

Clinical Science ◽

10.1042/cs20130186 ◽

2013 ◽

Vol 126 (1) ◽

pp. 67-74 ◽

Cited By ~ 17

Author(s):

Victoria S. Sprung ◽

Helen Jones ◽

Christopher J. A. Pugh ◽

Nabil F. Aziz ◽

Christina Daousi ◽

...

Keyword(s):

Skeletal Muscle ◽

Endothelial Dysfunction ◽

Polycystic Ovary Syndrome ◽

Disease Risk ◽

Polycystic Ovary ◽

Whole Body ◽

Resonance Spectroscopy ◽

Model Assessment ◽

Ovary Syndrome ◽

Alcoholic Fatty Liver

PCOS (polycystic ovary syndrome) is associated with IR (insulin resistance), increased visceral fat and NAFLD (non-alcoholic fatty liver disease) all of which may contribute to endothelial dysfunction, an early marker of CVD (cardiovascular disease) risk. Our objective was to examine the relationships between endothelial dysfunction in PCOS, the volume of AT (adipose tissue) compartments and the size of intracellular TAG (triacylglycerol) pools in liver and skeletal muscle. A total of 19 women with PCOS (means±S.D.; 26±6 years, 36±5 kg/m2) and 16 control women (31±8 years, 30±6 kg/m2) were recruited. Endothelial function was assessed in the brachial artery using FMD (flow-mediated dilation). VAT (visceral AT) and abdominal SAT (subcutaneous AT) volume were determined by whole body MRI, and liver and skeletal muscle TAG by 1H-MRS (proton magnetic resonance spectroscopy). Cardiorespiratory fitness and HOMA-IR (homoeostasis model assessment of IR) were also determined. Differences between groups were analysed using independent Student's t tests and ANCOVA (analysis of co-variance). FMD was impaired in PCOS by 4.6% [95% CI (confidence interval), 3.0–7.7; P<0.001], and this difference decreased only slightly to 4.2% (95% CI, 2.4–6.1; P<0.001) when FMD was adjusted for individual differences in visceral and SAT and HOMA-IR. This magnitude of impairment was also similar in lean and obese PCOS women. The results suggest that endothelial dysfunction in PCOS is not explained by body fat distribution or volume. FMD might be a useful independent prognostic tool to assess CVD risk in this population.

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Osteosarcopenia in Reproductive-Aged Women with Polycystic Ovary Syndrome: A Multicenter Case-Control Study

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgaa426 ◽

2020 ◽

Vol 105 (9) ◽

pp. e3400-e3414 ◽

Cited By ~ 2

Author(s):

Maryam Kazemi ◽

Brittany Y Jarrett ◽

Stephen A Parry ◽

Anna E Thalacker-Mercer ◽

Kathleen M Hoeger ◽

...

Keyword(s):

Skeletal Muscle ◽

Polycystic Ovary Syndrome ◽

Case Control Study ◽

Polycystic Ovary ◽

Case Control ◽

Mineral Density ◽

Ovary Syndrome ◽

Skeletal Muscle Index ◽

Pcos Group ◽

Control Study

Abstract Context Osteosarcopenia (loss of skeletal muscle and bone mass and/or function usually associated with aging) shares pathophysiological mechanisms with polycystic ovary syndrome (PCOS). However, the relationship between osteosarcopenia and PCOS remains unclear. Objective We evaluated skeletal muscle index% (SMI% = [appendicular muscle mass/weight (kg)] × 100) and bone mineral density (BMD) in PCOS (hyperandrogenism + oligoamenorrhea), and contrasted these musculoskeletal markers against 3 reproductive phenotypes (i): HA (hyperandrogenism + eumenorrhea) (ii); OA (normoandrogenic + oligoamenorrhea) and (iii), controls (normoandrogenic + eumenorrhea). Endocrine predictors of SMI% and BMD were evaluated across the groups. Design, Setting, and Participants Multicenter case-control study of 203 women (18-48 years old) in New York State. Results PCOS group exhibited reduced SMI% (mean [95% confidence interval (CI)]; 26.2% [25.1,27.3] vs 28.8% [27.7,29.8]), lower-extremity SMI% (57.6% [56.7,60.0] vs 62.5% [60.3,64.6]), and BMD (1.11 [1.08,1.14] vs 1.17 [1.14,1.20] g/cm2) compared to controls. PCOS group also had decreased upper (0.72 [0.70,0.74] vs 0.77 [0.75,0.79] g/cm2) and lower (1.13 [1.10,1.16] vs 1.19 [1.16,1.22] g/cm2) limb BMD compared to HA. Matsuda index was lower in PCOS vs controls and positively associated with SMI% in all groups (all Ps ≤ 0.05). Only controls showed associations between insulin-like growth factor (IGF) 1 and upper (r = 0.84) and lower (r = 0.72) limb BMD (all Ps < 0.01). Unlike in PCOS, IGF-binding protein 2 was associated with SMI% in controls (r = 0.45) and HA (r = 0.67), and with upper limb BMD (r = 0.98) in HA (all Ps < 0.05). Conclusions Women with PCOS exhibit early signs of osteosarcopenia when compared to controls likely attributed to disrupted insulin function. Understanding the degree of musculoskeletal deterioration in PCOS is critical for implementing targeted interventions that prevent and delay osteosarcopenia in this clinical population.

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

Frontiers in Physiology ◽

10.3389/fphys.2020.573505 ◽

2020 ◽

Vol 11 ◽

Author(s):

Maria Manti ◽

Elisabet Stener-Victorin ◽

Anna Benrick

Keyword(s):

Skeletal Muscle ◽

Polycystic Ovary Syndrome ◽

Polycystic Ovary ◽

Meta Analysis ◽

Ovary Syndrome

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Intense electroacupuncture normalizes insulin sensitivity, increases muscle GLUT4 content, and improves lipid profile in a rat model of polycystic ovary syndrome

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00323.2010 ◽

2010 ◽

Vol 299 (4) ◽

pp. E551-E559 ◽

Cited By ~ 48

Author(s):

Julia Johansson ◽

Yi Feng ◽

Ruijin Shao ◽

Malin Lönn ◽

Håkan Billig ◽

...

Keyword(s):

Skeletal Muscle ◽

Insulin Sensitivity ◽

Polycystic Ovary Syndrome ◽

Lipid Profile ◽

Muscle Protein ◽

Polycystic Ovary ◽

Low Frequency ◽

Density Lipoprotein ◽

Female Rats ◽

Ovary Syndrome

Polycystic ovary syndrome (PCOS) is associated with hyperandrogenism and insulin resistance, possibly reflecting defects in skeletal muscle and adipocyte insulin signaling. Low-frequency (2 Hz) electroacupuncture (EA) increases insulin sensitivity in female rats with dihydrotestosterone (DHT)-induced PCOS, but the mechanism is unclear. We hypothesized that low-frequency EA regulates mediators involved in skeletal muscle glucose uptake and metabolism and alters the lipid profile in rats with DHT-induced PCOS. To test this hypothesis, we implanted in prepubescent female rats 90-day continuous-release pellets containing DHT (PCOS). At 70 days of age, the rats were randomly subdivided into two groups: one received low-frequency EA (evoking muscle twitches) for 20–25 min five times/wk for 4–5 wk; the other did not. Controls were implanted with pellets containing vehicle only. All three groups were otherwise handled similarly. Lipid profile was measured in fasting blood samples. Insulin sensitivity was determined by euglycemic hyperinsulinemic clamp, soleus muscle protein expression of glucose transporter 4 (GLUT4), and phosphorylated and nonphosphorylated Akt, and Akt substrate of 160 kDa was determined by Western blot analysis and GLUT4 location by immunofluorescence staining. PCOS EA rats had normalized insulin sensitivity, lower levels of total high-density lipoprotein and low-density lipoprotein cholesterol, and increased expression of GLUT4 in different compartments of skeletal muscle compared with PCOS rats. Total weight and body composition did not differ in the groups. Thus, in rats with DHT-induced PCOS, low-frequency EA has systemic and local effects involving intracellular signaling pathways in muscle that may, at least in part, account for the marked improved insulin sensitivity.

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Impaired Insulin Activation and Dephosphorylation of Glycogen Synthase in Skeletal Muscle of Women with Polycystic Ovary Syndrome Is Reversed by Pioglitazone Treatment

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2008-0760 ◽

2008 ◽

Vol 93 (9) ◽

pp. 3618-3626 ◽

Cited By ~ 22

Author(s):

Dorte Glintborg ◽

Kurt Højlund ◽

Nicoline R. Andersen ◽

Bo Falck Hansen ◽

Henning Beck-Nielsen ◽

...

Keyword(s):

Skeletal Muscle ◽

Polycystic Ovary Syndrome ◽

Glycogen Synthase ◽

Polycystic Ovary ◽

Ovary Syndrome ◽

Impaired Insulin ◽

Pioglitazone Treatment

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Defects in insulin receptor signaling in vivo in the polycystic ovary syndrome (PCOS)

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.2001.281.2.e392 ◽

2001 ◽

Vol 281 (2) ◽

pp. E392-E399 ◽

Cited By ~ 192

Author(s):

Andrea Dunaif ◽

Xinqi Wu ◽

Anna Lee ◽

Evanthia Diamanti-Kandarakis

Keyword(s):

Skeletal Muscle ◽

Polycystic Ovary Syndrome ◽

Insulin Receptor ◽

Polycystic Ovary ◽

Regulatory Subunit ◽

Glucose Disposal ◽

Receptor Signaling ◽

Ovary Syndrome ◽

Significant Difference ◽

Insulin Receptor Signaling

Women with polycystic ovary syndrome (PCOS) are insulin resistant secondary to a postbinding defect in insulin signaling. Sequential euglycemic glucose clamp studies at 40 and 400 mU · m−2 · min−1 insulin doses with serial skeletal muscle biopsies were performed in PCOS and age-, weight-, and ethnicity-matched control women. Steady-state insulin levels did not differ, but insulin-mediated glucose disposal was significantly decreased in PCOS women ( P < 0.05). Insulin receptor substrate (IRS)-1-associated phosphatidylinositol 3-kinase (PI 3K) activity was significantly decreased in PCOS ( n = 12) compared with control skeletal muscle ( n = 8; P < 0.05). There was no significant difference in the abundance of IR, IRS-1, or the p85 regulatory subunit of PI 3K in PCOS ( n = 14) compared with control ( n = 12) muscle. The abundance of IRS-2 was significantly increased ( P < 0.05) in PCOS skeletal muscle, suggesting a compensatory change. We conclude that there is a physiologically relevant defect in insulin receptor signaling in PCOS that is independent of obesity and type 2 diabetes mellitus.

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