Skeletal muscle mitochondrial function in polycystic ovarian syndrome

Rabøl, Rasmus; Svendsen, Pernille Fog; Skovbro, Mette; Boushel, Robert; Schjerling, Peter; Nilas, Lisbeth; Madsbad, Sten; Dela, Flemming

doi:10.1530/eje-11-0419

Cited by 26 publications

(21 citation statements)

References 22 publications

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“…Discrepancies likely reflect differences in age (16) (range ∼23–60 years) and severity of fasting hyperglycemia/insulinemia between subject pools (17) as well as in the methodologies used to quantify oxidative phosphorylation (18,19). A similar degree of heterogeneity exists in relation to mitochondrial content, with close to an equal number of investigations reporting lower (1,2,7–11) or no difference (3,12–14,20) in insulin-sensitive lean versus insulin-resistant obese subjects. The few studies that attempted to correlate indices of oxidative phosphorylation and/or mitochondrial content with insulin sensitivity did not find a significant relationship (12–14), but one did (8).…”

Section: Introductionmentioning

confidence: 80%

“…A similar degree of heterogeneity exists in relation to mitochondrial content, with close to an equal number of investigations reporting lower (1,2,7–11) or no difference (3,12–14,20) in insulin-sensitive lean versus insulin-resistant obese subjects. The few studies that attempted to correlate indices of oxidative phosphorylation and/or mitochondrial content with insulin sensitivity did not find a significant relationship (12–14), but one did (8). Regarding the second criteria, acutely elevating plasma free fatty acids through lipid infusion (3–6 h) has been shown to transiently depress skeletal muscle insulin sensitivity in humans without affecting mitochondrial function and/or content (21,22).…”

Section: Introductionmentioning

confidence: 80%

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Mitochondrial Respiratory Capacity and Content Are Normal in Young Insulin-Resistant Obese Humans

et al. 2013

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Considerable debate exists about whether alterations in mitochondrial respiratory capacity and/or content play a causal role in the development of insulin resistance during obesity. The current study was undertaken to determine whether such alterations are present during the initial stages of insulin resistance in humans. Young (∼23 years) insulin-sensitive lean and insulin-resistant obese men and women were studied. Insulin resistance was confirmed through an intravenous glucose tolerance test. Measures of mitochondrial respiratory capacity and content as well as H2O2 emitting potential and the cellular redox environment were performed in permeabilized myofibers and primary myotubes prepared from vastus lateralis muscle biopsy specimens. No differences in mitochondrial respiratory function or content were observed between lean and obese subjects, despite elevations in H2O2 emission rates and reductions in cellular glutathione. These findings were apparent in permeabilized myofibers as well as in primary myotubes. The results suggest that reductions in mitochondrial respiratory capacity and content are not required for the initial manifestation of peripheral insulin resistance.

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Section: Introductionmentioning

confidence: 80%

Section: Introductionmentioning

confidence: 80%

Mitochondrial Respiratory Capacity and Content Are Normal in Young Insulin-Resistant Obese Humans

et al. 2013

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“…Muscle mitochondrial oxidation gene expression for oxidative enzymes such as citrate synthase, or ␤-hydroxyacyl-CoA dehydrogenase were similar between women with and without HAS despite worse IR in the women with HAS, and gene expression did not change with exercise training, whereas IR improved (26). Furthermore, neither stage 1 or stage 3 oxidation was different in biopsy samples from women with PCOS compared with controls, again despite worse IR in the women with HAS (48). Mitochondrial function in myotubes grown from women with HAS was identical to controls, whereas the same investigators found abnormalities in myotubes from T2D participants (19,36).…”

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confidence: 87%

“…31 P MRS exercise protocol. Strength testing was done on a custombuilt MR-compatible plantar flexion device with force measurement capability as previously described (3,9,31,48). The force transducer box was connected to an external read-out stage (Omega Engineering, Stamford, CT), and finally to a laptop computer for constant recording of force throughout exercise with DAQ software (Labview, National Instruments, Austin, TX).…”

Section: Mri and Mrsmentioning

confidence: 99%

Peripheral insulin resistance in obese girls with hyperandrogenism is related to oxidative phosphorylation and elevated serum free fatty acids

Cree-Green

Newcomer

Coe

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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Cree-Green M, Newcomer BR, Coe G, Newnes L, Baumgartner A, Brown MS, Pyle L, Reusch JE, Nadeau KJ. Peripheral insulin resistance in obese girls with hyperandrogenism is related to oxidative phosphorylation and elevated serum free fatty acids. 31 phosphorus MR spectroscopy before, during, and after near-maximal isometric calf exercise, and peripheral IR was assessed with an 80 mU·m Ϫ2 ·min Ϫ1 hyperinsulinemic euglycemic clamp. Girls with HAS had higher androgens [free androgen index 7.9(6.6,15.5) vs. 3.5(3.0,4.0), P Ͻ 0.01] and more IR [glucose infusion rate 9.4(7.0, 12,2) vs. 14.5(13.2,15.8) mg·kg lean Ϫ1 ·min Ϫ1 , P Ͻ 0.01]. HAS girls also had increased markers of inflammation including CRP, platelets, and white blood cell count and higher serum free fatty acids during hyperinsulinemia. Mitochondrial oxidative phosphorylation was lower in HAS [0.11(0.06,0.19) vs. 0.18(0.12,0.23) mmol/s, P Ͻ 0.05], although other spectroscopy markers of mitochondrial function were similar between groups. In multivariate analysis of the entire cohort, IR related to androgens, oxidative phosphorylation, and free fatty acid concentrations during hyperinsulinemia. These relationships were present in just the HAS cohort as well. Obese girls with HAS have significant peripheral IR, which is related to elevated androgens and free fatty acids and decreased mitochondrial oxidative phosphorylation. These may provide future options as targets for therapeutic intervention.hyperandrogenism; insulin resistance; mitochondria; obesity; hyperandrogenic syndrome HYPERANDROGENIC SYNDROME (HAS), also known as polycystic ovarian syndrome (PCOS), affects at least 10 -15% of the female population in the United States, with a recent increase in prevalence associated with rising obesity rates (32). Women with HAS have a three-to fourfold increased risk of developing type 2 diabetes (T2D) compared with BMI-matched controls (37, 58). This increased risk is thought to be secondary to long-standing insulin resistance (IR) (37). There is also evidence of IR in youth with HAS (2). Similar to findings in T2D, peripheral IR as assessed with a hyperinsulinemic euglycemic clamp has been well documented in adults with HAS (7, 15), with similar but fewer data in youth (2). However, the mechanism of IR in HAS remains uncertain, and as a result the best treatments for HAS are also unclear.A leading theory explaining IR in T2D includes defects in mitochondrial function in combination with excess serum free fatty acids (FFA), which can cause alterations in intracellular insulin signaling (52). Other potential mechanisms involve altered fat metabolism and inflammation, which have been documented in T2D and HAS but have not been examined in adolescents with HAS (14,25,29,33,54). However, data examining the role of mitochondria in IR in HAS are limited and conflicting. Muscle mitochondrial oxidation gene expression for oxidative enzymes such as citrate synthase, or ␤-hydroxyacyl-CoA dehydrogenase were similar between women with and without HAS despite worse IR in the wom...

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“…PCOS is associated with oxidative stress characterised by increased production of free radicals followed by decreased serum total antioxidant levels even in non-obese women (184). Some data are indicative of increased oxidative stress from mitochondria of peripheral blood leucocytes (185), but this was not confirmed in mitochondria of muscle tissue (186). It has been shown that several circulating markers of oxidative stress are abnormal in women with PCOS, independent of weight excess (187).…”

Section: Role Of Lipo-oxidative Stressmentioning

confidence: 99%

The polycystic ovary syndrome: a position statement from the European Society of Endocrinology

Conway¹,

Dewailly²,

Diamanti-Kandarakis³

et al. 2014

European Journal of Endocrinology

576

492

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Polycystic ovary syndrome (PCOS) is the most common ovarian disorder associated with androgen excess in women, which justifies the growing interest of endocrinologists. Great efforts have been made in the last 2 decades to define the syndrome. The presence of three different definitions for the diagnosis of PCOS reflects the phenotypic heterogeneity of the syndrome. Major criteria are required for the diagnosis, which in turn identifies different phenotypes according to the combination of different criteria. In addition, the relevant impact of metabolic issues, specifically insulin resistance and obesity, on the pathogenesis of PCOS, and the susceptibility to develop earlier than expected glucose intolerance states, including type 2 diabetes, has supported the notion that these aspects should be considered when defining the PCOS phenotype and planning potential therapeutic strategies in an affected subject. This paper offers a critical endocrine and European perspective on the debate on the definition of PCOS and summarises all major aspects related to aetiological factors, including early life events, potentially involved in the development of the disorder. Diagnostic tools of PCOS are also discussed, with emphasis on the laboratory evaluation of androgens and other potential biomarkers of ovarian and metabolic dysfunctions. We have also paid specific attention to the role of obesity, sleep disorders and neuropsychological aspects of PCOS and on the relevant pathogenetic aspects of cardiovascular risk factors. In addition, we have discussed how to target treatment choices based according to the phenotype and individual patient's needs. Finally, we have suggested potential areas of translational and clinical research for the future with specific emphasis on hormonal and metabolic aspects of PCOS.

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Skeletal muscle mitochondrial function in polycystic ovarian syndrome

Cited by 26 publications

References 22 publications

Mitochondrial Respiratory Capacity and Content Are Normal in Young Insulin-Resistant Obese Humans

Mitochondrial Respiratory Capacity and Content Are Normal in Young Insulin-Resistant Obese Humans

Peripheral insulin resistance in obese girls with hyperandrogenism is related to oxidative phosphorylation and elevated serum free fatty acids

The polycystic ovary syndrome: a position statement from the European Society of Endocrinology

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