Reduced expression of nuclear-encoded genes involved in mitochondrial oxidative metabolism in skeletal muscle of insulin-resistant women with polycystic ovary syndrome
Reduced expression of nuclear-encoded genes involved in mitochondrial oxidative metabolism in skeletal muscle of insulin-resistant women with polycystic ovary syndrome
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DOI：
10.2337/db07-0275
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发表时间：
2007-09-01
期刊：
影响因子：
7.7
通讯作者：
Hojlund, Kurt
中科院分区：
文献类型：
--
作者：
Skov, Vibe;Glintborg, Dorte;Hojlund, Kurt
骨骼肌中的胰岛素抵抗是多囊卵巢综合征(PCOS)女性患2型糖尿病的主要危险因素。在2型糖尿病患者中，骨骼肌的胰岛素抵抗与胰岛素信号、脂肪酸代谢和线粒体氧化磷酸化(OXPHOS)的异常有关。在多囊卵巢综合征患者中，分子机制。然而，胰岛素抵抗的特征并不是很好。为了确定PCOS胰岛素抵抗发病机制中的重要生物学途径，我们使用两种不同的全局途径分析方法比较了具有代谢特征的PCOS患者(n=16)和健康对照组(n=13)骨骼肌中的基因表达：基因集丰富分析(GSEA 1.0)和基因图谱注释和途径分析(GenMAPP 2.0)。我们使用GSEA和GenMAPP分析证明，PCOS患者胰岛素刺激的总糖、氧化糖和非氧化糖代谢受损与OXPHOS基因表达的持续下调有关。实时定量聚合酶链式反应分析证实了这些发现，并表明PGC-1α在PCOS中OXPHOS基因下调中可能起到一定作用。在这些患有多囊卵巢综合征的女性中，骨骼肌中OXPHOS基因表达的减少不能归因于肥胖和糖尿病。这支持了胰岛素抵抗和线粒体氧化代谢受损之间存在早期关联的假说，线粒体氧化代谢受损的部分原因是PGC-1α水平降低。这些异常可能导致在患有多囊卵巢综合征的女性中观察到的2型糖尿病风险增加。
Insulin resistance in skeletal muscle is a major risk factor for the development of type 2 diabetes in women with polycystic ovary syndrome (PCOS). In patients with type 2 diabetes, insulin resistance in skeletal muscle is associated with abnormalities in insulin signaling, fatty acid metabolism, and mitochondrial oxidative phosphorylation (OXPHOS). In PCOS patients, the molecular mechanisms. of insulin resistance are, however, less well characterized. To identify biological pathways of importance for the pathogenesis of insulin resistance in PCOS, we compared gene expression in skeletal muscle of metabolically characterized PCOS patients (n = 16) and healthy control subjects (n = 13) using two different approaches for global pathway analysis: gene set enrichment analysis (GSEA 1.0) and gene map annotator and pathway profiler (GenMAPP 2.0). We demonstrate that impaired insulin-stimulated total, oxidative and nonoxidative glucose disposal in PCOS patients are associated with a consistent downregulation of OXPHOS gene expression using GSEA and GenMAPP analysis. Quantitative real-time PCR analysis validated these findings and showed that reduced levels of peroxisome proliferator-activated receptor gamma coactivator a (PGC-1 alpha) could play a role in the downregulation of OXPHOS genes in PCOS. In these women with PCOS, the decrease in OXPHOS gene expression in skeletal muscle cannot be ascribed to obesity and diabetes. This supports the hypothesis of an early association between insulin resistance and impaired mitochondrial oxidative metabolism, which is, in part, mediated by reduced PGC-1 alpha levels. These abnormalities may contribute to the increased risk of type 2 diabetes observed in women with PCOS.