BioProject

Recently, abnormalities in mitochondrial oxidative phosphorylation (OXPHOS) have been implicated in the pathogenesis of skeletal muscle insulin resistance in type 2 diabetes. In the present study, we hypothesized that decreased expression of OXPHOS genes could be of similar importance for insulin resistance in the polycystic ovary syndrome (PCOS). Using the HG-U133 Plus 2.0 expression array from Affymetrix, we analyzed gene expression in skeletal muscle from obese women with PCOS (n=16) and age- and body mass index-matched control women (n=13) metabolically characterized by euglycemic-hyperinsulinemic clamp and indirect calorimetry. To identify pathways of importance for the pathogenesis of insulin resistance in PCOS, we performed biological pathway analysis using Gene Set Enrichment Analysis (GSEA 1.0) and Gene Microarray Pathway Profiler (GenMAPP 2.0). The expression of 9 genes, selected according to biological relevance, was evaluated by quantitative real time PCR (q-RT-PCR). Women with PCOS were characterized by fasting hyperinsulinemia and impaired insulin-stimulated glucose disposal - caused by reduced glucose oxidation and storage - as well as impaired suppression of lipid oxidation (all P<0.01). GSEA and GenMAPP both revealed the same set of genes involved in OXPHOS, which was also the most downregulated biological pathway (P<0.01). These results were confirmed by q-RT-PCR of six genes from the OXPHOS gene set as well as three transcription factors known to regulate the transcription of these genes. Our results, for the first time, provide evidence for an association between insulin resistance and impaired mitochondrial oxidative metabolism in skeletal muscle in women with PCOS. This may contribute to the increased risk of type 2 diabetes observed in these women Keywords: PCOS, DNA microarray, global pathway analysis, mitochondrial oxidative metabolism, qantitative real time PCR, insulin resistance, skeletal muscle Overall design: 16 insulin resistant PCOS patients of fertile age were matched to 13 healthy control subjects.