Insulin resistance in polycystic ovary syndrome is associated with defective regulation of ERK1/2 by insulin in skeletal muscle in vivo
Résumé
Insulin resistance is a recognised feature of polycystic ovary syndrome (PCOS). However, the molecular reason(s) underlying this reduced cellular insulin sensitivity is not clear. This 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, insulin receptor substrate-1 (IRS1), protein kinase-B (PKB) and extracellular regulated protein kinase (ERK1/ERK2). There was no significant difference in the expression, basal activity, or activation of IRS1 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 PCOS women (the two most obese), and an accompanying trend towards higher basal phosphorylation of ERK1/2 in PCOS. These data are striking in that the metabolic actions of insulin are widely believed to require the IRS1-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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