Insulin resistance in the skeletal muscle of women with PCOS involves intrinsic and acquired defects in insulin signaling

Anne Corbould, Young Bum Kim, Jack F. Youngren, Celia Pender, Barbara B. Kahn, Anna Lee, Andrea Dunaif*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

178 Scopus citations

Abstract

Insulin resistance in polycystic ovary syndrome (PCOS) is due to a postbinding defect in signaling that persists in cultured skin fibroblasts and is associated with constitutive serine phosphorylation of the insulin receptor (IR). Cultured skeletal muscle from obese women with PCOS and age- and body mass index-matched control women (n = 10/group) was studied to determine whether signaling defects observed in this tissue in vivo were intrinsic or acquired. Basal and insulin-stimulated glucose transport and GLUT1 abundance were significantly increased in cultured myotubes from women with PCOS. Neither IR β-subunit abundance and tyrosine autophosphorylation nor insulin receptor substrate (IRS)-1-associated phosphatidylinositol (PI) 3-kinase activity differed in the two groups. However, IRS-1 protein abundance was significantly increased in PCOS, resulting in significantly decreased PI 3-kinase activity when normalized for IRS-1. Phosphorylation of IRS-1 on Ser312, a key regulatory site, was significantly increased in PCOS, which may have contributed to this signaling defect. Insulin signaling via IRS-2 was also decreased in myotubes from women with PCOS. In summary, decreased insulin-stimulated glucose uptake in PCOS skeletal muscle in vivo is an acquired defect. Nevertheless, there are intrinsic abnormalities in glucose transport and insulin signaling in myotubes from affected women, including increased phosphorylation of IRS-1 Ser312, that may confer increased susceptibility to insulin resistance-inducing factors in the in vivo environment. These abnormalities differ from those reported in other insulin resistant states consistent with the hypothesis that PCOS is a genetically unique disorder conferring an increased risk for type 2 diabetes.

Original languageEnglish (US)
Pages (from-to)E1047-E1054
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume288
Issue number5 51-5
DOIs
StatePublished - May 2005

Keywords

  • Glucose transport
  • Glucose transporter 1
  • Insulin receptor substrate
  • Myotubes
  • Polycystic ovary syndrome
  • Serine phosphorylation

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)

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