Insulin resistance and the polycystic ovary syndrome revisited: An update on mechanisms and implications

Evanthia Diamanti-Kandarakis, Andrea Dunaif*

*Corresponding author for this work

Research output: Contribution to journalArticle

682 Scopus citations

Abstract

Polycystic ovary syndrome (PCOS) is now recognized as an important metabolic as well as reproductive disorder conferring substantially increased risk for type 2 diabetes. Affected women have marked insulin resistance, independent of obesity. This article summarizes the state of the science since we last reviewed the field in the Endocrine Reviews in 1997. There is general agreement that obese women with PCOS are insulin resistant, but some groups of lean affected women may have normal insulin sensitivity. There is a post-binding defect in receptor signaling likely due to increased receptor and insulin receptor substrate-1 serine phosphorylation that selectively affects metabolic but not mitogenic pathways in classic insulin target tissues and in the ovary. Constitutive activation of serine kinases in the MAPK-ERK pathway may contribute to resistance to insulin's metabolic actions in skeletal muscle. Insulin functions as a co-gonadotropin through its cognate receptor to modulate ovarian steroidogenesis. Genetic disruption of insulin signaling in the brain has indicated that this pathway is important for ovulation and body weight regulation. These insights have been directly translated into a novel therapy for PCOS with insulin-sensitizing drugs. Furthermore, androgens contribute to insulin resistance in PCOS. PCOS may also have developmental origins due to androgen exposure at critical periods or to intrauterine growth restriction. PCOS is a complex genetic disease, and first-degree relatives have reproductive and metabolic phenotypes. Several PCOS genetic susceptibility loci have been mapped and replicated. Some of the same susceptibility genes contribute to disease risk in Chinese and European PCOS populations, suggesting that PCOS is an ancient trait.

Original languageEnglish (US)
Pages (from-to)981-1030
Number of pages50
JournalEndocrine reviews
Volume33
Issue number6
DOIs
StatePublished - Dec 1 2012

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

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