Insulin resistance in the skeletal muscle of women with PCOS involves intrinsic and acquired defects in insulin signaling
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 Ser 312 , 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 Ser 312 , 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.
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Other abnormalities in downstream pathways, such as serine phosphorylation of insulin receptor substrates, inhibit binding with PI3K and prevent propagation of the signal downstream.
“However, other abnormalities have been observed also in downstream pathways, such as the serine phosphorylation of the insulin receptor substrates which inhibits its binding with PI3K and prevents the propagation of the signal downstream [26, 27].”
From From Prediabetes to Type 2 Diabetes Mellitus in Women with Polycystic Ovary Syndrome: Lifestyle and Pharmacological Management (2020) · cites this paper as [27]
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- Authors
- Corbould, A., Kim, Y.-B., Youngren, J. F., Pender, C., Kahn, B. B., Lee, A., & Dunaif, A.
- Affiliations
- Brigham and Women's Hospital (US)
- Harvard University (US)
- University of California, San Francisco (US)
- Venue
- American Journal of Physiology-Endocrinology and Metabolism
- Publisher
- American Physiological Society
- Published
- 2005-05
- Volume
- 288
- Issue
- 5
- Pages
- E1047-E1054
- ISSN
- 0193-1849 (ISSN-L)
- 1522-1555
- OpenAlex
- W2152304127
- Cited by
- 283
- References
- 57
- Citations by year
- 2026: 11 · 2025: 14 · 2024: 10 · 2023: 18 · 2022: 15 · 2021: 17 · 2020: 22 · 2019: 11 · 2018: 10 · 2017: 5 · 2016: 11 · 2015: 12 · 2014: 14 · 2013: 11 · 2012: 14
- FWCI
- 12.34
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Physiology-Endocrinology and Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK057521, R01 DK43051, R01DK040605, P30DK57521, R01 DK-40605, R01DK043051)
- National Center for Research Resources (RR02635, M01RR002635)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54-HD34449, U54HD034449)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Ovarian function and disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- polycystic ovary syndrome, insulin resistance, skeletal muscle, insulin signaling, insulin receptor, insulin receptor substrate 2, PI3-kinase, glucose transport, GLUT1, myotubes, type 2 diabetes risk
- MeSH terms
- Adult, Cells, Cultured, Female, Glucose, Humans, Insulin, Insulin Resistance, Polycystic Ovary Syndrome, Receptor, Insulin, Signal Transduction, Muscle, Skeletal, Muscle Fibers, Skeletal
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