Excessive insulin receptor serine phosphorylation in cultured fibroblasts and in skeletal muscle. A potential mechanism for insulin resistance in the polycystic ovary syndrome.

Dunaif, A; Xia, J; Book, C B; Schenker, E; Tang, Z

doi:10.1172/jci118126

Cited by 561Ovarian function and disordersMetabolism, Diabetes, and CancerDiabetes, Cardiovascular Risks, and Lipoproteins

Excessive insulin receptor serine phosphorylation in cultured fibroblasts and in skeletal muscle. A potential mechanism for insulin resistance in the polycystic ovary syndrome.

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Dunaif, A, Xia, J, Book, C B, Schenker, E, Tang, Z·1995·Journal of Clinical Investigation

DOI 10.1172/jci118126PMC PMC185266

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Abstract

We investigated the cellular mechanisms of the unique disorder of insulin action found in the polycystic ovary syndrome (PCOS). Approximately 50% of PCOS women (PCOS-Ser) had a significant increase in insulin-independent beta-subunit [32P]phosphate incorporation (3.7-fold, P < 0.05 vs other groups) in skin fibroblast insulin receptors that was present in serine residues while insulin-induced tyrosine phosphorylation was decreased (both P < 0.05 vs other groups). PCOS skeletal muscle insulin receptors had the same abnormal phosphorylation pattern. The remaining PCOS women (PCOS-n1) had basal and insulin-stimulated receptor autophosphorylation similar to control. Phosphorylation of the artificial substrate poly GLU4:TYR1 by the PCOS-Ser insulin receptors was significantly decreased (P < 0.05) compared to control and PCOS-n1 receptors. The factor responsible for excessive serine phosphorylation appeared to be extrinsic to the receptor since no insulin receptor gene mutations were identified, immunoprecipitation before autophosphorylation corrected the phosphorylation defect and control insulin receptors mixed with lectin eluates from affected PCOS fibroblasts displayed increased serine phosphorylation. Our findings suggest that increased insulin receptor serine phosphorylation decreases its protein tyrosine kinase activity and is one mechanism for the post-binding defect in insulin action characteristic of PCOS.

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Insulin resistance associated with PCOS seems to be determined also by alterations at the level of insulin receptor signalling, including increased insulin-independent autophosphorylation associated with reduced receptor activity.
“As shown by Dunaif et al., IR associated with PCOS, seems to be determined also by alterations at the level of the insulin receptor signalling. They observed that insulin receptors isolated from fibroblast cultured and skeletal muscle of women with PCOS presented increased insulin-independent autophosphorylation which is associated with reduced receptor activity [24, 25] and can lead to IR.”
From From Prediabetes to Type 2 Diabetes Mellitus in Women with Polycystic Ovary Syndrome: Lifestyle and Pharmacological Management (2020) · cites this paper as [24]

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Self-citation

Authors: Dunaif, A., Xia, J., Book, C. B., Schenker, E., & Tang, Z.
Affiliations: Pennsylvania State University (US)
ORCID: Dunaif, A
Schenker, E
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 1995-08-01
Volume: 96
Issue: 2
Pages: 801-810
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci118126
PMC: PMC185266
OpenAlex: W2124838987
Cited by: 561
References: 71
Citations by year: 2026: 3 · 2025: 15 · 2024: 7 · 2023: 17 · 2022: 20 · 2021: 18 · 2020: 15 · 2019: 6 · 2018: 9 · 2017: 13 · 2016: 8 · 2015: 19 · 2014: 18 · 2013: 23 · 2012: 21
FWCI: 18.65
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Clinical Investigation (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK040605, R01 DK-40605)
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, insulin receptor, serine phosphorylation, tyrosine phosphorylation, receptor autophosphorylation, protein tyrosine kinase activity, dermal fibroblasts, skeletal muscle, insulin signaling
MeSH terms: Adult, Blood Glucose, Cells, Cultured, Diabetes Mellitus, Type 2, Female, Fibroblasts, Humans, Insulin, Insulin Resistance, Obesity, Peptides, Phosphorylation, Phosphoserine, Polycystic Ovary Syndrome, Protein Processing, Post-Translational, Receptor, Insulin, Skin, Protein Serine-Threonine Kinases, Muscle, Skeletal, Intercellular Signaling Peptides and Proteins

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Excessive insulin receptor serine phosphorylation in cultured fibroblasts and in skeletal muscle. A potential mechanism for insulin resistance in the polycystic ovary syndrome.

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