Insulin resistance in polycystic ovary syndrome is associated with defective regulation of ERK1/2 by insulin in skeletal muscle in vivo

Madhurima Rajkhowa, Sandra Brett, Daniel J. Cuthbertson, Christopher Lipina, Antonio J. Ruiz-Alcaraz, Giles E. Thomas, Lisa Logie, John R. Petrie, Calum Sutherland

    Research output: Contribution to journalArticle

    24 Citations (Scopus)

    Abstract

    Insulin resistance is a recognized feature of PCOS (polycystic ovary syndrome). However, the molecular reason(s) underlying this reduced cellular insulin sensitivity is not clear. The present 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 hyper-insulinaemia 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 IRS-1 (insulin receptor substrate-1), PKB (protein kinase B) and ERK (extracellular-signal-regulated kinase) 1/2. There was no significant difference in the expression, basal activity or activation of IRS-1 or PKB between PCOS and control subjects. However, there was it severe attenuation of insulin stimulation of the ERK pathway in muscle from all but two of the women with PCOS (the two most obese), and,in accompanying trend towards. higher basal phosphorylation of ERK 1/2 in PCOS. These results are striking in that the metabolic actions of insulin are widely believed to require the IRS-1/PKB pathway rather than ERK, and the former has been reported its 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.

    Original languageEnglish
    Pages (from-to)665-671
    Number of pages7
    JournalBiochemical Journal
    Volume418
    DOIs
    Publication statusPublished - 15 Mar 2009

    Keywords

    • extracellular-signal-regulated kinase (ERK)
    • human muscle
    • insulin resistance
    • insulin signalling
    • polycystic ovary syndrome (PCOS)
    • protein kinase B (PKB)
    • IMPAIRED GLUCOSE-TOLERANCE
    • PROTEIN-KINASE-B
    • RECEPTOR SUBSTRATE-1
    • SERINE PHOSPHORYLATION
    • MOLECULAR-MECHANISMS
    • DIAGNOSTIC-CRITERIA
    • METABOLIC SYNDROME
    • SYNDROME PCOS
    • WOMEN
    • PREVALENCE

    Cite this

    Rajkhowa, Madhurima ; Brett, Sandra ; Cuthbertson, Daniel J. ; Lipina, Christopher ; Ruiz-Alcaraz, Antonio J. ; Thomas, Giles E. ; Logie, Lisa ; Petrie, John R. ; Sutherland, Calum. / Insulin resistance in polycystic ovary syndrome is associated with defective regulation of ERK1/2 by insulin in skeletal muscle in vivo. In: Biochemical Journal. 2009 ; Vol. 418. pp. 665-671.
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    abstract = "Insulin resistance is a recognized feature of PCOS (polycystic ovary syndrome). However, the molecular reason(s) underlying this reduced cellular insulin sensitivity is not clear. The present 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 hyper-insulinaemia 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 IRS-1 (insulin receptor substrate-1), PKB (protein kinase B) and ERK (extracellular-signal-regulated kinase) 1/2. There was no significant difference in the expression, basal activity or activation of IRS-1 or PKB between PCOS and control subjects. However, there was it severe attenuation of insulin stimulation of the ERK pathway in muscle from all but two of the women with PCOS (the two most obese), and,in accompanying trend towards. higher basal phosphorylation of ERK 1/2 in PCOS. These results are striking in that the metabolic actions of insulin are widely believed to require the IRS-1/PKB pathway rather than ERK, and the former has been reported its 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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    author = "Madhurima Rajkhowa and Sandra Brett and Cuthbertson, {Daniel J.} and Christopher Lipina and Ruiz-Alcaraz, {Antonio J.} and Thomas, {Giles E.} and Lisa Logie and Petrie, {John R.} and Calum Sutherland",
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    Insulin resistance in polycystic ovary syndrome is associated with defective regulation of ERK1/2 by insulin in skeletal muscle in vivo. / Rajkhowa, Madhurima; Brett, Sandra; Cuthbertson, Daniel J.; Lipina, Christopher; Ruiz-Alcaraz, Antonio J.; Thomas, Giles E.; Logie, Lisa; Petrie, John R.; Sutherland, Calum.

    In: Biochemical Journal, Vol. 418, 15.03.2009, p. 665-671.

    Research output: Contribution to journalArticle

    TY - JOUR

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    AU - Rajkhowa, Madhurima

    AU - Brett, Sandra

    AU - Cuthbertson, Daniel J.

    AU - Lipina, Christopher

    AU - Ruiz-Alcaraz, Antonio J.

    AU - Thomas, Giles E.

    AU - Logie, Lisa

    AU - Petrie, John R.

    AU - Sutherland, Calum

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    N2 - Insulin resistance is a recognized feature of PCOS (polycystic ovary syndrome). However, the molecular reason(s) underlying this reduced cellular insulin sensitivity is not clear. The present 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 hyper-insulinaemia 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 IRS-1 (insulin receptor substrate-1), PKB (protein kinase B) and ERK (extracellular-signal-regulated kinase) 1/2. There was no significant difference in the expression, basal activity or activation of IRS-1 or PKB between PCOS and control subjects. However, there was it severe attenuation of insulin stimulation of the ERK pathway in muscle from all but two of the women with PCOS (the two most obese), and,in accompanying trend towards. higher basal phosphorylation of ERK 1/2 in PCOS. These results are striking in that the metabolic actions of insulin are widely believed to require the IRS-1/PKB pathway rather than ERK, and the former has been reported its 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.

    AB - Insulin resistance is a recognized feature of PCOS (polycystic ovary syndrome). However, the molecular reason(s) underlying this reduced cellular insulin sensitivity is not clear. The present 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 hyper-insulinaemia 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 IRS-1 (insulin receptor substrate-1), PKB (protein kinase B) and ERK (extracellular-signal-regulated kinase) 1/2. There was no significant difference in the expression, basal activity or activation of IRS-1 or PKB between PCOS and control subjects. However, there was it severe attenuation of insulin stimulation of the ERK pathway in muscle from all but two of the women with PCOS (the two most obese), and,in accompanying trend towards. higher basal phosphorylation of ERK 1/2 in PCOS. These results are striking in that the metabolic actions of insulin are widely believed to require the IRS-1/PKB pathway rather than ERK, and the former has been reported its 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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    KW - insulin signalling

    KW - polycystic ovary syndrome (PCOS)

    KW - protein kinase B (PKB)

    KW - IMPAIRED GLUCOSE-TOLERANCE

    KW - PROTEIN-KINASE-B

    KW - RECEPTOR SUBSTRATE-1

    KW - SERINE PHOSPHORYLATION

    KW - MOLECULAR-MECHANISMS

    KW - DIAGNOSTIC-CRITERIA

    KW - METABOLIC SYNDROME

    KW - SYNDROME PCOS

    KW - WOMEN

    KW - PREVALENCE

    U2 - 10.1042/BJ20082176

    DO - 10.1042/BJ20082176

    M3 - Article

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    SN - 0264-6021

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