Global assessment of regulation of phosphorylation of insulin receptor substrate-1 by insulin in vivo in human muscle

Zhengping Yi, Paul Langlais, Elena A. De Filippis, Moulun Luo, Charles R. Flynn, Stefanie Schroeder, Susan T. Weintraub, Rebekka Mapes, Lawrence J. Mandarino

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    Abstract

    OBJECTIVE - Research has focused on insulin receptor substrate (IRS)-1 as a locus for insulin resistance. Tyrosine phosphorylation of IRS-1 initiates insulin signaling, whereas serine/threonine phosphorylation alters the ability of IRS-1 to transduce the insulin signal. Of 1,242 amino acids in IRS-1, 242 are serine/threonine. Serine/threonine phosphorylation of IRS-1 is affected by many factors, including insulin. The purpose of this study was to perform global assessment of phosphorylation of serine/threonine residues in IRS-1 in vivo in humans. RESEARCH DESIGN AND METHODS - In this study, we describe our use of capillary high-performance liquid chromotography electrospray tandem mass spectrometry to identify/quantify site-specific phosphorylation of IRS-1 in human vastus lateralis muscle obtained by needle biopsy basally and after insulin infusion in four healthy volunteers. RESULTS - Twenty-two serine/threonine phosphorylation sites were identified; 15 were quantified. Three sites had not been previously identified (Thr495, Ser 527, and S1005). Insulin increased the phosphorylation of Ser312, Ser616, Ser636, Ser892, Ser1101, and Ser1223 (2.6 ± 0.4, 2.9 ± 0.8, 2.1 ± 0.3, 1.6 ± 0.1, 1.3 ± 0.1, and 1.3 ± 0.1-fold, respectively, compared with basal; P < 0.05); phosphorylation of Ser 348, Thr446, Thr495, and Ser1005 decreased (0.4 ± 0.1, 0.2 ± 0.1, 0.1 ± 0.1, and 0.3 ± 0.2-fold, respectively; P < 0.05). CONCLUSIONS - These results provide an assessment of IRS-1 phosphorylation in vivo and show that insulin has profound effects on IRS-1 serine/threonine phosphorylation in healthy humans.

    Original languageEnglish (US)
    Pages (from-to)1508-1516
    Number of pages9
    JournalDiabetes
    Volume56
    Issue number6
    DOIs
    StatePublished - Jun 2007

    Fingerprint

    Insulin Receptor Substrate Proteins
    Phosphorylation
    Insulin
    Threonine
    Muscles
    Serine
    Quadriceps Muscle
    Needle Biopsy
    Tandem Mass Spectrometry
    Tyrosine
    Insulin Resistance
    Healthy Volunteers
    Research Design

    ASJC Scopus subject areas

    • Internal Medicine
    • Endocrinology, Diabetes and Metabolism

    Cite this

    Yi, Z., Langlais, P., De Filippis, E. A., Luo, M., Flynn, C. R., Schroeder, S., ... Mandarino, L. J. (2007). Global assessment of regulation of phosphorylation of insulin receptor substrate-1 by insulin in vivo in human muscle. Diabetes, 56(6), 1508-1516. https://doi.org/10.2337/db06-1355

    Global assessment of regulation of phosphorylation of insulin receptor substrate-1 by insulin in vivo in human muscle. / Yi, Zhengping; Langlais, Paul; De Filippis, Elena A.; Luo, Moulun; Flynn, Charles R.; Schroeder, Stefanie; Weintraub, Susan T.; Mapes, Rebekka; Mandarino, Lawrence J.

    In: Diabetes, Vol. 56, No. 6, 06.2007, p. 1508-1516.

    Research output: Contribution to journalArticle

    Yi, Z, Langlais, P, De Filippis, EA, Luo, M, Flynn, CR, Schroeder, S, Weintraub, ST, Mapes, R & Mandarino, LJ 2007, 'Global assessment of regulation of phosphorylation of insulin receptor substrate-1 by insulin in vivo in human muscle', Diabetes, vol. 56, no. 6, pp. 1508-1516. https://doi.org/10.2337/db06-1355
    Yi, Zhengping ; Langlais, Paul ; De Filippis, Elena A. ; Luo, Moulun ; Flynn, Charles R. ; Schroeder, Stefanie ; Weintraub, Susan T. ; Mapes, Rebekka ; Mandarino, Lawrence J. / Global assessment of regulation of phosphorylation of insulin receptor substrate-1 by insulin in vivo in human muscle. In: Diabetes. 2007 ; Vol. 56, No. 6. pp. 1508-1516.
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    abstract = "OBJECTIVE - Research has focused on insulin receptor substrate (IRS)-1 as a locus for insulin resistance. Tyrosine phosphorylation of IRS-1 initiates insulin signaling, whereas serine/threonine phosphorylation alters the ability of IRS-1 to transduce the insulin signal. Of 1,242 amino acids in IRS-1, 242 are serine/threonine. Serine/threonine phosphorylation of IRS-1 is affected by many factors, including insulin. The purpose of this study was to perform global assessment of phosphorylation of serine/threonine residues in IRS-1 in vivo in humans. RESEARCH DESIGN AND METHODS - In this study, we describe our use of capillary high-performance liquid chromotography electrospray tandem mass spectrometry to identify/quantify site-specific phosphorylation of IRS-1 in human vastus lateralis muscle obtained by needle biopsy basally and after insulin infusion in four healthy volunteers. RESULTS - Twenty-two serine/threonine phosphorylation sites were identified; 15 were quantified. Three sites had not been previously identified (Thr495, Ser 527, and S1005). Insulin increased the phosphorylation of Ser312, Ser616, Ser636, Ser892, Ser1101, and Ser1223 (2.6 ± 0.4, 2.9 ± 0.8, 2.1 ± 0.3, 1.6 ± 0.1, 1.3 ± 0.1, and 1.3 ± 0.1-fold, respectively, compared with basal; P < 0.05); phosphorylation of Ser 348, Thr446, Thr495, and Ser1005 decreased (0.4 ± 0.1, 0.2 ± 0.1, 0.1 ± 0.1, and 0.3 ± 0.2-fold, respectively; P < 0.05). CONCLUSIONS - These results provide an assessment of IRS-1 phosphorylation in vivo and show that insulin has profound effects on IRS-1 serine/threonine phosphorylation in healthy humans.",
    author = "Zhengping Yi and Paul Langlais and {De Filippis}, {Elena A.} and Moulun Luo and Flynn, {Charles R.} and Stefanie Schroeder and Weintraub, {Susan T.} and Rebekka Mapes and Mandarino, {Lawrence J.}",
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    AU - Yi, Zhengping

    AU - Langlais, Paul

    AU - De Filippis, Elena A.

    AU - Luo, Moulun

    AU - Flynn, Charles R.

    AU - Schroeder, Stefanie

    AU - Weintraub, Susan T.

    AU - Mapes, Rebekka

    AU - Mandarino, Lawrence J.

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    N2 - OBJECTIVE - Research has focused on insulin receptor substrate (IRS)-1 as a locus for insulin resistance. Tyrosine phosphorylation of IRS-1 initiates insulin signaling, whereas serine/threonine phosphorylation alters the ability of IRS-1 to transduce the insulin signal. Of 1,242 amino acids in IRS-1, 242 are serine/threonine. Serine/threonine phosphorylation of IRS-1 is affected by many factors, including insulin. The purpose of this study was to perform global assessment of phosphorylation of serine/threonine residues in IRS-1 in vivo in humans. RESEARCH DESIGN AND METHODS - In this study, we describe our use of capillary high-performance liquid chromotography electrospray tandem mass spectrometry to identify/quantify site-specific phosphorylation of IRS-1 in human vastus lateralis muscle obtained by needle biopsy basally and after insulin infusion in four healthy volunteers. RESULTS - Twenty-two serine/threonine phosphorylation sites were identified; 15 were quantified. Three sites had not been previously identified (Thr495, Ser 527, and S1005). Insulin increased the phosphorylation of Ser312, Ser616, Ser636, Ser892, Ser1101, and Ser1223 (2.6 ± 0.4, 2.9 ± 0.8, 2.1 ± 0.3, 1.6 ± 0.1, 1.3 ± 0.1, and 1.3 ± 0.1-fold, respectively, compared with basal; P < 0.05); phosphorylation of Ser 348, Thr446, Thr495, and Ser1005 decreased (0.4 ± 0.1, 0.2 ± 0.1, 0.1 ± 0.1, and 0.3 ± 0.2-fold, respectively; P < 0.05). CONCLUSIONS - These results provide an assessment of IRS-1 phosphorylation in vivo and show that insulin has profound effects on IRS-1 serine/threonine phosphorylation in healthy humans.

    AB - OBJECTIVE - Research has focused on insulin receptor substrate (IRS)-1 as a locus for insulin resistance. Tyrosine phosphorylation of IRS-1 initiates insulin signaling, whereas serine/threonine phosphorylation alters the ability of IRS-1 to transduce the insulin signal. Of 1,242 amino acids in IRS-1, 242 are serine/threonine. Serine/threonine phosphorylation of IRS-1 is affected by many factors, including insulin. The purpose of this study was to perform global assessment of phosphorylation of serine/threonine residues in IRS-1 in vivo in humans. RESEARCH DESIGN AND METHODS - In this study, we describe our use of capillary high-performance liquid chromotography electrospray tandem mass spectrometry to identify/quantify site-specific phosphorylation of IRS-1 in human vastus lateralis muscle obtained by needle biopsy basally and after insulin infusion in four healthy volunteers. RESULTS - Twenty-two serine/threonine phosphorylation sites were identified; 15 were quantified. Three sites had not been previously identified (Thr495, Ser 527, and S1005). Insulin increased the phosphorylation of Ser312, Ser616, Ser636, Ser892, Ser1101, and Ser1223 (2.6 ± 0.4, 2.9 ± 0.8, 2.1 ± 0.3, 1.6 ± 0.1, 1.3 ± 0.1, and 1.3 ± 0.1-fold, respectively, compared with basal; P < 0.05); phosphorylation of Ser 348, Thr446, Thr495, and Ser1005 decreased (0.4 ± 0.1, 0.2 ± 0.1, 0.1 ± 0.1, and 0.3 ± 0.2-fold, respectively; P < 0.05). CONCLUSIONS - These results provide an assessment of IRS-1 phosphorylation in vivo and show that insulin has profound effects on IRS-1 serine/threonine phosphorylation in healthy humans.

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