Potential role of TBC1D4 in enhanced post-exercise insulin action in human skeletal muscle

J. T. Treebak, C. Frosig, C. Pehmoller, S. Chen, S. J. Maarbjerg, N. Brandt, C. MacKintosh, J. R. Zierath, D. G. Hardie, B. Kiens, E. A. Richter, H. Pilegaard, J. F. P. Wojtaszewski

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    Abstract

    TBC1 domain family, member 4 (TBC1D4; also known as AS160) is a cellular signalling intermediate to glucose transport regulated by insulin-dependent and -independent mechanisms. Skeletal muscle insulin sensitivity is increased after acute exercise by an unknown mechanism that does not involve modulation at proximal insulin signalling intermediates. We hypothesised that signalling through TBC1D4 is involved in this effect of exercise as it is a common signalling element for insulin and exercise.

    Insulin-regulated glucose metabolism was evaluated in 12 healthy moderately trained young men 4 h after one-legged exercise at basal and during a euglycaemic-hyperinsulinaemic clamp. Vastus lateralis biopsies were taken before and immediately after the clamp.

    Insulin stimulation increased glucose uptake in both legs, with greater effects (similar to 80%, p < 0.01) in the previously exercised leg. TBC1D4 phosphorylation, assessed using the phospho-AKT (protein kinase B)substrate antibody and phospho- and site-specific antibodies targeting six phosphorylation sites on TBC1D4, increased at similar degrees to insulin stimulation in the previously exercised and rested legs (p < 0.01). However, TBC1D4 phosphorylation on Ser-318, Ser-341, Ser-588 and Ser-751 was higher in the previously exercised leg, both in the absence and in the presence of insulin (p < 0.01; Ser-588, p = 0.09; observed power = 0.39). 14-3-3 binding capacity for TBC1D4 increased equally (p < 0.01) in both legs during insulin stimulation.

    We provide evidence for site-specific phosphorylation of TBC1D4 in human skeletal muscle in response to physiological hyperinsulinaemia. The data support the idea that TBC1D4 is a nexus for insulin- and exercise-responsive signals that may mediate increased insulin action after exercise.

    Original languageEnglish
    Pages (from-to)891-900
    Number of pages10
    JournalDiabetologia
    Volume52
    Issue number5
    DOIs
    Publication statusPublished - 2009

    Keywords

    • AKTsubstrate of 160 kDa
    • AS160
    • Glucose metabolism
    • TBC1D1
    • GTPASE-ACTIVATING PROTEIN
    • STIMULATED GLUCOSE-TRANSPORT
    • 160 KDA AS160
    • AKT SUBSTRATE
    • GLUT4 TRANSLOCATION
    • 14-3-3 BINDING
    • KINASE-C
    • EXERCISE
    • PHOSPHORYLATION
    • CONTRACTION

    Cite this

    Treebak, J. T., Frosig, C., Pehmoller, C., Chen, S., Maarbjerg, S. J., Brandt, N., MacKintosh, C., Zierath, J. R., Hardie, D. G., Kiens, B., Richter, E. A., Pilegaard, H., & Wojtaszewski, J. F. P. (2009). Potential role of TBC1D4 in enhanced post-exercise insulin action in human skeletal muscle. Diabetologia, 52(5), 891-900. https://doi.org/10.1007/s00125-009-1294-y