Cited by 119Metabolism, Diabetes, and CancerMuscle metabolism and nutritionCardiovascular and exercise physiology

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

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Treebak, J. T., Frøsig, C., Pehmøller, 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·Diabetologia

DOI 10.1007/s00125-009-1294-yPMC PMC3627047

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Abstract

AIMS/HYPOTHESIS: 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. METHODS: 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. RESULTS: Insulin stimulation increased glucose uptake in both legs, with greater effects (approximately 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. CONCLUSION/INTERPRETATION: 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.

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Authors: Treebak, J. T., Frøsig, C., Pehmøller, 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.
Affiliations: University of Copenhagen (DK)
University of Dundee (GB)
Karolinska Institutet (SE)
Corresponding author: Wojtaszewski, J. F. P.
ORCID: Treebak, J. T.
Pehmøller, C.
Maarbjerg, S. J.
Brandt, N.
MacKintosh, C.
Zierath, J. R.
Hardie, D. G.
Kiens, B.
Richter, E. A.
Pilegaard, H.
Wojtaszewski, J. F. P.
Venue: Diabetologia
Publisher: Springer Science and Business Media LLC
Published: 2009-02-28
Volume: 52
Issue: 5
Pages: 891-900
ISSN: 0012-186X (ISSN-L)
1432-0428
DOI: 10.1007/s00125-009-1294-y
PMC: PMC3627047
OpenAlex: W2000198788
Cited by: 119
References: 47
Citations by year: 2025: 4 · 2024: 4 · 2023: 6 · 2022: 3 · 2021: 8 · 2020: 10 · 2019: 9 · 2018: 5 · 2017: 7 · 2016: 8 · 2015: 9 · 2014: 8 · 2013: 8 · 2012: 10
FWCI: 4.02
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by-nc
creativecommons.org/licenses/by-nc/4.0/ (tdm)
creativecommons.org/licenses/by-nc/4.0/ (vor)
Locations: Diabetologia (publishedVersion, cc-by-nc)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Discovery Research Portal (University of Dundee) (submittedVersion)
Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
Funders: Sundhed og Sygdom, Det Frie Forskningsråd
European Commission (LSHMCT-2004-005272)
Lundbeckfonden
Novo Nordisk
Vetenskapsrådet
Novo Nordisk Fonden
H. Lundbeck A/S
Diabetesforeningen
Medical Research Council
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Health Sciences › Nursing › Nutrition and Dietetics › Muscle metabolism and nutrition
Health Sciences › Medicine › Physiology (medical) › Cardiovascular and exercise physiology
Keywords: TBC1D4, AS160, skeletal muscle glucose uptake, insulin signaling, physical activity, site-specific phosphorylation, 14-3-3 binding, Akt substrates, hyperinsulinemic-euglycemic clamp, glucose transport
MeSH terms: Adipose Tissue, Adult, Biopsy, Blood Glucose, Diet, Humans, Hyperinsulinism, Insulin, Knee Joint, Leg, Male, Oxygen Consumption, Phosphorylation, Rest, Signal Transduction, Exercise, Workload, Supine Position, DNA Primers, Muscle, Skeletal, GTPase-Activating Proteins, Young Adult

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

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