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Potential role of TBC1D4 in enhanced post-exercise insulin action in human skeletal muscle
Open accessAbstract
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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“Studies in humans have also revealed similar findings, whereby 60 minutes of leg extension exercise (80% of maximal exercise capacity) increases TBC1D4 phosphorylation on specific sites (S318, S341, S588, and S751) but not PAS or T642 phosphorylation 4 hours post exercise [77].”
From AMPK and Exercise: Glucose Uptake and Insulin Sensitivity (2013) · cites this paper as [77]
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“In this study, Treebak et al. [77] also found that 14-3-3 binding to TBC1D4 in skeletal muscle was not further enhanced by leg exercise when compared to insulin alone despite increased insulin-stimulated glucose uptake following exercise, suggesting that insulin sensitivity following exercise may not involve 14-3-3 binding to TBC1D4.”
From AMPK and Exercise: Glucose Uptake and Insulin Sensitivity (2013) · cites this paper as [77]
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Citations
Cites
Insulin-stimulated Phosphorylation of a Rab GTPase-activating Protein Regulates GLUT4 Translocation
Sano, H., Kane, S., Sano, E., Mı̂inea, C. P., Asara, J. M., Lane, W. S., Garner, C. W., & Lienhard, G. E. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.c300063200 · Cited by 964
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A Method to Identify Serine Kinase Substrates
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Muscle Glucose Metabolism following Exercise in the Rat
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Self-citationMîinea, C. P., Sano, H., Kane, S., Sano, E., Fukuda, M., Peränen, J., Lane, W. S., & Lienhard, G. E. (2005) · Biochemical Journal · doi:10.1042/bj20050887 · Cited by 449
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Self-citationLarance, M., Ramm, G., Stöckli, J., van Dam, E. M., Winata, S. C., Wasinger, V. C., Simpson, F., Graham, M. W., Junutula, J. R., Guilhaus, M., et al. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m503897200 · Cited by 392
Insulin signaling and insulin sensitivity after exercise in human skeletal muscle
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Self-citationEffect of exercise on insulin action in human skeletal muscle
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Self-citationProlonged increase in insulin-stimulated glucose transport in muscle after exercise
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Kjøbsted, R., Hingst, J. R., Fentz, J., Foretz, M., Sanz, M.-N., Pehmøller, C. K., Shum, M., Marette, A., Mounier, R., Treebak, J. T., et al. (2017) · The FASEB Journal · doi:10.1096/fj.201700442r · Cited by 517
Self-citationExercise Promotes Healthy Aging of Skeletal Muscle
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Self-citationA common Greenlandic TBC1D4 variant confers muscle insulin resistance and type 2 diabetes
Moltke, I., Grarup, N., Jørgensen, M. E., Bjerregaard, P., Treebak, J. T., Fumagalli, M., Korneliussen, T. S., Andersen, M. A., Nielsen, T. S., Krarup, N. T., et al. (2014) · Nature · doi:10.1038/nature13425 · Cited by 418
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Metadata
- 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
- Venue
- Diabetologia
- Published
- 2009-02-28
- Volume
- 52
- Issue
- 5
- Pages
- 891-900
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- 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
- 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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