Muscle glycogen inharmoniously regulates glycogen synthase activity, glucose uptake, and proximal insulin signaling
Abstract
Insulin-stimulated glucose uptake and incorporation of glucose into skeletal muscle glycogen contribute to physiological regulation of blood glucose concentration. In the present study, glucose handling and insulin signaling in isolated rat muscles with low glycogen (LG, 24-h fasting) and high glycogen (HG, refed for 24 h) content were compared with muscles with normal glycogen (NG, rats kept on their normal diet). In LG, basal and insulin-stimulated glycogen synthesis and glycogen synthase activation were higher and glycogen synthase phosphorylation (Ser 645, Ser 649, Ser 653, Ser 657) lower than in NG. GLUT4 expression, insulin-stimulated glucose uptake, and PKB phosphorylation were higher in LG than in NG, whereas insulin receptor tyrosyl phosphorylation, insulin receptor substrate-1-associated phosphatidylinositol 3-kinase activity, and GSK-3 phosphorylation were unchanged. Muscles with HG showed lower insulin-stimulated glycogen synthesis and glycogen synthase activation than NG despite similar dephosphorylation. Insulin signaling, glucose uptake, and GLUT4 expression were similar in HG and NG. This discordant regulation of glucose uptake and glycogen synthesis in HG resulted in higher insulin-stimulated glucose 6-phosphate concentration, higher glycolytic flux, and intracellular accumulation of nonphosphorylated 2-deoxyglucose. In conclusion, elevated glycogen synthase activation, glucose uptake, and GLUT4 expression enhance glycogen resynthesis in muscles with low glycogen. High glycogen concentration per se does not impair proximal insulin signaling or glucose uptake. “Insulin resistance” is observed at the level of glycogen synthase, and the reduced glycogen synthesis leads to increased levels of glucose 6-phosphate, glycolytic flux, and accumulation of nonphosphorylated 2-deoxyglucose.
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Muscle glycogen availability is inversely related to muscle cell membrane GLUT4 content during insulin stimulation, glycogen synthase activity, GLUT4 mRNA expression, and hence insulin sensitivity.
“This hypothesis is based on evidence that muscle glycogen availability is inversely related to muscle cell membrane GLUT4 content during insulin stimulation (Derave et al. 2000), glycogen synthase activity (Jensen et al. 2006), the expression of GLUT4 mRNA (Steinberg et al. 2006), and hence insulin sensitivity (Derave et al. 2000;Jensen et al. 2006;Kawanaka et al. 2000;Laurent et al. 2000;Lither”
From Towards the minimal amount of exercise for improving metabolic health: beneficial effects of reduced-exertion high-intensity interval training (2012) · cites this paper as Jensen et al. 2006
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Self-citationEffect of supramaximal exercise training on metabolic outcomes in obese adults
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Role of AMP-Activated Protein Kinase for Regulating Post-exercise Insulin Sensitivity
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A Transcriptomic Approach to Search for Novel Phenotypic Regulators in McArdle Disease
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Friedrichsen, M. H., Birk, J. B., Richter, E. A., Ribel‐Madsen, R., Pehmøller, C. K., Hansen, B. F., Beck‐Nielsen, H., Hirshman, M. F., Goodyear, L. J., Vaag, A. A., et al. (2013) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00494.2012 · Cited by 21 · see citing works
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Phenotype consequences of myophosphorylase dysfunction: insights from the McArdle mouse model
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Skeletal Muscle Consequences of Phosphatidylethanolamine Synthesis Deficiency
Grapentine, S., Singh, R. K., & Bakovic, M. (2023) · Function · doi:10.1093/function/zqad020 · Cited by 18 · see citing works
The evolution of insulin resistance in muscle of the glucose infused rat
Brandon, A. E., Hoy, A. J., Wright, L. E., Turner, N. A., Hegarty, B. D., Iseli, T. J., Xu, X. J., Cooney, G. J., Saha, A. K., Ruderman, N. B., et al. (2011) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2011.03.008 · Cited by 17 · see citing works
Montori-Grau, M., Minor, R. K., Lerín, C., Allard, J. S., Garcia‐Martínez, C., de Cabo, R., & Gómèz‐Foix, A. M. (2009) · Experimental Gerontology · doi:10.1016/j.exger.2009.03.005 · Cited by 17 · see citing works
Lai, Y., Lin, F. ‐., & Jensen, J. (2009) · Acta Physiologica · doi:10.1111/j.1748-1716.2009.01998.x · Cited by 17 · see citing works
Self-citationMontori-Grau, M., Tarrats, N., Osorio-Conles, Ó., Orozco, A., Serrano-Marco, L., Vázquez-Carrera, M., & Gómez-Foix, A. M. (2013) · Cellular Signalling · doi:10.1016/j.cellsig.2013.02.014 · Cited by 17 · see citing works
AMPK is required for exercise to enhance insulin sensitivity in skeletal muscles
Jensen, J., & O’Rahilly, S. (2017) · Molecular Metabolism · doi:10.1016/j.molmet.2017.01.012 · Cited by 15 · see citing works
Self-citationRole of glycogen content in insulin resistance in human muscle cells
Litherland, G. J., Morris, N. J., Walker, M., & Yeaman, S. J. (2006) · Journal of Cellular Physiology · doi:10.1002/jcp.20942 · Cited by 16 · see citing works
Scheffler, T. L., Park, S., Roach, P. J., & Gerrard, D. E. (2016) · Physiological Reports · doi:10.14814/phy2.12802 · Cited by 14 · see citing works
Jensen, J., Grønning-Wang, L. M., Jebens, E., Whitehead, J. P., Zorec, R., & Shepherd, P. R. (2008) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-008-0471-z · Cited by 14 · see citing works
Self-citationJabbour, G., & Iancu, H.-D. (2017) · BMJ Open Sport & Exercise Medicine · doi:10.1136/bmjsem-2017-000283 · Cited by 13 · see citing works
Discipline-specific insulin sensitivity in athletes
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Jelstad, S., Valsdottir, T. D., Johansen, E. I., & Jensen, J. (2019) · Archives of Physiology and Biochemistry · doi:10.1080/13813455.2018.1563189 · Cited by 12 · see citing works
Self-citationImprovement of Endurance of DMD Animal Model Using Natural Polyphenols
Sitzia, C., Farini, A., Colleoni, F., Fortunato, F., Razini, P., Erratico, S., Tavelli, A., Fabrizi, F., Belicchi, M., Meregalli, M., et al. (2015) · BioMed Research International · doi:10.1155/2015/680615 · Cited by 11 · see citing works
Kido, K., Egawa, T., Watanabe, S., Kawanaka, K., Treebak, J. T., & Hayashi, T. (2022) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00412.2021 · Cited by 10 · see citing works
Nanoparticle zinc oxide obviates oxidative stress of liver cells in induced-diabetes mellitus model
Elmetwalli, A., Hassan, J., Alaa, H., Hassan, M. S., Ali, M. A., Eltayeb, M., Mousa, E., Salah, M., Abdelaziz, M., Taha, K., et al. (2022) · Medical Journal of Viral Hepatitis /Medical Journal of Viral Hepatitis · doi:10.21608/mjvh.2022.279331 · Cited by 10 · see citing works
Regulation of glycogen synthase in muscle and its role in Type 2 diabetes
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Lin, F. C., Bolling, A., Stuenæs, J. T., Cumming, K. T., Ingvaldsen, A., Lai, Y., Ivy, J. L., & Jensen, J. (2012) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00430.2011 · Cited by 9 · see citing works
Self-citationRendimiento deportivo: glucógeno muscular y consumo proteico
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Adipocyte-derived factor reduces vasodilatory capability in ob−/ob− mice
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Measurement of Insulin Sensitivity in Skeletal Muscle In Vitro
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Self-citationLiver, but Not Muscle, Has an Entrainable Metabolic Memory
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Temporal changes in glycogenolytic enzyme mRNAs during myogenesis of primary porcine satellite cells
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GLUCOSAMINE REDUCES GLYCOGEN STORAGE IN L6 SKELETAL MUSCLE CELLS
Munoz, N. E. (2007) · Cited by 1 · see citing works
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Саркопенія при цукровому діабеті 2-го типу (огляд і власні спостереження)
Гончарова, О. А. (2017) · INTERNATIONAL JOURNAL OF ENDOCRINOLOGY (Ukraine) · doi:10.22141/2224-0721.13.2.2017.100611 · Cited by 1 · see citing works
- Authors
- Jensen, J., Jebens, E., Brennesvik, E. O., Ruzzin, J., Soos, M. A., Engebretsen, E. M. L., O'Rahilly, S., & Whitehead, J. P.
- Affiliations
- National Institute of Occupational Health (NO)
- Venue
- American Journal of Physiology-Endocrinology and Metabolism
- Publisher
- American Physiological Society
- Published
- 2006-01
- Volume
- 290
- Issue
- 1
- Pages
- E154-E162
- ISSN
- 0193-1849 (ISSN-L)
- 1522-1555
- OpenAlex
- W2107938341
- Cited by
- 114
- References
- 45
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 2 · 2023: 3 · 2022: 6 · 2021: 2 · 2020: 3 · 2019: 3 · 2018: 4 · 2017: 4 · 2016: 5 · 2015: 6 · 2014: 3 · 2013: 4 · 2012: 10
- FWCI
- 2.89
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Physiology-Endocrinology and Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- European Commission
- Norges Forskningsråd
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Rheumatology › Glycogen Storage Diseases and Myoclonus
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Muscle metabolism and nutrition
- Keywords
- skeletal muscle glycogen, glycogen synthase, glycogen synthase phosphorylation, insulin signaling, glucose uptake, GLUT4, glycogen resynthesis, insulin resistance, glucose-6-phosphate, glycolytic flux, IRS-1, phosphatidylinositol 3-kinase, glycogen synthase kinase-3, fasting and refeeding, blood glucose regulation
- MeSH terms
- Glycogen Synthase Kinase 3 beta, Animals, Deoxyglucose, Fasting, Glucose, Glycogen, Glycogen Synthase, Glycolysis, Insulin, Male, Phosphorylation, Receptor, Insulin, Signal Transduction, Rats, Wistar, Muscle, Skeletal, Glucose-6-Phosphate, Glycogen Synthase Kinase 3, Proto-Oncogene Proteins c-akt, Glucose Transporter Type 1, Glucose Transporter Type 4, Rats
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