Cited by 114Metabolism, Diabetes, and CancerGlycogen Storage Diseases and MyoclonusMuscle metabolism and nutrition

Muscle glycogen inharmoniously regulates glycogen synthase activity, glucose uptake, and proximal insulin signaling

Jensen, Jørgen, Jebens, Einar, Brennesvik, Erlend O., Ruzzin, Jérôme, Soos, Maria A., Engebretsen, Ellen M. L., O'Rahilly, Stephen, Whitehead, Jonathan P.·2006·American Journal of Physiology-Endocrinology and Metabolism

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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Crossref · 10.1152/ajpendo.00330.2005

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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”

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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
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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