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1 Department of Physiology, National Institute of Occupational Health, Oslo, Norway
2 Department of Medicine and Clinical Biochemistry, University of Cambridge, Cambridge, United Kingdom
3 Department of Medicine and Clinical Biochemistry, University of Cambridge, Cambridge, United Kingdom; Centre for Diabetes and Endocrine Research, University of Queensland, Brisbane, Australia
* To whom correspondence should be addressed. E-mail: jorgen.jensen{at}stami.no.
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 signalling in isolated rat muscles with low glycogen (LG -24 hours fasting) and high glycogen content (HG -refed for 24 hours) were compared to 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 (Ser645, Ser649, Ser653, Ser657) 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, IRS-1 associated PI 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 signalling, 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 non-phosphorylated 2-deoxyglucose. In conclusion, elevated glycogen synthase activation, glucose uptake, and GLUT4 expression enhances glycogen resynthesis in muscles with low glycogen. High glycogen concentration per se does not impair proximal insulin signalling 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 non-phosphorylated 2-deoxyglucose.
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