{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T22:11:43Z","timestamp":1793398303924,"version":"4.5.0"},"reference-count":29,"publisher":"American Physiological Society","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Endocrinology and Metabolism"],"published-print":{"date-parts":[[2008,1]]},"abstract":"<jats:p>Insulin promotes dephosphorylation and activation of glycogen synthase (GS) by inactivating glycogen synthase kinase (GSK) 3 through phosphorylation. Insulin also promotes glucose uptake and glucose 6-phosphate (G-6- P) production, which allosterically activates GS. The relative importance of these two regulatory mechanisms in the activation of GS in vivo is unknown. The aim of this study was to investigate if dephosphorylation of GS mediated via GSK3 is required for normal glycogen synthesis in skeletal muscle with insulin. We employed GSK3 knockin mice in which wild-type GSK3\u03b1 and -\u03b2 genes are replaced with mutant forms (GSK3\u03b1\/\u03b2<jats:sup>S21A\/S21A\/S9A\/S9A<\/jats:sup>), which are nonresponsive to insulin. Although insulin failed to promote dephosphorylation and activation of GS in GSK3\u03b1\/\u03b2<jats:sup>S21A\/S21A\/S9A\/S9A<\/jats:sup>mice, glycogen content in different muscles from these mice was similar compared with wild-type mice. Basal and epinephrine-stimulated activity of muscle glycogen phosphorylase was comparable between wild-type and GSK3 knockin mice. Incubation of isolated soleus muscle in Krebs buffer containing 5.5 mM glucose in the presence or absence of insulin revealed that the levels of G-6- P, the rate of [<jats:sup>14<\/jats:sup>C]glucose incorporation into glycogen, and an increase in total glycogen content were similar between wild-type and GSK3 knockin mice. Injection of glucose containing 2-deoxy-[<jats:sup>3<\/jats:sup>H]glucose and [<jats:sup>14<\/jats:sup>C]glucose also resulted in similar rates of muscle glucose uptake and glycogen synthesis in vivo between wild-type and GSK3 knockin mice. These results suggest that insulin-mediated inhibition of GSK3 is not a rate-limiting step in muscle glycogen synthesis in mice. This suggests that allosteric regulation of GS by G-6- P may play a key role in insulin-stimulated muscle glycogen synthesis in vivo.<\/jats:p>","DOI":"10.1152\/ajpendo.00481.2007","type":"journal-article","created":{"date-parts":[[2007,11,15]],"date-time":"2007-11-15T01:46:29Z","timestamp":1195091189000},"page":"E28-E35","source":"Crossref","is-referenced-by-count":91,"title":["Insulin promotes glycogen synthesis in the absence of GSK3 phosphorylation in skeletal muscle"],"prefix":"10.1152","volume":"294","author":[{"given":"Michale","family":"Bouskila","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael F.","family":"Hirshman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00f8rgen","family":"Jensen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurie J.","family":"Goodyear","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kei","family":"Sakamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"24","reference":[{"key":"R1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.2000.278.2.E234"},{"key":"R2","doi-asserted-by":"crossref","unstructured":"BondarRJ, Mead DC.Evaluation of glucose-6-phosphate dehydrogenase from Leuconostoc mesenteroides in the hexokinase method for determining glucose in serum.Clin Chem20: 586\u2013590, 1974.","DOI":"10.1093\/clinchem\/20.5.586"},{"key":"R3","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-5521(00)00025-9"},{"key":"R4","doi-asserted-by":"publisher","DOI":"10.1098\/rstb.1999.0399"},{"key":"R5","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.18.9660"},{"key":"R6","doi-asserted-by":"publisher","DOI":"10.1042\/bj2280103"},{"key":"R7","doi-asserted-by":"publisher","DOI":"10.1042\/bj3440231"},{"key":"R8","doi-asserted-by":"publisher","DOI":"10.1006\/abbi.2001.2623"},{"key":"R9","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.5.1679"},{"key":"R10","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.52.6.1393"},{"key":"R11","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.25.21.9713-9723.2005"},{"key":"R12","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M605461200"},{"key":"R13","doi-asserted-by":"publisher","DOI":"10.2337\/diab.46.4.541"},{"key":"R14","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.20.10707"},{"key":"R15","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7600633"},{"key":"R16","doi-asserted-by":"publisher","DOI":"10.1111\/j.1432-1033.1982.tb05904.x"},{"key":"R17","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.24.16.7179-7187.2004"},{"key":"R18","doi-asserted-by":"crossref","unstructured":"PedersonBA, Cheng C, Wilson WA, Roach PJ.Regulation of glycogen synthase. 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