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In this study, we illustrated that tilorone, a low\u2010molecular\u2010weight antiviral agent, improves glucose uptake in vitro and in vivo. Tilorone increased bone morphogenetic protein (BMP) signaling in C2C12 myoblasts, the transcription of multiple BMPs (BMP2, BMP4, BMP7, and BMP14), Smad4 expression, and the phosphorylation of BMP\u2010mediated Smad1\/5\/8. The activation of Akt2\/AS160\u00a0(TBC1D4) signaling, the critical regulator of GLUT4 translocation, was also increased, as well as the levels of GLUT4 and GLUT1, leading to enhanced uptake of the radioactively labeled glucose analog <jats:sup>18<\/jats:sup>F\u2010fluoro\u20102\u2010deoxyglucose (<jats:sup>18<\/jats:sup>FDG). However, this excess glucose content did not result in increased ATP formation by mitochondrial respiration; both basal and ATP\u2010linked respiration were diminished, thereby contributing to the induction of AMPK. In differentiated myotubes, AS160 phosphorylation and <jats:sup>18<\/jats:sup>FDG uptake also increased. Moreover, tilorone administration further increased insulin\u2010stimulated phosphorylation of Akt2 and glucose uptake of myotubes indicating an insulin\u2010sensitizing effect. Importantly, during in vivo experiments, the systemic administration of tilorone resulted in increased <jats:sup>18<\/jats:sup>FDG uptake of skeletal muscle, liver, and adipose tissue in C57BL\/6 mice. Our results provide new perspectives for the treatment of type 2 diabetes, which has a limited number of treatments that regulate protein expression or translocation.<\/jats:p>","DOI":"10.1002\/jcp.30998","type":"journal-article","created":{"date-parts":[[2023,4,4]],"date-time":"2023-04-04T05:16:31Z","timestamp":1680585391000},"page":"1080-1094","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Tilorone increases glucose uptake in vivo and in skeletal muscle cells by enhancing Akt2\/AS160 signaling and glucose transporter levels"],"prefix":"10.1002","volume":"238","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8299-105X","authenticated-orcid":false,"given":"Zoltan M.","family":"Kohler","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Albert Szent\u2010Gyorgyi Medical School University of Szeged Szeged 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