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In this study, we administered rosuvastatin (10\u00a0mg\/kg body weight) to male C57BL\/6J mice for 12\u00a0weeks and found that oral rosuvastatin dramatically reduced intraperitoneal glucose tolerance. Rosuvastatin\u2010treated mice showed considerably higher serum levels of branched\u2010chain amino acids (BCAAs) than control mice. They also showed dramatically altered expression of BCAA catabolism\u2010related enzymes in white adipose tissue and skeletal muscle, including downregulated mRNA expression of <jats:italic>BCAT2<\/jats:italic> and protein phosphatase 2Cm (<jats:italic>PP2Cm<\/jats:italic>) and upregulated mRNA expression of branched\u2010chain ketoacid dehydrogenase kinase (<jats:italic>BCKDK<\/jats:italic>). The levels of BCKD in the skeletal muscle were reduced in rosuvastatin\u2010treated mice, which was associated with lower PP2Cm protein levels and increased BCKDK levels. We also investigated the effects of rosuvastatin and insulin administration on glucose metabolism and BCAA catabolism in C2C12 myoblasts. We observed that incubation with insulin enhanced glucose uptake and facilitated BCAA catabolism in C2C12 cells, which was accompanied by elevated Akt and glycogen synthase kinase 3 \u03b2 (GSK3\u03b2) phosphorylation. These effects of insulin were prevented by co\u2010incubation of the cells with 25\u00a0\u03bcM rosuvastatin. Moreover, the effects of insulin and rosuvastatin administration on glucose uptake and Akt and GSK3\u03b2 signaling in C2C12 cells were abolished when PP2Cm was knocked down. Although the relevance of these data, obtained with high doses of rosuvastatin in mice, to therapeutic doses in humans remains to be elucidated, this study highlights a potential mechanism for the diabetogenic effects of rosuvastatin, and suggests that BCAA catabolism could be a pharmacological target for preventing the adverse effects of rosuvastatin.<\/jats:p>","DOI":"10.1113\/ep090305","type":"journal-article","created":{"date-parts":[[2023,5,4]],"date-time":"2023-05-04T08:04:22Z","timestamp":1683187462000},"page":"961-974","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["High doses of rosuvastatin induce impaired branched\u2010chain amino acid catabolism and lead to insulin resistance"],"prefix":"10.1113","volume":"108","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2342-0812","authenticated-orcid":false,"given":"Xue","family":"Bai","sequence":"first","affiliation":[{"name":"Department of Pharmacy Guizhou 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