{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T00:58:40Z","timestamp":1794013120969,"version":"4.8.0"},"reference-count":57,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2012,3,9]],"date-time":"2012-03-09T00:00:00Z","timestamp":1331251200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2012,4]]},"abstract":"<jats:p><jats:bold>BACKGROUND AND PURPOSE<\/jats:bold> mTOR inhibitors are currently used as immunosuppressants in transplanted patients and as promising anti\u2010cancer agents. However, new\u2010onset diabetes is a frequent complication occurring in patients treated with mTOR inhibitors such as rapamycin (Sirolimus). Here, we investigated the mechanisms associated with the diabetogenic effects of chronic Sirolimus administration in rats and in <jats:italic>in vitro<\/jats:italic> cell cultures.<\/jats:p><jats:p><jats:bold>EXPERIMENTAL APPROACH<\/jats:bold> Sirolimus was administered to rats fed either a standard or high\u2010fat diet for 21 days. Metabolic parameters were measured <jats:italic>in vivo<\/jats:italic> and in <jats:italic>ex vivo<\/jats:italic> tissues. Insulin sensitivity was assessed by glucose tolerance tests and euglycaemic hyperinsulinaemic clamps. Rapamycin effects on glucose metabolism and insulin signalling were further evaluated in cultured myotubes.<\/jats:p><jats:p><jats:bold>KEY RESULTS<\/jats:bold> Sirolimus induced a decrease in food intake and concomitant weight loss. It also induced specific fat mass loss that was independent of changes in food intake. Despite these beneficial effects, Sirolimus\u2010treated rats were glucose intolerant, hyperinsulinaemic and hyperglycaemic, but not hyperlipidaemic. The euglycaemic hyperinsulinaemic clamp measurements showed skeletal muscle is a major site of Sirolimus\u2010induced insulin resistance. At the molecular level, long\u2010term Sirolimus administration attenuated glucose uptake and metabolism in skeletal muscle by preventing full insulin\u2010induced Akt activation and altering the expression and translocation of glucose transporters to the plasma membrane. In rats fed a high\u2010fat diet, these metabolic defects were exacerbated, although Sirolimus\u2010treated animals were protected from diet\u2010induced obesity.<\/jats:p><jats:p><jats:bold>CONCLUSIONS AND IMPLICATIONS<\/jats:bold> Taken together, our data demonstrate that the diabetogenic effect of chronic rapamycin administration is due to an impaired insulin action on glucose metabolism in skeletal muscles.<\/jats:p>","DOI":"10.1111\/j.1476-5381.2011.01716.x","type":"journal-article","created":{"date-parts":[[2011,10,21]],"date-time":"2011-10-21T11:58:56Z","timestamp":1319198336000},"page":"2325-2340","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":133,"title":["Chronic mTOR inhibition by rapamycin induces muscle insulin resistance despite weight loss in rats"],"prefix":"10.1111","volume":"165","author":[{"given":"N","family":"Deblon","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L","family":"Bourgoin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C","family":"Veyrat\u2010Durebex","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Peyrou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Vinciguerra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A","family":"Caillon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C","family":"Maeder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Fournier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"X","family":"Montet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F","family":"Rohner\u2010Jeanrenaud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Foti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2012,3,9]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinbiochem.2008.02.014"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.52.11.2731"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-006-0374-5"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.2337\/db09-1602"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1742-7843.2009.00427.x"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature06322"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0811321106"},{"key":"e_1_2_8_9_1","first-page":"209","article-title":"mTOR signaling and drug development in cancer. 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