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The purpose of this study was to characterize further the effects of the continuous use of rapamycin on glucose homeostasis in lean <jats:styled-content style=\"fixed-case\">C57BL6\/J<\/jats:styled-content> mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Mice were fed a high\u2010protein diet (<jats:styled-content style=\"fixed-case\">HPD<\/jats:styled-content>) for 12 weeks to develop a lean model and then were treated daily with rapamycin for 5 weeks while remaining on a <jats:styled-content style=\"fixed-case\">HPD<\/jats:styled-content>. Metabolic parameters, endocrine profiles, glucose tolerance tests, insulin sensitivity index, the expression of the glucose transporter GLUT4 and chromium distribution were measured <jats:italic>in vivo<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Lower body weight gain as well as a decreased caloric intake, fat pads, fatty liver scores, adipocyte size and glucose tolerance test values were observed in <jats:styled-content style=\"fixed-case\">HPD<\/jats:styled-content>\u2010fed mice compared with mice fed a high\u2010fat or standard diet. Despite these beneficial effects, rapamycin\u2010treated lean mice showed greater glucose intolerance, reduced insulin sensitivity, lower muscle GLUT4 expression and changes in chromium levels in tissues even with high insulin levels.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>Our findings demonstrate that continuous rapamycin administration may lead to the development of diabetes syndrome, as it was found to induce hyperglycaemia and glucose intolerance in a lean animal model.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.13168","type":"journal-article","created":{"date-parts":[[2015,4,17]],"date-time":"2015-04-17T10:19:05Z","timestamp":1429265945000},"page":"3793-3804","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Rapamycin impairs <scp>HPD<\/scp>\u2010induced beneficial effects on glucose 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