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The present study investigated whether rapamycin, a specific inhibitor of mTOR, ameliorates inflammatory stress-induced insulin resistance <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic>. We used tumor necrosis factor-alpha (TNF-\u03b1) and interleukin-6 (IL-6) stimulation in HepG2 hepatocytes, C2C12 myoblasts and 3T3-L1 adipocytes and casein injection in C57BL\/6J mice to induce inflammatory stress. Our results showed that inflammatory stress impairs insulin signaling by reducing the expression of total IRS-1, p-IRS-1 (tyr632) and p-AKT (ser473); it also activates the mTOR\/S6K signaling pathway both <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic>. <jats:italic>In vitro<\/jats:italic>, rapamycin treatment reversed inflammatory cytokine-stimulated IRS-1 serine phosphorylation, increased insulin signaling to AKT and enhanced glucose utilization. <jats:italic>In vivo<\/jats:italic>, rapamycin treatment also ameliorated the impaired insulin signaling induced by inflammatory stress, but it induced pancreatic \u03b2-cell apoptosis, reduced pancreatic \u03b2-cell function and enhanced hepatic gluconeogenesis, thereby resulting in hyperglycemia and glucose intolerance in casein-injected mice. Our results indicate a paradoxical effect of rapamycin on insulin resistance between the <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> environments under inflammatory stress and provide additional insight into the clinical application of rapamycin.<\/jats:p>","DOI":"10.1038\/srep14959","type":"journal-article","created":{"date-parts":[[2015,10,9]],"date-time":"2015-10-09T09:18:57Z","timestamp":1444382337000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Paradoxical effect of rapamycin on inflammatory stress-induced insulin resistance in vitro and in vivo"],"prefix":"10.1038","volume":"5","author":[{"given":"Ping","family":"Yang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunfei","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zac","family":"Varghese","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John F.","family":"Moorhead","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaxi","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiong Z.","family":"Ruan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2015,10,9]]},"reference":[{"key":"BFsrep14959_CR1","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1146\/annurev.physiol.68.040104.124723","volume":"68","author":"SB Biddinger","year":"2006","unstructured":"Biddinger, S. 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