title: Paradoxical effect of rapamycin on inflammatory stress-induced insulin resistance in vitro and in vivo.
abstract: Insulin resistance is closely related to inflammatory stress and the mammalian target of rapamycin/S6 kinase (mTOR/S6K) pathway. The present study investigated whether rapamycin, a specific inhibitor of mTOR, ameliorates inflammatory stress-induced insulin resistance in vitro and in vivo. We used tumor necrosis factor-alpha (TNF-α) 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 in vitro and in vivo. In vitro, rapamycin treatment reversed inflammatory cytokine-stimulated IRS-1 serine phosphorylation, increased insulin signaling to AKT and enhanced glucose utilization. In vivo, rapamycin treatment also ameliorated the impaired insulin signaling induced by inflammatory stress, but it induced pancreatic β-cell apoptosis, reduced pancreatic β-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 in vitro and in vivo environments under inflammatory stress and provide additional insight into the clinical application of rapamycin.
authors.affiliation: Centre for Lipid Research, Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400016, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Yang
authors.affiliation: School of Biological &Chemical Engineering, Chongqing University of Education, Chongqing, 400067, China.
authors.forename: Yunfei
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Centre for Lipid Research, Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400016, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Centre for Lipid Research, Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400016, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Yuan
authors.affiliation: Centre for Lipid Research, Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400016, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Chen
authors.affiliation: John Moorhead Research Laboratory, Centre for Nephrology, University College London (UCL) Medical School, Royal Free Campus, London, NW3 2PF, UK.
authors.forename: Zac
authors.initials: Z
authors.lastname: Varghese
authors.affiliation: John Moorhead Research Laboratory, Centre for Nephrology, University College London (UCL) Medical School, Royal Free Campus, London, NW3 2PF, UK.
authors.forename: John F
authors.initials: JF
authors.lastname: Moorhead
authors.affiliation: Centre for Lipid Research, Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400016, China.
authors.forename: Yaxi
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Centre for Lipid Research, Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400016, China.|John Moorhead Research Laboratory, Centre for Nephrology, University College London (UCL) Medical School, Royal Free Campus, London, NW3 2PF, UK.
authors.forename: Xiong Z
authors.initials: XZ
authors.lastname: Ruan
mesh_terms: D041721:3T3-L1 Cells; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002460:Cell Line; D056945:Hep G2 Cells; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007249:Inflammation / Q000378:metabolism / Q000503:physiopathology*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D050417:Insulin-Secreting Cells / Q000378:metabolism; D015850:Interleukin-6 / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D007166:Immunosuppressive Agents; D055504:Insulin Receptor Substrate Proteins; D015850:Interleukin-6; C526295:Irs1 protein, mouse; D014409:Tumor Necrosis Factor-alpha; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus