title: mTOR inhibition with rapamycin causes impaired insulin signalling and glucose uptake in human subcutaneous and omental adipocytes.
abstract: Rapamycin is an immunosuppressive agent used after organ transplantation, but its molecular effects on glucose metabolism needs further evaluation. We explored rapamycin effects on glucose uptake and insulin signalling proteins in adipocytes obtained via subcutaneous (n=62) and omental (n=10) fat biopsies in human donors. At therapeutic concentration (0.01 μM) rapamycin reduced basal and insulin-stimulated glucose uptake by 20-30%, after short-term (15 min) or long-term (20 h) culture of subcutaneous (n=23 and n=10) and omental adipocytes (n=6 and n=7). Rapamycin reduced PKB Ser473 and AS160 Thr642 phosphorylation, and IRS2 protein levels in subcutaneous adipocytes. Additionally, it reduced mTOR-raptor, mTOR-rictor and mTOR-Sin1 interactions, suggesting decreased mTORC1 and mTORC2 formation. Rapamycin also reduced IR Tyr1146 and IRS1 Ser307/Ser616/Ser636 phosphorylation, whereas no effects were observed on the insulin stimulated IRS1-Tyr and TSC2 Thr1462 phosphorylation. This is the first study to show that rapamycin reduces glucose uptake in human adipocytes through impaired insulin signalling and this may contribute to the development of insulin resistance associated with rapamycin therapy.
authors.affiliation: The Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, The Sahlgrenska Academy at University of Gothenburg, 413 45 Gothenburg, Sweden. maria.pereira@gu.se
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Pereira
authors.forename: Jenny
authors.initials: J
authors.lastname: Palming
authors.forename: Magnus
authors.initials: M
authors.lastname: Rizell
authors.forename: Manuel
authors.initials: M
authors.lastname: Aureliano
authors.forename: Eugénia
authors.initials: E
authors.lastname: Carvalho
authors.forename: Maria K
authors.initials: MK
authors.lastname: Svensson
authors.forename: Jan W
authors.initials: JW
authors.lastname: Eriksson
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000328:Adult; D000368:Aged; D001692:Biological Transport / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance; D008297:Male; D008875:Middle Aged; D009852:Omentum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000009:adverse effects*; D012867:Skin / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D020690:GTPase-Activating Proteins; D007166:Immunosuppressive Agents; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C518767:TBC1D4 protein, human; D064413:3-Phosphoinositide-Dependent Protein Kinases; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D005947:Glucose; D020123:Sirolimus