title: Antidepressants induce cellular insulin resistance by activation of IRS-1 kinases.
abstract: Certain selective serotonin reuptake inhibitors (SSRIs) induce the clinical and biochemical manifestations of a metabolic syndrome by as yet unknown mechanism. Here we demonstrate that incubation (1 h) of rat hepatoma Fao cells with the SSRIs paroxetine and sertraline, but not with the atypical antipsychotic drug olanzapine, inhibited the insulin-stimulated Tyr phosphorylation of the insulin receptor substrate-1 (IRS-1) with half-maximal effects at approximately 10 microM. This inhibition correlated with a rapid phosphorylation and activation of a number of Ser/Thr IRS-1 kinases including JNK, S6K1, ERK and p38 MAPK, but not PKB (Akt). JNK appears as a key player activated by SSRIs because specific JNK inhibitors partially eliminated the effects of these drugs. The SSRIs induced the phosphorylation of IRS-1 on S307 and S408, which inhibits IRS-1 function and insulin signaling. These results implicate selected SSRIs as inhibitors of insulin signaling and as potential inducers of cellular insulin resistance.
authors.affiliation: Laboratory of Biological Psychiatry, Felsenstein Medical Research Center, Rabin Campus, Petah-Tiqva, Israel.
authors.forename: Yechiel
authors.initials: Y
authors.lastname: Levkovitz
authors.forename: Galit
authors.initials: G
authors.lastname: Ben-Shushan
authors.forename: Avia
authors.initials: A
authors.lastname: Hershkovitz
authors.forename: Roi
authors.initials: R
authors.lastname: Isaac
authors.forename: Irit
authors.initials: I
authors.lastname: Gil-Ad
authors.forename: Dima
authors.initials: D
authors.lastname: Shvartsman
authors.forename: Denise
authors.initials: D
authors.lastname: Ronen
authors.forename: Abraham
authors.initials: A
authors.lastname: Weizman
authors.forename: Yehiel
authors.initials: Y
authors.lastname: Zick
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003920:Diabetes Mellitus / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000187:drug effects* / Q000378:metabolism; D024821:Metabolic Syndrome / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D017374:Paroxetine / Q000009:adverse effects; D010750:Phosphoproteins / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D012694:Serine / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000009:adverse effects*; D020280:Sertraline / Q000009:adverse effects; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
chemical_list: D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D017374:Paroxetine; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D012694:Serine; D017367:Selective Serotonin Reuptake Inhibitors; D020280:Sertraline; C526296:Irs1 protein, rat