Antidepressants induce cellular insulin resistance by activation of IRS-1 kinases.
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.
Levkovitz
Yechiel
Y
Laboratory of Biological Psychiatry, Felsenstein Medical Research Center, Rabin Campus, Petah-Tiqva, Israel.
Ben-Shushan
Galit
G
Hershkovitz
Avia
A
Isaac
Roi
R
Gil-Ad
Irit
I
Shvartsman
Dima
D
Ronen
Denise
D
Weizman
Abraham
A
Zick
Yehiel
Y
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
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