Antidepressants induce cellular insulin resistance by activation of IRS-1 kinases

Yechiel Levkovitz, Galit Ben-shushan, Avia Hershkovitz, Roi Isaac, Irit Gil-Ad, Dima Shvartsman, Denise Ronen, Abraham Weizman, Yehiel Zick*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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 ∼ 10 μM. 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.

Original languageEnglish
Pages (from-to)305-312
Number of pages8
JournalMolecular and Cellular Neuroscience
Issue number3
StatePublished - Nov 2007
Externally publishedYes


FundersFunder number
D-CURE Israel
Mitchel Kaplan Fund
Juvenile Diabetes Research Foundation International
Israel Academy of Sciences and Humanities
Israel Science Foundation


    • Antidepressants
    • Insulin receptor substrates
    • Insulin resistance
    • Selective serotonin reuptake inhibitors


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