title: Selective serotonin reuptake inhibitors (SSRIs) inhibit insulin secretion and action in pancreatic β cells.
abstract: Selective serotonin reuptake inhibitors (SSRIs) are antidepressants used for the treatment of mood and anxiety disorders. Here, we demonstrate that incubation (2 h) of murine islets or Min6 β cell line with the SSRIs paroxetine, fluoxetine, or sertraline inhibited insulin-induced Tyr phosphorylation of insulin receptor substrate (IRS)-2 protein and the activation of its downstream targets Akt and the ribosomal protein S6 kinase-1 (S6K1). Inhibition was dose-dependent with half-maximal effects at ∼15-20 μM. It correlated with a rapid dephosphorylation and activation of the IRS kinase GSK3β. Introduction of GSK3β siRNAs eliminated the inhibitory effects of the SSRIs. Inhibition of IRS-2 action by 30 μM SSRI was associated with a marked inhibition of glucose-stimulated insulin secretion from murine and human pancreatic islets. Secretion induced by basic secretagogues (KCl and Arg) was not affected by these drugs. Prolonged treatment (16 h) of Min6 cells with sertraline resulted in the induction of inducible nitric oxide synthase; activation of endoplasmic reticulum stress, and the initiation of the unfolded protein response, manifested by enhanced transcription of ATF4 and C/EBP homologous protein. This triggered an apoptotic process, manifested by enhanced caspase 3/7 activity, which resulted in β cell death. These findings implicate SSRIs as inhibitors of IRS protein function and insulin action through the activation of GSK3β. They further suggest that SSRIs inhibit insulin secretion; induce the unfolded protein response; activate an apoptotic process, and trigger β cell death. Given that SSRIs promote insulin resistance while inhibiting insulin secretion, these drugs might accelerate the transition from an insulin-resistant state to overt diabetes.
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100 Israel.
authors.forename: Roi
authors.initials: R
authors.lastname: Isaac
authors.forename: Sigalit
authors.initials: S
authors.lastname: Boura-Halfon
authors.forename: Diana
authors.initials: D
authors.lastname: Gurevitch
authors.forename: Alla
authors.initials: A
authors.lastname: Shainskaya
authors.forename: Yechiel
authors.initials: Y
authors.lastname: Levkovitz
authors.forename: Yehiel
authors.initials: Y
authors.lastname: Zick
mesh_terms: D000818:Animals; D017209:Apoptosis; D016923:Cell Death; D002460:Cell Line; D003920:Diabetes Mellitus / Q000139:chemically induced / Q000378:metabolism; D005473:Fluoxetine / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017374:Paroxetine / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D020280:Sertraline / Q000494:pharmacology; D015398:Signal Transduction; D056811:Unfolded Protein Response
chemical_list: D005473:Fluoxetine; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D017374:Paroxetine; D017367:Selective Serotonin Reuptake Inhibitors; D020280:Sertraline