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J. Biol. Chem. 288 (8): 5682-5693

© 2013 by The American Society for Biochemistry and Molecular Biology, Inc.

Background: Selective serotonin reuptake inhibitors (SSRIs) are used for the treatment of mood and anxiety disorders.

Results: SSRIs inhibit insulin action and secretion, promote the unfolded protein response, and induce apoptosis of pancreatic β cells.

Conclusion: SSRIs inhibit insulin signaling and beta cell function.

Significance: SSRIs might accelerate the transition from an insulin-resistant state to overt diabetes.

Selective Serotonin Reuptake Inhibitors (SSRIs) Inhibit Insulin Secretion and Action in Pancreatic β Cells*Formula

Roi Isaac{ddagger}§, Sigalit Boura-Halfon{ddagger}, Diana Gurevitch{ddagger}, Alla Shainskaya, Yechiel Levkovitz§, , and Yehiel Zick{ddagger}1

From the Departments of {ddagger}Molecular Cell Biology and
Biological Services, The Weizmann Institute of Science, Rehovot 76100 Israel and
§Shalvata Mental Health Center, Sackler Faculty of Medicine, Tel-Aviv University, Ramat Aviv 6997801, Israel

ABSTRACT Back to Top

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.

Key Words: Beta Cell • Cell Death • Cell Signaling • Insulin Resistance • Insulin Secretion • insulin Receptor Substrate Proteins • Selective Serotonin Reuptake Inhibitors

Received for publication August 7, 2012. Revision received December 24, 2012.

1 An incumbent of the Marte R. Gomez Professorial Chair. To whom correspondence should be addressed: Dept. of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel. Tel.: 972-89-342380; Fax: 972-89-344125; E-mail: Yehiel.Zick{at}

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