Editors' ChoicePharmacology

Swapping Mood Disorders for Diabetes

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Sci. Signal.  05 Mar 2013:
Vol. 6, Issue 265, pp. ec54
DOI: 10.1126/scisignal.2004120

Long-term use of selective serotonin reuptake inhibitors (SSRIs), antidepressants used to treat anxiety and mood disorders, is associated with diabetes. Isaac et al. found that SSRIs inhibited the function of the insulin receptor substrate 2 (IRS-2) and induced endoplasmic reticulum (ER) stress and cell death in pancreatic islet cells. In a murine pancreatic β cell line (Min6), short-term treatment with various SSRIs inhibited both basal and insulin-induced stimulatory phosphorylation of tyrosine residues in IRS-2. The SSRI sertraline activated mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK), and glycogen synthase kinase-3β (GSK-3β). JNK induces inhibitory phosphorylation of IRS-2 on serine and threonine residues. Indeed, sertraline induced serine- and threonine-specific phosphorylation of IRS-2 in Min6 cells and prevented its association with phosphoinositide 3-kinase (PI3K) and subsequent activation of downstream targets, including the kinases Akt and ribosomal S6 kinase 1 (S6K1). However, depletion of GSK-3β, but not JNK, restored tyrosine-specific phosphorylation and activation of Akt. Sertraline exerted similar effects in isolated mouse islet cells. Short-term treatment with sertraline reduced the ability of Min6 cells and isolated islets to perform glucose-powered metabolic reduction reactions, an essential step in insulin secretion that was partially restored by inclusion of LiCl, an inhibitor of GSK-3β. Sertraline inhibited glucose-stimulated insulin secretion from Min6 cells as well as from isolated mouse or human islet cells. Long-term treatment with sertraline increased the transcription of ATF4, CHOP, and iNOS, genes that encode key components of the unfolded protein response, indicating that sertraline induced ER stress. Long-term sertraline exposure also induced apoptosis in Min6 cells, which was prevented by LiCl treatment and reduced by depletion of JNK. Together, the findings indicate that SSRIs may trigger diabetes by disrupting insulin signaling and islet cell function.

R. Isaac, S. Boura-Halfon, D. Gurevitch, A. Shainskaya, Y. Levkovitz, Y. Zick, Selective serotonin reuptake inhibitors (SSRIs) inhibit insulin secretion and action in pancreatic β cells. J. Biol. Chem. 288, 5682–5693 (2013). [Abstract] [Full Text]