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 ␤ cells. Conclusion: SSRIs inhibit insulin signaling and beta cell function. Significance: SSRIs might accelerate the transition from an insulin-resistant state to overt diabetes.

Upon exposure, TiO(2) nanoparticles (NPs) have been recovered in internal organs such as the liver, and are proposed to cause cellular/organ dysfunction, particularly in the liver and lungs. We hypothesized that despite being considered "inert" as bulk material, TiO(2) NPs may impair insulin responses in liver-derived cells, either indirectly by inflammatory activation of macrophages, and/or by directly interfering with insulin signaling. Using qRT-PCR and conditioned medium (CM) approaches, we show that exposure to TiO(2) NPs activates macrophages' expression of TNF-α, IL-6, IL-8, IL-1α and IL-1β and the resulting CM induces insulin resistance in Fao cells. Furthermore, direct exposure of Fao cells to TiO(2) results in activation of the stress kinases JNK and p38MAP kinase, and in induction of insulin resistance at the signaling and metabolic levels. Collectively, our findings provide a proof-of-concept for the ability of man-made NPs to induce insulin resistance in liver-derived cells, an endocrine abnormality underlying some of the most common human diseases.

OBJECTIVECellular stress and proinflammatory cytokines induce phosphorylation of insulin receptor substrate (IRS) proteins at Ser sites that inhibit insulin and IGF-1 signaling. Here, we examined the role of Ser phosphorylation of IRS-2 in mediating the inhibitory effects of proinflammatory cytokines and cellular stress on β-cell function.RESEARCH DESIGN AND METHODSFive potential inhibitory Ser sites located proximally to the P-Tyr binding domain of IRS-2 were mutated to Ala. These IRS-2 mutants, denoted IRS-25A, and their wild-type controls (IRS-2WT) were introduced into adenoviral constructs that were infected into Min6 cells or into cultured murine islets.RESULTSWhen expressed in cultured mouse islets, IRS-25A was better than IRS-2WT in protecting β-cells from apoptosis induced by a combination of IL-1β, IFN-γ, TNF-α, and Fas ligand. Cytokine-treated islets expressing IRS25A secreted significantly more insulin in response to glucose than did islets expressing IRS-2WT. This could be attributed to the higher transcription of Pdx1 in cytokine-treated islets that expressed IRS-25A. Accordingly, transplantation of 200 islets expressing IRS25A into STZ-induced diabetic mice restored their ability to respond to a glucose load similar to naïve mice. In contrast, mice transplanted with islets expressing IRS2WT maintained sustained hyperglycemia 3 days after transplantation.CONCLUSIONSElimination of a physiological negative feedback control mechanism along the insulin-signaling pathway that involves Ser/Thr phosphorylation of IRS-2 affords protection against the adverse effects of proinflammatory cytokines and improves β-cell function under stress. Genetic approaches that promote IRS25A expression in pancreatic β-cells, therefore, could be considered a rational treatment against β-cell failure after islet transplantation.

Insulin receptor substrate-1 (IRS-1) plays a pivotal role in insulin signaling, therefore its degradation is exquisitely regulated. Here, we show that insulin-stimulated degradation of IRS-1 requires the presence of a highly conserved Ser/Thr-rich domain that we named domain involved in degradation of IRS-1 (DIDI). DIDI (amino acids 386-430 of IRS-1) was identified by comparing the intracellular degradation rate of several truncated forms of IRS-1 transfected into CHO cells. The isolated DIDI domain underwent insulin-stimulated Ser/Thr phosphorylation, suggesting that it serves as a target for IRS-1 kinases. The effects of deletion of DIDI were studied in Fao rat hepatoma and in CHO cells expressing Myc-IRS-1(WT) or Myc-IRS-1(Δ386-430). Deletion of DIDI maintained the ability of IRS-1(Δ386-434) to undergo ubiquitination while rendering it insensitive to insulin-induced proteasomal degradation, which affected IRS-1(WT) (80% at 8 h). Consequently, IRS-1(Δ386-434) mediated insulin signaling (activation of Akt and glycogen synthesis) better than IRS-1(WT). IRS-1(Δ386-434) exhibited a significant greater preference for nuclear localization, compared with IRS-1(WT). Higher nuclear localization was also observed when cells expressing IRS-1(WT) were incubated with the proteasome inhibitor MG-132. The sequence of DIDI is conserved more than 93% across species, from fish to mammals, as opposed to approximately 40% homology of the entire IRS-1. These findings implicate DIDI as a novel, highly conserved domain of IRS-1, which mediates its cellular localization, rate of degradation, and biological activity, with a direct impact on insulin signal transduction.

Figs. 1B, 2A, 3A, 4B, 5A, and 7 did not indicate the borders between the images. This error has now been corrected and does not affect the results or conclusions of this work.