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Aims Methods Results Conclusions To investigate the effects of the selective serotonin reuptake inhibitors (SSRIs) sertraline and paroxetine at therapeutically relevant concentrations on beta‐cell mass and function.Viability was quantified in mouse insulinoma (MIN6) beta cells and mouse islets after 48‐h exposure to sertraline (1–10 μM) or paroxetine (0.01–1 μM) using the Trypan blue exclusion test. The effects of therapeutic concentrations of these SSRIs on insulin secretion were determined by static incubation and perifusion experiments, while islet apoptosis was investigated by Caspase‐Glo 3/7 assay, TUNEL staining and quantitative PCR analysis. Finally, proliferation of MIN6 and mouse islet beta cells was assessed by bromodeoxyuridine (BrdU) enzyme‐linked immunosorbent assay and immunofluorescence.Sertraline (0.1–1 μM) and paroxetine (0.01–0.1 μM) were well tolerated by MIN6 beta cells and islets, whereas 10 μM sertraline and 1 μM paroxetine were cytotoxic. Exposure to 1 μM sertraline and 0.1 μM paroxetine significantly potentiated glucose‐stimulated insulin secretion from mouse and human islets. Moreover, they showed protective effects against cytokine‐ and palmitate‐induced apoptosis of islets, they downregulated cytokine‐induced Stat1 and Traf1 mRNA expression, and they significantly increased proliferation of mouse beta cells.Our data demonstrate that sertraline and paroxetine act directly on beta cells to enhance glucose‐stimulated insulin secretion and stimulate beta‐cell mass expansion by increasing proliferation and decreasing apoptosis. These drugs are therefore likely to be appropriate for treating depression in people with type 2 diabetes. [ABSTRACT FROM AUTHOR]