Defining direct effects of selective serotonin reuptake inhibitors at islets to improve glucose homeostasis

Use of selective serotonin reuptake inhibitors (SSRIs) in people with concomitant occurrence of depression and diabetes is associated with reductions in plasma glucose and glycated haemoglobin (HbA1c) levels that are independent of changes in body weight. We have previously shown that the SSRI fluoxetine, at therapeutically relevant concentrations, enhances glucose-stimulated insulin secretion and β-cell mass expansion in vitro and in vivo. However, the effects of other SSRIs on β-cells are not well understood, and it is not clear whether SSRIs have a common mode of action on islets since the intracellular signalling cascades through which fluoxetine exerts its beneficial effects in β-cells are not established. The aim of this PhD project is to investigate whether sertraline and paroxetine, two other commonly used SSRIs, have direct effects on β-cells and if they improve glucose homeostasis. The PhD student will also determine the molecular mechanisms by which fluoxetine, sertraline and paroxetine regulate β-cell function and mass. Investigating the effects of SSRIs on islet function in vitro and their roles in maintaining normoglycaemia in healthy and insulin resistant mice has the potential to identify novel approaches for treating diabetes that could lead to the repurposing these safe drugs as diabetes therapies.