During pregnancy insulin resistance increases and the maternal islets of Langerhans adapt by increasing both insulin secretory response and β-cell mass. Gestational diabetes (GDM) occurs when the islets are unable to adapt sufficiently. The signals underlying this islet adaptation are poorly understood, however studies show islet serotonin to be a key local mediator. Normally β-cell serotonin expression is negligible, but levels increase during pregnancy due to placental signals such as lactogens and kisspeptin. Reduced islet serotonin signalling during pregnancy leads to impaired glucose tolerance and GDM.
GDM is also associated with depression, though the mechanism is unclear. The most common therapeutics for treatment of depression are serotonin reuptake inhibitors (SSRIs), which increase availability of endogenous serotonin. SSRIs have also been shown to stimulate islet function and are likely to influence the action of endogenous islet serotonin during pregnancy.
This project will use a combination of in vivo and primary tissue studies to address two aims:
• Does depression influence endogenous β-cell serotonin during pregnancy?
• Do SSRIs improve the islet adaptation to pregnancy?
During the first year of the project the student will use tissues from mouse models to assess the in vitro effects of serotonin on β-cells. Techniques will include RNAscope, immunohistochemistry and hormone assays.
From the second year of the project and onwards the student will use in vivo models to examine the effects of SSRIs on glucose homeostasis in pregnant animals and models of depression. These experiments will involve multiple in vivo techniques including assessing glucose homeostasis (e.g. glucose tolerance testing), behavioral testing and telemetric monitoring of blood glucose levels.
Depending on the progress of the in vivo studies above, from the third year of the project the student may start to examine the longer-term effects of SSRIs in pregnancy on the metabolic health of both mother and offspring.