Depression and SSRIs: effects on the islet adaptation to pregnancy

Lorna Smith, King's College London

 

Aims

There is a clinical correlation between depression and women developing gestational diabetes (GDM) during pregnancy, though the underlying pathophysiology is unclear. Several studies have shown that peripheral serotonin synthesis is reduced in models of depression. Our preliminary data and previous studies support an important role for local pancreatic islet serotonin in mediating β-cell adaptations to the demands of pregnancy necessary to prevent GDM. Thus, a depression-induced reduction in islet serotonin synthesis may result in an insufficient adaptive response representing a mechanistic link between depression and GDM.

This project was initially funded through a one-year grant from the European Foundation for the Study of Diabetes. I aimed to address the hypothesis that a mouse model of depression will a) influence islet serotonin synthesis during pregnancy, b) contribute to insufficient islet adaptation and glucose intolerance. Prior to the Covid-19 lockdown I had characterized a mouse model of depression, induced pregnancy and assessed glucose homeostasis. I had collected terminal tissue samples and was preparing to analyse serotonin synthesis in these samples, the primary endpoint of the study.

This funding from the Bioscientifica Trust would provide support enabling me to complete the necessary tissue analysis, determining whether depression influences islet serotonin synthesis during pregnancy.

 

Evaluation

This project aimed to address the hypothesis that a mouse model of depression will a) influence islet serotonin synthesis during pregnancy, b) contribute to insufficient islet adaptation and glucose intolerance. Prior to the Covid-19 lockdown I had characterized a mouse model of depression, induced pregnancy and assessed glucose homeostasis. I had collected terminal tissue samples and was preparing to analyse serotonin synthesis in these samples, the primary endpoint of the study.

The funding provided me with continued salary support so that I was able to perform immunohistochemistry (IHC) for serotonin and for BRDU-labelled proliferative cells in the terminal pancreatic samples. I was able to learn to use the quantification software; CellProfiler, in order to analyse the resulting IHC images, which significantly sped up the time taken to quantify the results and will be a valuable tool to use in IHC going forward.

Attempts to use a novel small molecule fluorescence in situ hybridization (smFISH) technique for detecting levels of serotonin synthesis enzymes; Tph1 and Tph1 RNA, in the tissue were unsuccessful and we have therefore not been able to confirm our IHC findings as of yet, although we have plans to revert to the more expensive but more reliable commercial kit from RNAscope in order to complete this work in the future.

We were also able to undertake a small preliminary in vivo study to implant osmotic minipumps containing the selective serotonin reuptake inhibitor (SSRI) antidepressant; fluoxetine, into pregnant mice in order to determine direct effect of increased serotonin on glucose homeostasis during pregnancy.

 

Grant awarded: £5,000