Protective role of serotonin in pancreatic $\beta$-cell stress

Abstract

$\beta$-cells play an important role in the pathogenesis of diabetes. Serotonin is well known as a neurotransmitter, but it has recently been shown to play an important role in energy metabolism in the body. Serotonin is involved in $\beta$-cell proliferation and insulin secretion during pregnancy. In this study, we investigated the mechanism of serotonin synthesis in $\beta$-cell of $\beta$-cell specific transgenic mouse, which is commonly used in the field of $\beta$-cell research. $RIP-Cre^{Mgn}$, MIP-GFP, and MIP-Cre/ERT produced serotonin in $\beta$-cell. It was confirmed that the human growth hormone gene introduced to increase the gene expression in the gene design process of the transgenic mouse was different from the intention. The human growth hormone synthesized in the $\beta$-cells activated the Jak2-Stat5 signaling pathway by binding to prolactin receptors in mouse $\beta$-cell. The phosphorylated Stat5 formed a dimer and entered into the nucleus to induce tryptophan hydroxylase (Tph1). This process was confirmed by prolactin receptor and Stat5 $\beta$-cell specific knock out mice. In addition, Cre mouse driven by an insulin promoter except the human growth hormone gene was newly developed. During the study, I found that protective effect of serotonin against $\beta$-cell death. $\beta$-cells of $RIP-Cre^{Mgn}$ mice, in which serotonin is continuously synthesized, were resistant to streptozotocin and alloxan, which caused $\beta$-cell specific cell death. In addition, I found that AKITA mouse model, which is a diabetes model that caused $\beta$-cell death by increasing the ER stress of $\beta$-cells, also showed resistance. These results suggest that serotonin protects $\beta$-cells against ER stress and oxidative stress. 5-HTP, a precursor of serotonin, decreased cell death by hydrogen peroxide in MIN6 cells. In the DCF-DA assay, the amount of reactive oxygen species in the $\beta$-cells was reduced by 5-HTP treatment. On the other hand, the expression levels of Sod, Gpx and Cat, which were known to eliminate reactive oxygen species, were not significantly changed. These findings suggest that serotonin directly acts on the removal of reactive oxygen species in the $\beta$-cells. This study demonstrated the problems of transgenic mice commonly used for $\beta$-cell study and to develop new mice which had improved them. In the process, I found that serotonin relieves oxidative stress in $\beta$-cells. This study demonstrated that serotonin has a protective effect on $\beta$-cells and suggested the possibility of improving $\beta$-cells function using serotonin.