Not Just the Happy Chemical

Not Just the Happy Chemical 

Mari Yamamoto and Hadeel Saab

Much of the previous research involving the chemical serotonin has focused on its functions in the central nervous system. Recently, however, more evidence of its role in the immune system has emerged, pointing research interest towards studying serotonin in the context of autoimmune diseases. Let’s take a closer look: 

Researchers in Berlin studied serotonin specifically in pancreatic beta-cells, finding that mice lacking serotonin, or 5-hydroxytryptamine (5-HT), were diabetic and had weakened insulin secretion. Consistently, they concluded that extracellular 5-HT inhibited insulin secretion, while intracellular 5-HT had the opposite effect. They also identified a process called serotonylation, where 5-HT is coupled by transglutaminases in a receptor-independent signaling mechanism. Inhibiting this process caused insulin secretion to decline. 

Other researchers also identified 5-HT’s importance in regulating adult beta-cell mass, which is critical for preventing diabetes. What exactly goes on?

  • During fetal development, insulin-producing beta cells differentiate from the endocrine progenitor cells, and these cells proliferate during the perinatal period to achieve the beta cell mass.
  • 5-HT regulates this proliferation process through the 5-HT 2B receptor.
  • By analyzing Tph1 beta-KO mice, it was discovered that:
    • Perinatal beta-cell proliferation and the consequent production of serotonin in beta-cells was reduced, which led to glucose intolerance and decreased beta-cell mass.

Beyond the Beta

One study expanded on this research to understand the effect of 5-HT on other islet endocrine cells, including the glucagon-secreting alpha cells. 

  • Using immunostaining and RNAscope technology, researchers were able to locate the 5-HT1F receptor in glucagon-immunoreactive alpha cells.
  • It was also found that in vivo activation of the 5-HT1F receptor controls glucagon secretion, affecting glucose homeostasis.
    • How? When alpha cells are exposed to 5-HT, cAMP (a 2nd messenger for glucagon secretion) is downregulated, thus reducing glucagon secretion and preventing hyperglycemic effects.

A recent review published earlier this year also covers this role of serotonin in beta-cells, as well as with other autoimmune diseases like inflammatory bowel disease, rheumatoid arthritis and multiple sclerosis. Overall, it was confirmed that 5-HT regulates the balance of Th17 cells to Tregs, and promotes M2 polarization of macrophages. However, differences in cell types, 5-HT receptors and diseases themselves can affect the pro- and anti-inflammatory effects of 5-HT. 

Got milk? Lactation induces serotonin 

Lactation has been shown to reduce the risk of postpartum diabetes, but the exact mechanisms were previously unknown. A new study, done both in mice and humans, showed improved glucose tolerance with those lactating versus those who were not. Lactation increases the concentration of prolactin, which in turn induces the production of serotonin in beta-cells, improving insulin secretion. Here are some of their other findings: 

  • Increased beta-cell mass and improved beta-cell function in lactated mice
  • Serotonin protected beta-cells from oxidative stress by scavenging reactive oxygen species (ROS)
  • Beneficial effects of lactation lasted long-term, months in mice and years in humans

Looking ahead: Given 5-HT’s  proven involvement in the immune system,targeting its signaling pathway has potential for treating many kinds of autoimmune diseases but more research is needed to confirm its effects.