Serotonin regulates glucose-stimulated insulin secretion from pancreatic β cells during pregnancy.

Abstract

In response to the increased insulin resistance during pregnancy, pancreatic islets undergo not only an increase in β cell proliferation but also an increase in glucose stimulated insulin secretion (GSIS). Although several mechanisms for the increase of  cell proliferation during pregnancy have been reported, the mechanism of the increased GSIS has yet to be elucidated. Here we explored the role of 5-HT in the regulation of GSIS by analyzing Htr3a KO mice. Htr3a KO mice showed impaired glucose tolerance during pregnancy in spite of normal increase of  cell mass. GSIS was markedly increased in the pancreatic islets isolated from pregnant mice but not in the islets isolated from pregnant Htr3a KO mice. Activation of 5-HT3 receptor (Htr3) during pregnancy induced increased uptake of Ca2+ in response to glucose stimulation, which resulted in increased insulin exocytosis. Electrophysiological studies showed that activation of Htr3 induced a depolarizing shift of resting membrane potential in β cells, which decreased glucose threshold for insulin secretion. Thus, our data indicated that Htr3 signaling, in a paracrine/autocrine manner, plays an essential role in the increase of GSIS during pregnancy.