Probing the Role of 5-HT in pancreatic beta-cell

Abstract

Probing the Role of 5-HT in pancreatic -cell

During pregnancy, the energy requirements of the fetus impose changes in maternal metabolism and maternal body increases the demand for insulin secretion. In preparation for the metabolic demands of pregnancy, β cells in the pancreatic islets increase both in number and in glucose stimulated insulin secretion per cell. Thus fasting serum insulin concentration increased and fasting glucose concentration decreased slightly during gestation both in human and rodents. These adaptive changes of beta-cell are critical for maintenance of glucose homeostasis in the face of changing physiological stimuli during pregnancy. However, the precise mechanism has been elucidated only in part. Among many hormones that increase during pregnancy, lactogenic hormones, prolactin (PRL) and placental lactogen (PL), were thought to regulate the changes in beta-cell mass during pregnancy. Recently, we have shown that 5-HT mediates lactogenic hormone dependent beta-cell expansion during pregnancy. Serotonin synthetic enzyme Tph1 and serotonin production increased sharply in β-cells during pregnancy or after treatment with lactogens in vitro. Inhibition of serotonin synthesis by dietary tryptophan restriction or Tph inhibition blocked β-cell expansion and induced glucose intolerance in pregnant mice. Blocking Htr2b signaling in pregnant mice also blocked β-cell expansion and caused glucose intolerance. In addition to Htr2b, we tested whether flux through the ionotropic serotonin receptor Htr3 impacts GSIS during pregnancy. Pregnant Htr3a-/- mice exhibited impaired glucose tolerance despite normally increased  cell mass, and their islets lacked the increase in GSIS seen in islets from pregnant wildtype mice. Electrophysiological studies showed that activation of Htr3 decreased the resting membrane potential in β cells, which increased Ca2+ uptake and insulin exocytosis in response to glucose. Thus, 5-HT, acting in a paracrine/autocrine manner through Htr3, plays an essential role in the increased GSIS of pregnancy. These studies reveal an integrated signaling pathway linking adaptive beta-cell change to anticipated insulin need during pregnancy. Modulation of this pathway, including medications and diet, may affect the risk of diabetes.