Serotonin regulates pancreatic beta cell mass during pregnancy.
Serotonin regulates pancreatic beta cell mass during pregnancy.
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在怀孕期间，胎儿的能量需求引起了母体代谢的变化。母亲体内胰岛素抵抗的增加维持了营养物质流向生长中的胎儿，而催乳素和胎盘的乳酸平衡了这种抵抗，并通过驱动母体中胰岛素生成β细胞的扩张来防止母体高血糖。然而，乳原激素驱动β细胞扩增的确切机制仍不确定。在这里，我们表明血清素作用于乳原信号的下游，以驱动β细胞增殖。5 -羟色胺合成酶Tph1和5 -羟色胺产量急剧增加β-细胞在怀孕期间或体外乳原处理后。通过饮食色氨酸限制或Tph抑制血清素合成可阻断妊娠小鼠β细胞扩增并诱导葡萄糖耐受不良，但不影响胰岛素敏感性。母体胰岛中g αq- 5 -羟色胺受体Htr2b的表达在妊娠期间升高，并在分娩前趋于正常，而g αi- 5 -羟色胺受体Htr1d的表达在妊娠末期和产后升高。阻断妊娠小鼠的Htr2b信号传导也会阻断β细胞扩增并引起葡萄糖耐受不良。这些研究揭示了妊娠期间β细胞质量与预期胰岛素需求之间的综合信号通路。这一途径的调节剂，包括药物和饮食，可能会影响妊娠糖尿病的风险。
During pregnancy, the energy requirements of the fetus impose changes in maternal metabolism. Increasing insulin resistance in the mother maintains nutrient flow to the growing fetus, while prolactin and placental lactogen counterbalance this resistance and prevent maternal hyperglycemia by driving expansion of the maternal population of insulin-producing β-cells. However, the exact mechanisms by which the lactogenic hormones drive β-cell expansion remain uncertain. Here we show that serotonin acts downstream of lactogen signaling to drive β-cell proliferation. 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 without affecting insulin sensitivity. Expression of the Gαq-linked serotonin receptor Htr2b in maternal islets increased during pregnancy and normalized just prior to parturition, while expression of the Gαi-linked receptor Htr1d increased at the end of pregnancy and postpartum. Blocking Htr2b signaling in pregnant mice also blocked β-cell expansion and caused glucose intolerance. These studies reveal an integrated signaling pathway linking β-cell mass to anticipated insulin need during pregnancy. Modulators of this pathway, including medications and diet, may affect the risk of gestational diabetes.