Serotonin regulates pancreatic beta cell mass during pregnancy

H Kim, Y Toyofuku, FC Lynn, E Chak, T Uchida… - Nature medicine, 2010 - nature.com
H Kim, Y Toyofuku, FC Lynn, E Chak, T Uchida, H Mizukami, Y Fujitani, R Kawamori…
Nature medicine, 2010nature.com
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, whereas prolactin and placental lactogen counterbalance this resistance and
prevent maternal hyperglycemia by driving expansion of the maternal population of insulin-
producing beta cells,,. However, the exact mechanisms by which the lactogenic hormones
drive beta cell expansion remain uncertain. Here we show that serotonin acts downstream of …
Abstract
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, whereas prolactin and placental lactogen counterbalance this resistance and prevent maternal hyperglycemia by driving expansion of the maternal population of insulin-producing beta cells,,. However, the exact mechanisms by which the lactogenic hormones drive beta cell expansion remain uncertain. Here we show that serotonin acts downstream of lactogen signaling to stimulate beta cell proliferation. Expression of serotonin synthetic enzyme tryptophan hydroxylase-1 (Tph1) and serotonin production rose sharply in beta cells during pregnancy or after treatment with lactogens in vitro. Inhibition of serotonin synthesis by dietary tryptophan restriction or Tph inhibition blocked beta cell expansion and induced glucose intolerance in pregnant mice without affecting insulin sensitivity. Expression of the Gαq-linked serotonin receptor 5-hydroxytryptamine receptor-2b (Htr2b) in maternal islets increased during pregnancy and normalized just before parturition, whereas expression of the Gαi-linked receptor Htr1d increased at the end of pregnancy and postpartum. Blocking Htr2b signaling in pregnant mice also blocked beta cell expansion and caused glucose intolerance. These studies reveal an integrated signaling pathway linking beta cell mass to anticipated insulin need during pregnancy. Modulators of this pathway, including medications and diet, may affect the risk of gestational diabetes.
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