Serotonin regulates pancreatic beta cell mass during pregnancy

Hail Kim, Yukiko Toyofuku, Francis C. Lynn, Eric W Chak, Toyoyoshi Uchida, Hiroki Mizukami, Yoshio Fujitani, Ryuzo Kawamori, Takeshi Miyatsuka, Yasuhiro Kosaka, Katherine Yang, Gerard Honig, Marieke Van Der Hart, Nina Kishimoto, Juehu Wang, Soroku Yagihashi, Laurence H. Tecott, Hirotaka Watada, Michael S. German

Research output: Contribution to journalArticlepeer-review

384 Scopus citations


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 1-3. 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 Gα q-linked serotonin receptor 5-hydroxytryptamine receptor-2b (Htr2b) in maternal islets increased during pregnancy and normalized just before parturition, whereas expression of the Gα i-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.

Original languageEnglish (US)
Pages (from-to)804-808
Number of pages5
JournalNature Medicine
Issue number7
StatePublished - Jul 2010
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)


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