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Serotonin regulates pancreatic beta cell mass during pregnancy


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 cells1,2,3. 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 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 diabetes4.

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Figure 1: 5-HT production in islets during pregnancy.
Figure 2: 5-HT signaling and glucose metabolism in pregnancy.
Figure 3: Htr2b signaling and beta cell proliferation in pregnancy.
Figure 4: 5-HT– and lactogen-induced beta cell proliferation.

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We thank G. Grodsky, W. Rutter and members of the German laboratory for helpful discussions; F. Schaufle and the UCSF Diabetes and Endocrinology Research Center Microscopy Core Laboratory; G. Szot and the UCSF Diabetes and Endocrinology Research Center Islet Core; Y. Zhang, Z. Li and S. Zhao for technical assistance with mouse husbandry and genotyping; N. Daimaru, E. Magoshi and K. Nakamura for technical assistance; K. Takahashi, W. Inaba, M. Tsujii and S. Nakayama for immunohistochemical studies; Y. Katayama (Hirosaki University) and P. Ursell (UCSF) for providing human pancreatic samples; and D. Kuhn (Wayne State University), L. Maroteaux (Institut National de la Santé et de la Recherche Médicale) and M. Hara (University of Chicago) for generously providing the Tph1-specific antisera, Htr2b-targeted mice and MIP-GFP mice, respectively. This work was supported by grants from the Larry L. Hillblom Foundation, the Juvenile Diabetes Research Foundation, the American Diabetes Association, the US National Institutes of Health–National Institute of Diabetes and Digestive and Kidney Diseases and the Ministry of Education, Sports and Culture of Japan.

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H.K., H.W. and M.S.G. designed the research; H.K., Y.T., F.C.L., E.C., T.U., H.M., Y.F., T.M., Y.K., G.H., M.v.d.H., K.Y., N.K. and J.W. performed the research; H.K., F.C.L., R.K., S.Y., H.W., L.H.T. and M.S.G. analyzed the data; and H.K., F.C.L., H.W. and M.S.G. wrote the paper.

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Correspondence to Michael S German.

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Kim, H., Toyofuku, Y., Lynn, F. et al. Serotonin regulates pancreatic beta cell mass during pregnancy. Nat Med 16, 804–808 (2010).

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