Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Serotonin regulates pancreatic beta cell mass during pregnancy

Nature Medicine volume 16, pages 804–808 (2010)Cite this article

Subjects

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 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.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

Buy

All prices are NET prices.

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.

Accession codes

Accessions

Gene Expression Omnibus

References

  1. Van Assche, F.A., Aerts, L. & De Prins, F. A morphological study of the endocrine pancreas in human pregnancy. Br. J. Obstet. Gynaecol. 85, 818–820 (1978).

    CAS  Article  Google Scholar 

  2. Parsons, J.A., Brelje, T.C. & Sorenson, R.L. Adaptation of islets of Langerhans to pregnancy: increased islet cell proliferation and insulin secretion correlates with the onset of placental lactogen secretion. Endocrinology 130, 1459–1466 (1992).

    CAS  PubMed  Google Scholar 

  3. Huang, C., Snider, F. & Cross, J.C. Prolactin receptor is required for normal glucose homeostasis and modulation of beta-cell mass during pregnancy. Endocrinology 150, 1618–1626 (2009).

    CAS  Article  Google Scholar 

  4. Buchanan, T.A. & Xiang, A.H. Gestational diabetes mellitus. J. Clin. Invest. 115, 485–491 (2005).

    CAS  Article  Google Scholar 

  5. Freemark, M. et al. Targeted deletion of the PRL receptor: effects on islet development, insulin production, and glucose tolerance. Endocrinology 143, 1378–1385 (2002).

    CAS  Article  Google Scholar 

  6. Vasavada, R.C. et al. Targeted expression of placental lactogen in the beta cells of transgenic mice results in beta cell proliferation, islet mass augmentation and hypoglycemia. J. Biol. Chem. 275, 15399–15406 (2000).

    CAS  Article  Google Scholar 

  7. Sorenson, R.L. & Brelje, T.C. Adaptation of islets of Langerhans to pregnancy: beta-cell growth, enhanced insulin secretion and the role of lactogenic hormones. Horm. Metab. Res. 29, 301–307 (1997).

    CAS  Article  Google Scholar 

  8. Brelje, T.C. et al. Effect of homologous placental lactogens, prolactins, and growth hormones on islet B-cell division and insulin secretion in rat, mouse, and human islets: implication for placental lactogen regulation of islet function during pregnancy. Endocrinology 132, 879–887 (1993).

    CAS  Article  Google Scholar 

  9. Karnik, S.K. et al. Menin controls growth of pancreatic β-cells in pregnant mice and promotes gestational diabetes mellitus. Science 318, 806–809 (2007).

    CAS  Article  Google Scholar 

  10. Ben-Jonathan, N., LaPensee, C.R. & LaPensee, E.W. What can we learn from rodents about prolactin in humans? Endocr. Rev. 29, 1–41 (2008).

    CAS  Article  Google Scholar 

  11. Sakowski, S.A. et al. Differential tissue distribution of tryptophan hydroxylase isoforms 1 and 2 as revealed with monospecific antibodies. Brain Res. 1085, 11–18 (2006).

    CAS  Article  Google Scholar 

  12. Hara, M. et al. Transgenic mice with green fluorescent protein–labeled pancreatic beta cells. Am. J. Physiol. Endocrinol. Metab. 284, E177–E183 (2003).

    CAS  Article  Google Scholar 

  13. Fadda, F. Tryptophan-free diets: a physiological tool to study brain serotonin function. News Physiol. Sci. 15, 260–264 (2000).

    CAS  PubMed  Google Scholar 

  14. Hoyer, D. et al. International union of pharmacology classification of receptors for 5-hydroxytryptamine (serotonin). Pharmacol. Rev. 46, 157–203 (1994).

    CAS  PubMed  Google Scholar 

  15. Lesurtel, M. et al. Platelet-derived serotonin mediates liver regeneration. Science 312, 104–107 (2006).

    CAS  Article  Google Scholar 

  16. Nebigil, C.G. et al. Serotonin 2B receptor is required for heart development. Proc. Natl. Acad. Sci. USA 97, 9508–9513 (2000).

    CAS  Article  Google Scholar 

  17. Wouters, M.M. et al. Exogenous serotonin regulates proliferation of interstitial cells of Cajal in mouse jejunum through 5–HT2B receptors. Gastroenterology 133, 897–906 (2007).

    CAS  Article  Google Scholar 

  18. Rothman, R.B. et al. Evidence for possible involvement of 5-HT2B receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications. Circulation 102, 2836–2841 (2000).

    CAS  Article  Google Scholar 

  19. Fitzgerald, L.W. et al. Possible role of valvular serotonin 5-HT2B receptors in the cardiopathy associated with fenfluramine. Mol. Pharmacol. 57, 75–81 (2000).

    CAS  PubMed  Google Scholar 

  20. Collet, C. et al. The serotonin 5-HT2B receptor controls bone mass via osteoblast recruitment and proliferation. FASEB J. 22, 418–427 (2008).

    CAS  Article  Google Scholar 

  21. De Lucchini, S., Ori, M., Cremisi, F., Nardini, M. & Nardi, I. 5-HT2B–mediated serotonin signaling is required for eye morphogenesis in Xenopus. Mol. Cell. Neurosci. 29, 299–312 (2005).

    CAS  Article  Google Scholar 

  22. Gannon, M., Shiota, C., Postic, C., Wright, C.V. & Magnuson, M. Analysis of the Cre-mediated recombination driven by rat insulin promoter in embryonic and adult mouse pancreas. Genesis 26, 139–142 (2000).

    CAS  Article  Google Scholar 

  23. Matsuda, M. et al. Serotonin regulates mammary gland development via an autocrine-paracrine loop. Dev. Cell 6, 193–203 (2004).

    CAS  Article  Google Scholar 

  24. Møldrup, A., Petersen, E.D. & Nielsen, J.H. Effects of sex and pregnancy hormones on growth hormone and prolactin receptor gene expression in insulin-producing cells. Endocrinology 133, 1165–1172 (1993).

    Article  Google Scholar 

  25. Leahy, J.L., Bonner-Weir, S. & Weir, G.C. Abnormal glucose regulation of insulin secretion in models of reduced B-cell mass. Diabetes 33, 667–673 (1984).

    CAS  Article  Google Scholar 

  26. Goodner, C.J., Koerker, D.J., Weigle, D.S. & McCulloch, D.K. Decreased insulin- and glucagon-pulse amplitude accompanying beta-cell deficiency induced by streptozocin in baboons. Diabetes 38, 925–931 (1989).

    CAS  Article  Google Scholar 

  27. Butler, A.E. et al. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 52, 102–110 (2003).

    CAS  Article  Google Scholar 

  28. Mezuk, B., Eaton, W.W., Albrecht, S. & Golden, S.H. Depression and type 2 diabetes over the lifespan: a meta-analysis. Diabetes Care 31, 2383–2390 (2008).

    Article  Google Scholar 

  29. Kozhimannil, K.B., Pereira, M.A. & Harlow, B.L. Association between diabetes and perinatal depression among low-income mothers. J. Am. Med. Assoc. 301, 842–847 (2009).

    CAS  Article  Google Scholar 

  30. Gianfrancesco, F.D., Grogg, A.L., Mahmoud, R.A., Wang, R.H. & Nasrallah, H.A. Differential effects of risperidone, olanzapine, clozapine, and conventional antipsychotics on type 2 diabetes: findings from a large health plan database. J. Clin. Psychiatry 63, 920–930 (2002).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

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.

Author information

Author notes

  1. Francis C Lynn

    Present address: Current address: Departments of Surgery and Cellular and Physiological Sciences, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.,

Authors and Affiliations

  1. Diabetes Center, University of California–San Francisco (UCSF), San Francisco, California, USA

    Hail Kim, Francis C Lynn, Eric Chak, Takeshi Miyatsuka, Yasuhiro Kosaka, Katherine Yang, Nina Kishimoto, Juehu Wang & Michael S German

  2. Department of Medicine, Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan

    Yukiko Toyofuku, Toyoyoshi Uchida, Yoshio Fujitani, Ryuzo Kawamori & Hirotaka Watada

  3. Department of Pathology and Molecular Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, Japan

    Hiroki Mizukami

  4. Center for Therapeutic Innovations in Diabetes, Juntendo University Graduate School of Medicine, Tokyo, Japan

    Yoshio Fujitani, Ryuzo Kawamori & Soroku Yagihashi

  5. Center for Beta Cell Biology and Regeneration, Juntendo University Graduate School of Medicine, Tokyo, Japan

    Ryuzo Kawamori

  6. Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan

    Ryuzo Kawamori & Hirotaka Watada

  7. Department of Psychiatry, UCSF, San Francisco, California, USA

    Gerard Honig, Marieke van der Hart & Laurence H Tecott

  8. Department of Medicine, UCSF, San Francisco, California, USA

    Michael S German

Authors
  1. Hail Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yukiko Toyofuku
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Francis C Lynn
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Eric Chak
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Toyoyoshi Uchida
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hiroki Mizukami
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yoshio Fujitani
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ryuzo Kawamori
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Takeshi Miyatsuka
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yasuhiro Kosaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Katherine Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Gerard Honig
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Marieke van der Hart
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Nina Kishimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Juehu Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Soroku Yagihashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Laurence H Tecott
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Hirotaka Watada
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Michael S German
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

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.

Corresponding author

Correspondence to Michael S German.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Tables 1 and 2, Supplementary Figures 1–6 and Supplementary Methods (PDF 625 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Kim, H., Toyofuku, Y., Lynn, F. et al. Serotonin regulates pancreatic beta cell mass during pregnancy. Nat Med 16, 804–808 (2010). https://doi.org/10.1038/nm.2173

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.2173

Further reading

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing