Serotonin regulates pancreatic beta cell mass during pregnancy
Open accessAbstract
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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In animal studies, β-cell proliferation occurs during pregnancy via prolactin receptor-STAT5-serotonin-HTR2B activation.
“In animal studies, β-cell proliferation occurs during pregnancy via prolactin receptor-STAT5-serotonin-HTR2B activation [80].”
From Gestational Diabetes Mellitus: Diagnostic Approaches and Maternal-Offspring Complications (2022) · cites this paper as [80]
The paper reports that prolactin induces Tph1 in mouse islets and that serotonin signaling through Htr2b stimulates β-cell proliferation during pregnancy (passages labeled Abstract; Fig. 4a and 4h). It mentions increased prolactin-receptor signaling, but our copy does not establish STAT5 as a step in this pathway. (LLM, conf=0.88)
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Cites
β-Cell Deficit and Increased β-Cell Apoptosis in Humans With Type 2 Diabetes
Butler, A. E., Janson, J., Bonner-Weir, S., Ritzel, R., Rizza, R. A., & Butler, P. C. (2003) · Diabetes · doi:10.2337/diabetes.52.1.102 · Cited by 4,011 · see citing works
International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (Serotonin).
Hoyer, D., Clarke, D. E., Fozard, J. R., Hartig, P. R., Martin, G. R., Mylecharane, E. J., Saxena, P. R., & Humphrey, P. P. A. (1994) · Pharmacological Reviews · doi:10.1016/s0031-6997(25)06783-3 · Cited by 2,997 · see citing works
Buchanan, T. A., & Xiang, A. H. (2005) · Journal of Clinical Investigation · doi:10.1172/jci200524531 · Cited by 2,123 · see citing works
Depression and Type 2 Diabetes Over the Lifespan
Mezuk, B., Eaton, W. W., Albrecht, S., & Golden, S. H. (2008) · Diabetes Care · doi:10.2337/dc08-0985 · Cited by 1,558 · see citing works
Platelet-Derived Serotonin Mediates Liver Regeneration
Lesurtel, M., Graf, R., Aleil, B., Walther, D. J., Tian, Y., Jochum, W., Gachet, C., Bäder, M., & Clavien, P. (2006) · Science · doi:10.1126/science.1123842 · Cited by 783 · see citing works
Rothman, R. B., Baumann, M. H., Savage, J. E., Rauser, L., McBride, A., Hufeisen, S. J., & Roth, B. L. (2000) · Circulation · doi:10.1161/01.cir.102.23.2836 · Cited by 722 · see citing works
Sorenson, R., & Brelje, T. (1997) · Hormone and Metabolic Research · doi:10.1055/s-2007-979040 · Cited by 531 · see citing works
What Can We Learn from Rodents about Prolactin in Humans?
Ben‐Jonathan, N., LaPensee, C. R., & LaPensee, E. W. (2007) · Endocrine Reviews · doi:10.1210/er.2007-0017 · Cited by 527 · see citing works
Parsons, J. A. (1992) · Endocrinology · doi:10.1210/en.130.3.1459 · Cited by 476 · see citing works
Possible Role of Valvular Serotonin 5-HT2B Receptors in the Cardiopathy Associated with Fenfluramine
Fitzgerald, L. W., Burn, T. C., Brown, B. S., Patterson, J. P., Corjay, M. H., Valentine, P. A., Sun, J., Link, J. R., Abbaszade, I. G., Hollis, J. M., et al. (2000) · Molecular Pharmacology · doi:10.1016/s0026-895x(24)26444-0 · Cited by 440 · see citing works
Brelje, T. C., Scharp, D. W., Lacy, P. E., Ogren, L., Talamantes, F. J., Robertson, M. C., Friesen, H. G., & Sorenson, R. L. (1993) · Endocrinology · doi:10.1210/endo.132.2.8425500 · Cited by 409 · see citing works
Serotonin 2B receptor is required for heart development
Nebigil, C. G., Choi, D., Dierich, A., Hickel, P., LeMeur, M., Messaddeq, N., Launay, J., & Maroteaux, L. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.17.9508 · Cited by 382 · see citing works
Karnik, S. K., Chen, H., McLean, G. W., Heit, J. J., Gu, X., Zhang, A. Y., Fontaine, M., Yen, M. H., & Kim, S. K. (2007) · Science · doi:10.1126/science.1146812 · Cited by 353 · see citing works
Transgenic mice with green fluorescent protein-labeled pancreatic β-cells
Hara, M., Wang, X., Kawamura, T., Bindokas, V. P., Dizon, R. F., Alcoser, S. Y., Magnuson, M. A., & Bell, G. I. (2003) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00321.2002 · Cited by 293 · see citing works
Huang, C., Snider, F., & Cross, J. C. (2009) · Endocrinology · doi:10.1210/en.2008-1003 · Cited by 275 · see citing works
A MORPHOLOGICAL STUDY OF THE ENDOCRINE PANCREAS IN HUMAN PREGNANCY
Van Assche, F. A., Aerts, L., & Prins, F. D. (1978) · BJOG: An International Journal of Obstetrics & Gynaecology · doi:10.1111/j.1471-0528.1978.tb15835.x · Cited by 267 · see citing works
Freemark, M. (2002) · Endocrinology · doi:10.1210/en.143.4.1378 · Cited by 258 · see citing works
Serotonin Regulates Mammary Gland Development via an Autocrine-Paracrine Loop
Matsuda, M., Imaoka, T., Vomachka, A. J., Gudelsky, G. A., Hou, Z., Mistry, M. J., Bailey, J. P., Nieport, K. M., Walther, D. J., Bäder, M., et al. (2004) · Developmental Cell · doi:10.1016/s1534-5807(04)00022-x · Cited by 250 · see citing works
Gianfrancesco, F. D., Grogg, A. L., Mahmoud, R. A., Wang, R., & Nasrallah, H. A. (2002) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.v63n1010 · Cited by 238 · see citing works
Association between diabetes and perinatal depression among low-income mothers.
Kozhimannil, K., Pereira, M. A., & Harlow, B. (2009) · Journal of the American Medical Association (JAMA) · doi:10.1001/jama.2009.201 · Cited by 227 · see citing works
Vasavada, R. C., Garcia-Ocaña, A., Zawalich, W. S., Sorenson, R. L., Dann, P., Syed, M., Ogren, L., Talamantes, F., & Stewart, A. F. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.20.15399 · Cited by 212 · see citing works
CaMKII?-cre transgene expression and recombination patterns in the mouse brain
Dragatsis, I., & Zeitlin, S. O. (2000) · genesis · doi:10.1002/(sici)1526-968x(200002)26:2 · Cited by 171 · see citing works
Sakowski, S. A., Geddes, T. J., Thomas, D. M., Levi, E., Hatfield, J. S., & Kuhn, D. M. (2006) · Brain Research · doi:10.1016/j.brainres.2006.02.047 · Cited by 147 · see citing works
The serotonin 5‐HT 2B receptor controls bone mass via osteoblast recruitment and proliferation
Collet, C., Schiltz, C., Geoffroy, V., Maroteaux, L., Launay, J., & de Vernejoul, M. C. (2007) · The FASEB Journal · doi:10.1096/fj.07-9209com · Cited by 119 · see citing works
Møldrup, A., Petersen, E. D., & Nielsen, J. H. (1993) · Endocrinology · doi:10.1210/endo.133.3.8365359 · Cited by 115 · see citing works
Wouters, M., Gibbons, S., Roeder, J. L., Distad, M., Ou, Y., Strege, P., Szurszewski, J., & Farrugia, G. (2007) · Gastroenterology · doi:10.1053/j.gastro.2007.06.017 · Cited by 87 · see citing works
Abnormal Glucose Regulation of Insulin Secretion in Models of Reduced B-Cell Mass
Leahy, J. L., Bonner‐Weir, S., & Weir, G. C. (1984) · Diabetes · doi:10.2337/diab.33.7.667 · Cited by 84 · see citing works
Tryptophan-Free Diets: A Physiological Tool to Study Brain Serotonin Function
Fadda, F. (2000) · Physiology · doi:10.1152/physiologyonline.2000.15.5.260 · Cited by 55 · see citing works
Goodner, C. J., Koerker, D. J., Weigle, D. S., & McCulloch, D. K. (1989) · Diabetes · doi:10.2337/diab.38.7.925 · Cited by 42 · see citing works
5-HT2B-mediated serotonin signaling is required for eye morphogenesis in Xenopus
Lucchini, S. D., Ori, M., Cremisi, F., Nardini, M., & Nardi, I. (2005) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2005.03.008 · Cited by 28 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
The use of animal models in diabetes research
King, A. J. (2012) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2012.01911.x · Cited by 1,303 · see citing works
A transient placental source of serotonin for the fetal forebrain
Bonnin, A., Goeden, N., Chen, K., Wilson, M. L., King, J., Shih, J. C., Blakely, R. D., Deneris, E. S., & Levitt, P. (2011) · Nature · doi:10.1038/nature09972 · Cited by 608 · see citing works
The serotonin system in autism spectrum disorder: From biomarker to animal models
Muller, C. L., Anacker, A. M. J., & Veenstra-VanderWeele, J. (2016) · Neuroscience · doi:10.1016/j.neuroscience.2015.11.010 · Cited by 531 · see citing works
The Role of Placental Hormones in Mediating Maternal Adaptations to Support Pregnancy and Lactation
Napso, T., Yong, H. E. J., Lopez-Tello, J., & Sferruzzi-Perri, A. N. (2018) · Frontiers in Physiology · doi:10.3389/fphys.2018.01091 · Cited by 470 · see citing works
Gestational Diabetes Mellitus: Diagnostic Approaches and Maternal-Offspring Complications
Moon, J. H., & Jang, H. C. (2022) · Diabetes & Metabolism Journal · doi:10.4093/dmj.2021.0335 · Cited by 377 · see citing works
Benner, C., van der Meulen, T., Cacéres, E., Tigyi, K., Donaldson, C. J., & Huising, M. O. (2014) · BMC Genomics · doi:10.1186/1471-2164-15-620 · Cited by 302 · see citing works
Non-conventional features of peripheral serotonin signalling — the gut and beyond
Spohn, S. N., & Mawe, G. M. (2017) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2017.51 · Cited by 282 · see citing works
Inter-organ cross-talk in metabolic syndrome
Priest, C., & Tontonoz, P. (2019) · Nature Metabolism · doi:10.1038/s42255-019-0145-5 · Cited by 279 · see citing works
The diverse metabolic roles of peripheral serotonin
Martin, A. M., Young, R. L., Leong, L., Rogers, G. B., Spencer, N. J., Jessup, C. F., & Keating, D. J. (2017) · Endocrinology · doi:10.1210/en.2016-1839 · Cited by 261 · see citing works
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Baeyens, L., Hindi, S., Sorenson, R. L., & German, M. S. (2016) · Diabetes, Obesity and Metabolism · doi:10.1111/dom.12716 · Cited by 210 · see citing works
Self-citationLorenzo-Almorós, A., Hang, T., Peiró, C., Soriano-Guillén, L., Egido, J., Tuñón, J., & Lorenzo, Ó. (2019) · Cardiovascular Diabetology · doi:10.1186/s12933-019-0935-9 · Cited by 202 · see citing works
Human β-Cell Proliferation and Intracellular Signaling: Part 3
Stewart, A. F., Hussain, M. A., García-Ocaña, A., Vasavada, R. C., Bhushan, A., Bernal-Mizrachi, E., & Kulkarni, R. N. (2015) · Diabetes · doi:10.2337/db14-1843 · Cited by 142 · see citing works
Liver-derived systemic factors drive β cell hyperplasia in insulin-resistant states
El Ouaamari, A., Kawamori, D., Dirice, E., Liew, C. W., Shadrach, J. L., Hu, J., Katsuta, H., Hollister-Lock, J., Qian, W.-J., Wagers, A. J., et al. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.01.007 · Cited by 136 · see citing works
Sex differences underlying pancreatic islet biology and its dysfunction
Gannon, M., Kulkarni, R. N., Tse, H. M., & Mauvais-Jarvis, F. (2018) · Molecular Metabolism · doi:10.1016/j.molmet.2018.05.017 · Cited by 133 · see citing works
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Banerjee, R. R., Cyphert, H. A., Walker, E. M., Chakravarthy, H., Peiris, H., Gu, X., Liu, Y., Conrad, E., Goodrich, L., Stein, R. W., et al. (2016) · Diabetes · doi:10.2337/db15-1527 · Cited by 131 · see citing works
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Love, C., Sominsky, L., O’Hely, M., Berk, M., Vuillermin, P., & Dawson, S. L. (2024) · BMC Medicine · doi:10.1186/s12916-024-03617-3 · Cited by 110 · see citing works
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Mazucanti, C. H., Liu, Q.-R., Lang, D., Huang, N., O’Connell, J. F., Camandola, S., & Egan, J. M. (2019) · JCI Insight · doi:10.1172/jci.insight.131682 · Cited by 101 · see citing works
Advancements and challenges in generating accurate animal models of gestational diabetes mellitus
Pasek, R. C., & Gannon, M. (2013) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00425.2013 · Cited by 90 · see citing works
Lactation improves pancreatic β cell mass and function through serotonin production
Moon, J. H., Kim, H., Kim, H., Park, J., Choi, W., Choi, W., Hong, H. J., Ro, H.-J., Jun, S., Choi, S. H., et al. (2020) · Science Translational Medicine · doi:10.1126/scitranslmed.aay0455 · Cited by 67 · see citing works
Self-citationRetnakaran, R., Ye, C., Kramer, C. K., Connelly, P. W., Hanley, A. J., Sermer, M., & Zinman, B. (2016) · Diabetes Care · doi:10.2337/dc16-0043 · Cited by 64 · see citing works
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Auffret, J., Freemark, M., Carré, N., Mathieu, Y., Tourrel-Cuzin, C., Lombès, M., Movassat, J., & Binart, N. (2013) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00636.2012 · Cited by 46 · see citing works
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Hwang, H.-J., Yang, Y. R., Kim, H. Y., Choi, Y., Park, K.-S., Lee, H., Ma, J. S., Yamamoto, M., Kim, J., Chae, Y. C., et al. (2019) · The FASEB Journal · doi:10.1096/fj.201802732rr · Cited by 20 · see citing works
Self-citation
- Authors
- Kim, H., Toyofuku, Y., Lynn, F. C., Chak, E., Uchida, T., Mizukami, H., Fujitani, Y., Kawamori, R., Miyatsuka, T., Kosaka, Y., Yang, K., Honig, G., van der Hart, M., Kishimoto, N., Wang, J., Yagihashi, S., Tecott, L. H., Watada, H., & German, M. S.
- Affiliations
- University of California, San Francisco (US)
- Juntendo University (JP)
- University of British Columbia (CA)
- Hirosaki University (JP)
- Corresponding author
- German, Michael S
- ORCID
- Venue
- Nature Medicine
- Published
- 2010-06-27
- Volume
- 16
- Issue
- 7
- Pages
- 804-808
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC2921604
- OpenAlex
- W2051567027
- Semantic Scholar
- 6cdf0b29e2974bf0d57eb10db3b0055499dc324e
- Cited by
- 586
- References
- 30
- Citations by year
- 2026: 19 · 2025: 32 · 2024: 36 · 2023: 29 · 2022: 49 · 2021: 41 · 2020: 34 · 2019: 44 · 2018: 43 · 2017: 47 · 2016: 39 · 2015: 38 · 2014: 37 · 2013: 30 · 2012: 39
- FWCI
- 32.69
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (U19DK061245, R01DK021344, P30DK063720)
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Health Sciences › Medicine › Obstetrics and Gynecology › Gestational Diabetes Research and Management
- Keywords
- serotonin, pancreatic beta cells, beta-cell mass, pregnancy, prolactin, placental lactogen, tryptophan hydroxylase 1, HTR2B, impaired glucose tolerance, gestational diabetes mellitus, insulin resistance, maternal metabolism
- MeSH terms
- Animals, Female, Glucose, Insulin, Islets of Langerhans, Mice, Inbred C57BL, Placental Lactogen, Pregnancy, Pregnancy, Animal, Prolactin, Serotonin, Tryptophan Hydroxylase, Gene Expression Profiling, Insulin-Secreting Cells, Mice
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