Serotonin Regulates Pancreatic β-Cell Mass during Pregnancy

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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, while prolactin and placental lactogen counterbalance this resistance and prevent maternal hyperglycemia by driving expansion of the maternal population of insulin-producing β-cells 1– 3. However, the exact mechanisms by which the lactogenic hormones drive β-cell expansion remain uncertain. Here we show that serotonin acts downstream of lactogen signaling to drive β-cell proliferation. Serotonin synthetic enzyme Tph1 and serotonin production increased sharply in β-cells during pregnancy or after treatment with lactogens in vitro. Inhibition of serotonin synthesis by dietary tryptophan restriction or Tph inhibition blocked β-cell expansion and induced glucose intolerance in pregnant mice without affecting insulin sensitivity. Expression of the Gα _q-linked serotonin receptor Htr2b in maternal islets increased during pregnancy and normalized just prior to parturition, while expression of the Gα _i-linked receptor Htr1d increased at the end of pregnancy and postpartum. Blocking Htr2b signaling in pregnant mice also blocked β-cell expansion and caused glucose intolerance. These studies reveal an integrated signaling pathway linking β-cell mass to anticipated insulin need during pregnancy. Modulators of this pathway, including medications and diet, may affect the risk of gestational diabetes 4.

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Most cited references 20

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Gestational diabetes mellitus.

Thomas A Buchanan, Anny H Xiang (2005)

Gestational diabetes mellitus (GDM) is defined as glucose intolerance of various degrees that is first detected during pregnancy. GDM is detected through the screening of pregnant women for clinical risk factors and, among at-risk women, testing for abnormal glucose tolerance that is usually, but not invariably, mild and asymptomatic. GDM appears to result from the same broad spectrum of physiological and genetic abnormalities that characterize diabetes outside of pregnancy. Indeed, women with GDM are at high risk for having or developing diabetes when they are not pregnant. Thus, GDM provides a unique opportunity to study the early pathogenesis of diabetes and to develop interventions to prevent the disease.

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What can we learn from rodents about prolactin in humans?

Nira Ben-Jonathan, Christopher LaPensee, Elizabeth W. LaPensee (2008)

Prolactin (PRL) is a 23-kDa protein hormone that binds to a single-span membrane receptor, a member of the cytokine receptor superfamily, and exerts its action via several interacting signaling pathways. PRL is a multifunctional hormone that affects multiple reproductive and metabolic functions and is also involved in tumorigenicity. In addition to being a classical pituitary hormone, PRL in humans is produced by many tissues throughout the body where it acts as a cytokine. The objective of this review is to compare and contrast multiple aspects of PRL, from structure to regulation, and from physiology to pathology in rats, mice, and humans. At each juncture, questions are raised whether, or to what extent, data from rodents are relevant to PRL homeostasis in humans. Most current knowledge on PRL has been obtained from studies with rats and, more recently, from the use of transgenic mice. Although this information is indispensable for understanding PRL in human health and disease, there is sufficient disparity in the control of the production, distribution, and physiological functions of PRL among these species to warrant careful and judicial extrapolation to humans.

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Adaptation of islets of Langerhans to pregnancy: increased islet cell proliferation and insulin secretion correlates with the onset of placental lactogen secretion.

J. Parsons, R Sorenson, T Brelje (1992)

To elucidate the temporal profile of adaptive changes of the islets of Langerhans to the increased insulin demands of pregnancy, we have studied islet cell proliferation and insulin secretion during gestation in the rat. 5-Bromo-2'-deoxyuridine incorporation into dividing islet cells was significantly (P less than 0.05) increased over age-matched controls by day 10, rose continuously to a peak at day 14, and then returned to control levels by day 18. By day 20, cell division was significantly inhibited (P less than 0.05). The pattern of changes in insulin secretory profiles observed with perfused pancreata of pregnant animals was similar to that obtained for islet cell proliferation. Both the threshold of glucose-stimulated insulin secretion and the amount of above threshold insulin secretion began to diverge from controls by day 10. By day 12, the glucose-stimulation threshold was significantly decreased from 5.7 mM glucose to 3.3 mM (P less than 0.05), remained at this low level through day 15, and returned toward normal by day 20. Concomitant with the increased sensitivity of B cells to glucose, the above threshold insulin secretion was significantly increased by day 12 (P less than 0.05), peaked at day 15, and returned to control levels by day 20. This insulin secretory data demonstrates that the increased sensitivity of B cells to glucose is an important component of the adaptation of islets during pregnancy to the increased demand for insulin at physiological concentrations of plasma glucose. To correlate the above changes in islet cell proliferation and insulin secretion with levels of placental lactogen (PL), serum lactogenic hormone activity was measured by Nb2 lymphoma cell replication assays. This analysis revealed the expected biphasic pattern: a midpregnancy peak at day 12, followed by a nadir at day 14, and then continuously elevated levels until term. The bioassay data agreed with the known secretory profiles of rat (r) PL-I (midpregnancy) and rPL-II (late pregnancy). Our results provide the first systematic evaluation of changes in islet function during pregnancy in the rat. In addition, they provide evidence that rPL-I may be the critical hormonal signal which triggers the primary adaptive changes in islet function characteristic of pregnancy. The return to normal values of insulin secretion and inhibition of cell division observed at day 20 in the presence of high concentrations of rPL-II suggests that other inhibitory influences become dominant in the later stages of rat pregnancy.(ABSTRACT TRUNCATED AT 400 WORDS)

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Author and article information

Journal

Journal ID (nlm-journal-id): 9502015

Journal ID (pubmed-jr-id): 8791

Journal ID (nlm-ta): Nat Med

Title: Nature medicine

ISSN (Print): 1078-8956

ISSN (Electronic): 1546-170X

Publication date Nihms-submitted: 9 July 2010

Publication date (Electronic): 27 June 2010

Publication date (Print): July 2010

Publication date PMC-release: 1 January 2011

Volume: 16

Issue: 7

Pages: 804-808

Affiliations

[1 ] Diabetes Center, University of California San Francisco, San Francisco, CA 94143, USA

[2 ] Department of Medicine, Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo 113–8421, Japan

[4 ] Department of Pathology and Molecular Medicine, Hirosaki University Graduate Schoolof Medicine, Hirosaki 036–8562, Japan

[5 ] Center for Therapeutic Innovations in Diabetes, Juntendo University Graduate School of Medicine, Tokyo 113–8421, Japan

[6 ] Center for Beta Cell Biology and Regeneration, Juntendo University Graduate School of Medicine, Tokyo 113–8421, Japan

[7 ] Sportology Center, Juntendo University Graduate School of Medicine, Tokyo 113–8421, Japan

[8 ] Department of Psychiatry, University of California San Francisco, San Francisco, CA 94143, USA

[9 ] Department of Medicine, University of California San Francisco, San Francisco, CA 94143, USA

Author notes

[10 ]Corresponding author: UCSF Diabetes Center, University of California San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143-0534, Tel: (415) 476-9262, Fax: (415) 731-3612, mgerman@ 123456diabetes.ucsf.edu

[3]

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

Correspondence and requests for materials should be addressed to M.S.G. ( mgerman@ 123456diabetes.ucsf.edu )

Present address of F.C.L.: Child and Family Research Institute, Departments of Surgery and Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada.

Article

Manuscript ID: nihpa210087

DOI: 10.1038/nm.2173

PMC ID: 2921604

PubMed ID: 20581837

SO-VID: 0564252d-c59c-4ec6-960d-84fa74a16db3

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