Serotonin regulates pancreatic beta cell mass during pregnancy

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-cells1–3. 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 Gαq-linked serotonin receptor Htr2b in maternal islets increased during pregnancy and normalized just prior to parturition, while expression of the Gαi-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 diabetes4.

Effects of Glucocorticoid Treatment on β- and α-Cell Mass in Japanese Adults With and Without Diabetes

“…It has been reported that BCM is increased by 20 to 50% in obese adult humans without diabetes (8,11), to a smaller degree than in rodents, which usually show a two-to threefold increase (4,5), consistent with lower b-cell turnover in adult humans. Recently, we have also reported that in the Japanese population, no significant increase in BCM was observed in obese adults without diabetes (12).…”

“…In rodents, b-cells have been shown to be able to adaptively increase in response to an increased insulin demand such as obesity or pregnancy (3)(4)(5). However, b-cell proliferation in humans has been reported to rapidly decrease within 5 years after birth, and only minimal b-cell proliferation is observed in adults (6)(7)(8).…”

Diabetes Enhances the Proliferation of Adult Pancreatic Multipotent Progenitor Cells and Biases Their Differentiation to More β-Cell Production

“…Detection of b-cell regeneration under physiologic conditions such as pregnancy or diabetes predisposition is a relatively old concept (3,4), but the mechanisms involved, such as self-replication of preexisting b-cells or participation of a stem-like cell population, are still the topic of ongoing debates. Nevertheless, the presence and contribution of adult pancreatic multipotent progenitor (PMP) populations in b-cell maintenance, particularly in injured pancreas, have been documented (5)(6)(7).…”

Epidermal growth factor (EGF)-receptor signalling is needed for murine beta cell mass expansion in response to high-fat diet and pregnancy but not after pancreatic duct ligation

“…Recently it has been shown that EGFR regulates the stability of survivin [42], an oncofetal protein with both pro-proliferative and antiapoptotic functions. Furthermore, it was also shown that, during pregnancy, the synthesis of serotonin and its receptor 5-hydroxytryptamine receptor-2b (5-HTR2B) are upregulated in beta cells and by inhibiting the 5-Htr2b, the maternal beta cell mass expansion is blocked [43,44]. These cells were not present in the unligated pancreatic head in (a) wild-type or (c) E1-DN mice.…”