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 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 G alpha(q)-linked serotonin receptor 5-hydroxytryptamine receptor-2b (Htr2b) in maternal islets increased during pregnancy and normalized just before parturition, whereas expression of the G alpha(i)-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.
Kim
Hail
H
Diabetes Center, University of California-San Francisco, San Francisco, California, USA.
Toyofuku
Yukiko
Y
Lynn
Francis C
FC
Chak
Eric
E
Uchida
Toyoyoshi
T
Mizukami
Hiroki
H
Fujitani
Yoshio
Y
Kawamori
Ryuzo
R
Miyatsuka
Takeshi
T
Kosaka
Yasuhiro
Y
Yang
Katherine
K
Honig
Gerard
G
van der Hart
Marieke
M
Kishimoto
Nina
N
Wang
Juehu
J
Yagihashi
Soroku
S
Tecott
Laurence H
LH
Watada
Hirotaka
H
German
Michael S
MS
D000818:Animals; D005260:Female; D020869:Gene Expression Profiling; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000502:physiology; D007515:Islets of Langerhans / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D010928:Placental Lactogen / Q000378:metabolism; D011247:Pregnancy; D011270:Pregnancy, Animal; D011388:Prolactin / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D014365:Tryptophan Hydroxylase / Q000378:metabolism
D007328:Insulin; D012701:Serotonin; D011388:Prolactin; D010928:Placental Lactogen; C497467:TPH1 protein, human; C494784:TPH2 protein, human; C487801:Tph1 protein, mouse; C487802:Tph2 protein, mouse; D014365:Tryptophan Hydroxylase; D005947:Glucose