Gestational Diabetes Mellitus From Inactivation of Prolactin Receptor and MafB in Islet β-Cells

beta-Cell proliferation and expansion during pregnancy are crucial for maintaining euglycemia in response to increased metabolic demands placed on the mother. Prolactin and placental lactogen signal through the prolactin receptor (PRLR) and contribute to adaptive beta-cell responses in pregnancy; however, the in vivo requirement for PRLR signaling specifically in maternal beta-cell adaptations remains unknown. We generated a floxed allele of Prlr, allowing conditional loss of PRLR in beta-cells. In this study, we show that loss of PRLR signaling in beta-cells results in gestational diabetes mellitus (GDM), reduced beta-cell proliferation, and failure to expand beta-cell mass during pregnancy. Targeted PRLR loss in maternal beta-cells in vivo impaired expression of the transcription factor Foxm1, both G(1)/S and G(2)/M cyclins, tryptophan hydroxylase 1 (Tph1), and islet serotonin production, for which synthesis requires Tph1. This conditional system also revealed that PRLR signaling is required for the transient gestational expression of the transcription factor MafB within a subset of beta-cells during pregnancy. MafB deletion in maternal beta-cells also produced GDM, with inadequate beta-cell expansion accompanied by failure to induce PRLR-dependent target genes regulating beta-cell proliferation. These results unveil molecular roles for PRLR signaling in orchestrating the physiologic expansion of maternal beta-cells during pregnancy.