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

Abstract

β-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 β-cell responses in pregnancy; however, the in vivo requirement for PRLR signaling specifically in maternal β-cell adaptations remains unknown. We generated a floxed allele of Prlr, allowing conditional loss of PRLR in β-cells. In this study, we show that loss of PRLR signaling in β-cells results in gestational diabetes mellitus (GDM), reduced β-cell proliferation, and failure to expand β-cell mass during pregnancy. Targeted PRLR loss in maternal β-cells in vivo impaired expression of the transcription factor Foxm1, both G1/S and G2/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 β-cells during pregnancy. MafB deletion in maternal β-cells also produced GDM, with inadequate β-cell expansion accompanied by failure to induce PRLR-dependent target genes regulating β-cell proliferation. These results unveil molecular roles for PRLR signaling in orchestrating the physiologic expansion of maternal β-cells during pregnancy.

Genetic Disruption of Adenosine Kinase in Mouse Pancreatic β-Cells Protects Against High-Fat Diet–Induced Glucose Intolerance

“…Overexpression of CTGF in mature β-cells has no impact on β-cell proliferation but enhances β-cell expansion under diabetogenic conditions (37). Similarly, β-cell–specific deletion of the prolactin receptor has no impact on β-cell mass or function under basal conditions but predisposes female mice to gestational diabetes mellitus by dampening the β-cell replication response during pregnancy (38). Although the molecular links among CTGF, prolactin signaling, and ADK are not immediately obvious, these models highlight the potential to therapeutically manipulate the adaptive response of β-cells.…”

Prolactin Receptor Signaling Regulates a Pregnancy-Specific Transcriptional Program in Mouse Islets

“…Female transgenic mice lacking PRLR within pancreatic β-cells (βPRLRKO) were used in the current study, as previously developed and described (14). For gestational studies, 8-week-old virgin females were mated with C57Bl6/J males and vaginal plugs scored as GD0.5.…”

“…Islets were isolated from donor mice using retrograde perfusion of the pancreatic duct with collagenase and purified using density centrifugation as previously described (14). Donor mice included βPRLRKO and littermate controls or C57Bl6/J mice either from virgin females (nonpregnant) or at gestational day (GD) 16.5 (pregnant).…”

“…Most mammals, including rodents and primates, produce pituitary-derived prolactin and placental lactogens, which both signal through the prolactin receptor (PRLR) (9–12). We and others have established a critical role for PRLR signaling in rodent gestational β-cell proliferation (13), with the lack of PRLR expression in β-cells resulting in a failure of islets to proliferate during gestation (14). Conversely, β-cell specific overexpression of placental lactogens increases pancreatic islet proliferation and mass (15).…”

“…Together these studies illustrate that increases in circulating lactogens during pregnancy are essential and sufficient to orchestrate key components of metabolic adaptations to pregnancy. Downstream targets of PRLR signaling that contribute to gestational proliferation include tryptophan hydroxylase 1 ( Tph1) , the rate limiting enzyme for islet serotonin synthesis (16), transcription factors such as Foxm1 (17) and MafB (14), osteoprotegerin ( Tnfrsf11b ), menin ( Men1 ), as well as cyclins, cyclin-dependent kinases, cell cycle inhibitors and Prlr itself (14,16,18-20). However, a global assessment of how PRLR signaling regulates β-cell transcription during gestation is lacking.…”