Pancreatic prolactin receptor signaling regulates maternal glucose homeostasis.

Prolactin (PRL) signaling has been implicated in the regulation of glucose homeostatic adaptations to pregnancy. In this report, the PRL receptor (Prir) gene was conditionally disrupted in the pancreas, creating an animal model which proved useful for investigating the biology and pathology of gestational diabetes including its impacts on fetal and placental development. In mice, pancreatic PRLR signaling was demonstrated to be required for pregnancy-associated changes in maternal l cell mass and function. Disruption of the Prlr gene in the pancreas resulted in fewer insulin-producing cells, which failed to expand appropriately during pregnancy resulting in reduced blood insulin levels and maternal glucose intolerance. This inability to sustain normal blood glucose balance during pregnancy worsened with age and a successive pregnancy. The etiology of the insulin insufficiency was attributed to deficits in regulatory pathways controlling cell differentiation. Additionally, the disturbance in maternal blood glucose homeostasis was associated with fetal overgrowth and dysregulation of inflammation and PRL-associated transcripts in the placenta. Overall, these results indicate that the PRLR, acting within the pancreas, mediates maternal pancreatic adaptations to pregnancy. PRLR dysfunction is associated with glucose intolerance during pregnancy and pathological features consistent with gestational diabetes.