Beta-cell adaptation to metabolic stresses requires prolactin receptor signaling

Abstract

AbstractThe role of prolactin receptor (PRLR) signaling in β-cell adaptation to maternal insulin resistance of pregnancy has been well demonstrated. Using transgenic mice with an inducible β-cell-specific Prlr deletion (βPrlr-/-), we found that intact PRLR, as found in βPrlr+/+mice, were protected from developing glucose intolerance during pregnancy, and the main mechanism responsible for this PRLR-mediated effect is the up regulation of β-cell proliferation and insulin synthesis. Interestingly, studies in male mice and humans have found a link between diminished PRLR signaling and abnormal β-cell function. We aimed to determine whether PRLR has a role in regulating β-cell function outside of pregnancy, protecting β-cell against exposure to metabolic stressors.In this study, we found that β-cell-specific PRLR reduction resulted in impaired glucose tolerance in multiparous female mice challenged with a 12-week course of high-fat diet (HFD). Unlike in pregnancy, where PRLR signaling up regulates β-cell proliferation resulting in a greater β-cell mass, we observed no difference in β-cell mass between the wild type (βPrlr+/+) and mutant (βPrlr-/-) mice. In vitro glucose-stimulated insulin secretion using isolated islets from wild type (βPrlr+/+) and mutant (βPrlr-/-) mice showed comparable insulin response, but βPrlr-/-mice showed blunted first-phase insulin release in vivo, although only when challenged with glucose orally and not intraperitoneally, suggesting an impairment of the incretin effect. In support of the observed defect in incretin action, we found a reduction in expression of both incretin hormone receptors,GiprandGlp-1r, and several of their upstream regulators, such asE2f1, Nkx6.1, Pax6, Pparγ, andTcf7l2. Islets from the mutant mice also have a lower insulin content and reduced levels of genes that regulate glucose metabolism. Together, these results suggested that PRLR signaling plays an important role in preserving β-cell function in mice exposed to metabolic stress by maintaining incretin receptor expression and insulin secretory capacity in β cells.