Beta cell adaptation to pregnancy requires prolactin action on both beta and non-beta cells
Vipul Shrivastava, Megan Lee, Daniel Lee, Marle Pretorius, Bethany N. Radford, Guneet Makkar, Carol Huang
Abstract
Abstract Pancreatic islets adapt to insulin resistance of pregnancy by up regulating β-cell mass and increasing insulin secretion. Previously, using a transgenic mouse with global, heterozygous deletion of prolactin receptor (Prlr +/− ), we found Prlr signaling is important for this adaptation. However, since Prlr is expressed in tissues outside of islets as well as within islets and prolactin signaling affects β-cell development, to understand β-cell-specific effect of prolactin signaling in pregnancy, we generated a transgenic mouse with an inducible conditional deletion of Prlr from β-cells. Here, we found that β-cell-specific Prlr reduction in adult mice led to elevated blood glucose, lowed β-cell mass and blunted in vivo glucose-stimulated insulin secretion during pregnancy. When we compared gene expression profile of islets from transgenic mice with global (Prlr +/− ) versus β-cell-specific Prlr reduction (βPrlR +/− ), we found 95 differentially expressed gene, most of them down regulated in the Prlr +/− mice in comparison to the βPrlR +/− mice, and many of these genes regulate apoptosis, synaptic vesicle function and neuronal development. Importantly, we found that islets from pregnant Prlr +/− mice are more vulnerable to glucolipotoxicity-induced apoptosis than islets from pregnant βPrlR +/− mice. These observations suggest that down regulation of prolactin action during pregnancy in non-β-cells secondarily and negatively affect β-cell gene expression, and increased β-cell susceptibility to external insults.