Beta cell adaptation to pregnancy requires prolactin action on both beta and non-beta cells

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.

Prolactin-Induced Adaptation in Glucose Homeostasis in Mouse Pregnancy Is Mediated by the Pancreas and Not in the Forebrain

“…Identification of the site of action is an important step to determining the mechanism of prolactin receptor activity, and if this will be a useful target for intervention. Our work has replicated previous studies that have deleted Prlr specifically from the beta-cells (11), pancreas (12), and adult onset deletion from the pancreas (42) demonstrating that Prlr activity in the pancreas is required for maternal adaptations in beta-cells during pregnancy. Moreover, in the current study we have demonstrated that these transgenic mice lines with beta-cellor pancreas-specific deletions of the Prlr also show deletion of Prlr in the hypothalamus, particularly the arcuate nucleus, an area known to contribute to central regulation of insulin secretion and glucose homeostasis (18-20, 35, 43, 44).…”

“…A critical omission from previous studies examining the effect of specific deletion of Prlr from the pancreas ( 11 , 12 ) was an examination of the brain to determine the extent to which central Prlr were affected in these transgenic mice lines ( 15 ). This has been somewhat addressed in a recent study in mice in which Prlr was deleted from the pancreas in adulthood using a tamoxifen-inducible Cre line, as mRNA for Prlr in the entire hypothalamus was reported to be no different to control mice ( 42 ). Given that we only detected recombination of the Prlr gene in a small population of cells in the arcuate nucleus using the Pdx-cre line, however, and that Prlr is extensively expressed in the hypothalamus ( 16 ) it is perhaps not surprising that no change of Prlr mRNA would be detected when assessing the entire hypothalamus as a whole.…”

“…Again, an important caveat is that transcriptome data for humans came from post mortem subjects (both male and female), mostly beyond reproductive age. There is also evidence from mice that non-beta cells in the pancreas are important for Prlr related effects on beta-cells ( 42 ) and Prlr expression is also enriched in non-beta cells from the human pancreas ( 64 ). In mice, alpha-cells in the pancreas undergo Prlr-induced adaptations in function during pregnancy ( 65 ).…”

Research Advances in the Roles of Circular RNAs in Pathophysiology and Early Diagnosis of Gestational Diabetes Mellitus

“…In GDM, inactivation of prolactin receptors on the surface of islet β cells promotes apoptosis and inhibits proliferation of β cells ( Banerjee et al, 2016 ). Moreover, down-regulation of prolactin action in non-beta cells during pregnancy negatively secondary affects beta cell gene expression and increases beta cell susceptibility to external injury ( Shrivastava et al, 2021 ). Adiponectin plays an important role in the proliferation of beta cells during pregnancy by promoting prolactin expression in trophoblast cells ( Qiao et al, 2021 ).…”

Exogenous Lactogenic Signaling Stimulates Beta Cell Replication In Vivo and In Vitro

“…While the models of PRL overexpression and PRLR activation have been informative, their conclusions are confounded by multiple factors in the endogenous pregnancy milieu [ 8 , 12 , 13 , 14 , 15 ]. Litter size dictates exposure to PL expression during pregnancy, making it difficult to titrate PL concentrations in vivo to understand how PL activates PLR signaling.…”