The role of placental lactogens in the regulation of pancreatic beta-cell mass and function

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Pancreatic islets contain ß cells that synthesize insulin, the main hormone responsible for glucose utilization. Pancreatic ß-cell mass and function are dynamic and adapts to physiological stressors such as insulin resistance of pregnancy, nutrient excess, and aging by increasing insulin production. The long-term goal of my NSERC program is to understand the mechanisms that regulate ß-cell mass, function, and survival under normal and metabolically stressed conditions. Our published work showed that the prolactin receptor (Prlr) is vital for maternal ß-cell adaptation during pregnancy, and that activation of Prlr-mediated signaling to increase ß-cell proliferation and insulin synthesis is part of this adaptive response. Increased insulin synthesis, however, activates the unfolded protein response (UPR), which if unresolved, leads to endoplasmic reticulum (ER) stress and apoptosis. A discovery-based experiment identified Lrrc55 as a novel pro-survival factor in ß cells during pregnancy. Lrrc55 is a putative auxiliary protein of large conductance, Ca2+-activated K+ channels. Lrrc55 expression is upregulated in islets during pregnancy, as well by cytotoxic concentration of free fatty acids (FFA), in obesity, and by chemical induction of ER stress. Overexpression experiments found that it likely prevented FFA-mediated activation of sustained UPR and ß-cell apoptosis by maintaining ER Ca2+ store. We hypothesize that Lrrc55 regulates the activity of ER Ca2+ channels in ß cells. The ubiquitous expression of Prlr raise the possibility that Prlr has a non-cell autonomous role on ß cells. To address this, we generated a transgenic mouse with an inducible, ß-cell-specific Prlr deletion. Comparing global vs. ß-cell specific Prlr-null mice identified important differences in the expression of genes that protect ß cells against apoptosis, supporting the hypothesis that Prlr has a non-cell autonomous role in the regulation of ß-cell survival. The Prlr-mediated effects on ß-cell adaptation to pregnancy are likely to be applicable in other physiological conditions of insulin resistance, namely nutrient excess and aging. Supporting this, we found that islets from pregnant heterozygous Prlr+/- mice were more susceptible to FFA-induced apoptosis and islets from Prlr-/- mice expressed a higher level of a ß-cell aging marker. These observations suggest that Prlr may have a broad beneficial role beyond pregnancy. Our objective is to understand how Prlr regulates ß-cell adaptation to metabolic stressors. We will investigate 1) the function and signaling mechanism of novel Prlr targets, specifically the actions of Lrrc55, 2) the non-cell autonomous role of Prlr, and 3) the role of Prlr in protecting ß cells against metabolic stresses imposed by pregnancy, nutrient excess, and aging. Our program spans biochemistry, cellular and molecular biology, and whole organism physiology, providing excellent training opportunities for highly qualified personnel.