Beta-Cell Adaptation to Pregnancy - Role of Calcium Dynamics.

During pregnancy, the mother develops insulin resistance to shunt nutrients to the growing fetus. As a result, the maternal islets of Langerhans undergo several changes to increase insulin secretion in order to maintain glucose homeostasis and prevent the development of gestational diabetes. These changes include an increase in ß-cell proliferation and ß-cell mass, upregulation of insulin synthesis and insulin content, enhanced cell-to-cell communication, and a lowering of the glucose threshold for insulin secretion, all of which resulting in an increase in glucose-stimulated insulin secretion. Emerging data suggests that a change in intracellular calcium dynamics occurs in the ß-cell during pregnancy as part of the adaptive process. Influx of calcium into ß-cells is crucial in the regulation of glucose-stimulated insulin secretion. Calcium fluxes into and out of the cytosol, endoplasmic reticulum, and mitochondria are also important in controlling ß-cell function and survival. Here, we review calcium dynamics in islets in response to pregnancy-induced changes in hormones and signaling molecules, and how these changes may enhance insulin secretion to stave off gestational diabetes.

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

Pancreatic islets adapt to insulin resistance of pregnancy by up regulating ß-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 ß-cell development, to understand ß-cell-specific effect of prolactin signaling in pregnancy, we generated a transgenic mouse with an inducible conditional deletion of Prlr from ß-cells. Here, we found that ß-cell-specific Prlr reduction in adult mice led to elevated blood glucose, lowed ß-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 ß-cell-specific Prlr reduction (ßPrlR+/-), we found 95 differentially expressed gene, most of them down regulated in the Prlr+/- mice in comparison to the ßPrlR+/- 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 ßPrlR+/- mice. These observations suggest that down regulation of prolactin action during pregnancy in non-ß-cells secondarily and negatively affect ß-cell gene expression, and increased ß-cell susceptibility to external insults.

Lrrc55 is a novel prosurvival factor in pancreatic islets.

Pancreatic islets adapt to the increase in insulin demand during pregnancy by upregulating ß-cell number, insulin synthesis, and secretion. These changes require prolactin receptor (PrlR) signaling, as mice with PrlR deletion are glucose intolerant with a lower ß-cell mass. Prolactin also prevents ß-cell apoptosis. Many genes participate in these adaptive changes in the islet, and Lrrc55 is one of the most upregulated genes with unknown function in islets. Because Lrrc55 expression increases in parallel to the increase in ß-cell number and insulin production during pregnancy, we hypothesize that Lrrc55 might regulate ß-cell proliferation/apoptosis (thus ß-cell number) and insulin synthesis. Here, we found that Lrrc55 expression was upregulated by >60-fold during pregnancy in a PrlR-dependent manner, and this increase was restricted only to the islets. Overexpression of Lrrc55 in ß-cells had minimal effect on ß-cell proliferation and glucose-stimulated insulin secretion but protected ß-cells from glucolipotoxicity-induced reduction in insulin gene expression. Moreover, Lrrc55 protects ß-cells from glucolipotoxicity-induced apoptosis, with upregulation of prosurvival signals and downregulation of proapoptotic signals of the endoplasmic reticulum (ER) stress pathway. Furthermore, Lrrc55 attenuated calcium depletion induced by glucolipotoxicity, which may contribute to its antiapoptotic effect. Hence our findings suggest that Lrrc55 is a novel prosurvival factor that is upregulated specifically in islets during pregnancy, and it prevents conversion of adaptive unfolded protein response to unresolved ER stress and apoptosis in ß-cells. Lrrc55 could be a potential therapeutic target in diabetes by reducing ER stress and promoting ß-cell survival.