Kahlon, R. | Search bioRxiv

bioRxiv2025

Lrrc55 modulates beta-cell resilience and calcium transporter expression under metabolic and physiologic stress

During pregnancy, pancreatic {beta}-cell mass and function are increased in adaptation to insulin resistance; this requires the action of prolactin receptor signaling. Recently, we discovered the Lrrc55, an auxiliary subunit of the voltage- and calcium-activated potassium channel (BK channel), is a prosurvival factor in {beta}-cell, and its expression and highly and specifically up regulated in the pancreatic islets during pregnancy. We found that overexpression of Lrrc55 protects {beta}-cells from glucolipotoxicity (GLT)-induced apoptosis. The protective effect of Lrrc55 is associated with dampening of the ER stress response and preservation of the releasable pool of calcium in the ER. Thus, we hypothesized that Lrrc55 protects {beta}-cells from GLT-induced ER stress and apoptosis by regulating ER calcium handling. Here, we report that Lrrc55 restored the GLT-mediated decrease in expression levels the insulin regulators, Pdx-1 and MafA, as well as the ER calcium regulator SERCA. Lrrc55 also attenuated the GLT-induced increase in expression of the ER calcium channel RyR2. Lrrc55 also attenuated GLT-mediated increase in protein expression of pro-apoptotic molecules CHOP and IRE1, and increased activation of the anti-apoptotic molecule Akt. However, Lrrc55 does not alter the activity levels of SERCA or IP3R under physiologic conditions. Transgenic mice with global deletion of Lrrc55 (Lrrc55-/-) are more susceptible to streptozotocin-induced diabetes. Surprisingly, Lrrc55-/- mice are more glucose tolerant and secreted more insulin during pregnancy. Together, these results suggest a role for Lrrc55 in maintaining expression of the ER calcium regulators in the presence of GLT but it may negatively regulate insulin secretion.

physiology↗

bioRxiv2024

Beta-cell adaptation to metabolic stresses requires prolactin receptor signaling

The role of prolactin receptor (PRLR) signaling in {beta}-cell adaptation to maternal insulin resistance of pregnancy has been well demonstrated. Using transgenic mice with an inducible {beta}-cell-specific Prlr deletion ({beta}Prlr-/-), we found that intact PRLR, as found in {beta}Prlr+/+ mice, were protected from developing glucose intolerance during pregnancy, and the main mechanism responsible for this PRLR-mediated effect is the up regulation of {beta}-cell proliferation and insulin synthesis. Interestingly, studies in male mice and humans have found a link between diminished PRLR signaling and abnormal {beta}-cell function. We aimed to determine whether PRLR has a role in regulating {beta}-cell function outside of pregnancy, protecting {beta}-cell against exposure to metabolic stressors. In this study, we found that {beta}-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 {beta}-cell proliferation resulting in a greater {beta}-cell mass, we observed no difference in {beta}-cell mass between the wild type ({beta}Prlr+/+) and mutant ({beta}Prlr-/-) mice. In vitro glucose-stimulated insulin secretion using isolated islets from wild type ({beta}Prlr+/+) and mutant ({beta}Prlr-/-) mice showed comparable insulin response, but {beta}Prlr-/- 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, Gipr and Glp-1r, and several of their upstream regulators, such as E2f1, Nkx6.1, Pax6, Ppar{gamma}, and Tcf7l2. 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 {beta}-cell function in mice exposed to metabolic stress by maintaining incretin receptor expression and insulin secretory capacity in {beta} cells.

physiology↗