Lrrc55 modulates beta-cell resilience and calcium transporter expression under metabolic and physiologic stress
Bibliographic record
Abstract
Abstract During pregnancy, pancreatic β-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 β-cell, and its expression and highly and specifically up regulated in the pancreatic islets during pregnancy. We found that overexpression of Lrrc55 protects β-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 β-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 IRE1α, 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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".