Bcl-xL restricts transcriptional, morphological and functional decompensation of β-cell mitochondria under chronic glucose excess
Bibliographic record
Abstract
ABSTRACT In the progression of diabetes, pancreatic islet β-cells respond to increased metabolic demand with functional compensation, followed by pathogenic decompensation of mitochondria-dependent insulin secretion. It is not clear what mechanisms drive, or control, mitochondrial decompensation. Here, we report that anti-apoptotic Bcl-x L maintains mitochondrial integrity in β-cells under non-apoptotic levels of glucose stress. Prolonged glucose excess causes transcriptional reprogramming of glycolysis and β-cell identity genes, while sensitizing glucose-stimulated Ca 2+ signaling and insulin secretion. Deletion of Bcl-x L amplifies this insulin hypersecretion and increases mitochondrial fusion, mitochondrial volume, and oxygen consumption, whereas ATP-coupled respiration and mitochondrial hyperpolarization become impaired. Of note, Bcl-x L -deficient β-cells have impaired Pgc-1α expression, and develop specific defects in the expression of Tfam, mitochondrial ribosomal genes, and OXPHOS components under glucose stress. Bcl-x L limits high glucose-induced mitochondrial ROS (mitoROS) levels and pharmacological normalization of mitoROS in Bcl-x L KO cells rescues glucose-induced defects in mitochondrial gene expression and changes to β-cell identity. Our data identify mitoROS as a primary retrograde driver of transcriptional re-wiring in β-cells exposed to excess glucose, and reveal Bcl-x L as an important safeguard against transcriptional and functional decompensation of β-cell mitochondria. Bcl-x L and mitoROS may thus be viable targets to prevent early β-cell dysfunction and the progression of diabetes.
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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".