I-BET151 modulates glucokinase gene expression and beta cell function in part through changes in FOXO1 expression
Bibliographic record
Abstract
AIMS/HYPOTHESIS: The bromodomain and extra-terminal (BET) protein family acts as 'epigenetic readers' to identify the acetylation marks on histones that convert the acetylated lysine residues into observable phenotypes. BET proteins have gained attention due to their ability to modulate the transcription of pathology-related genes involved in cancer and autoimmune diseases, including type 1 diabetes mellitus. However, targeting BET proteins may have secondary effects on other host cells. We aimed to elucidate possible secondary effects of BET inhibition on pancreatic beta cell function. METHODS: We studied the effect of the small-molecule BET inhibitor I-BET151 on pancreatic beta cells in vitro, ex vivo and in vivo. GTTs, ITTs and glucose-stimulated insulin secretion assays were performed in healthy mice and a mouse model of diabetes following daily i.p. injections of I-BET151 for 2 weeks. Transcriptomic analysis was carried out on primary mouse islets, which were subjected to ex vivo I-BET151 treatment. Changes in expression were further validated in primary human islets. RESULTS: Administration of I-BET151 modestly but significantly increased glucose excursions and reduced insulin responses in both healthy mice and diabetic mice. We found that I-BET151 exposure significantly reduced the expression of Hnf4α (also known as Hnf4a; MODY1), Gck (MODY2), Hnf1α (also known as Hnf1a; MODY3), Glut2 and other genes essential for beta cell function in rat INS-1E insulinoma cells and in mouse primary islets and human islets. Global gene expression analysis in cells treated with I-BET151 showed a downregulation of the phosphoinositide-3-kinase (PI3K)-Akt pathway. Downregulation of forkhead box protein O1, a downstream transcriptional factor of the PI3K-Akt pathway, partially rescued I-BET151-driven downregulation of Gck and insulin secretion. Likewise, islets from I-BET151-treated mice showed a modest reduction in glucose-stimulated insulin secretion. CONCLUSIONS/INTERPRETATION: The results presented here suggest that BET inhibition therapy should be used with caution due to possible bimodal effects at high concentrations at the detriment of pancreatic beta cell function.
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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 | 0.000 |
| 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".