Loss of RREB1 in pancreatic beta cells reduces cellular insulin content and affects endocrine cell gene expression
Bibliographic record
Abstract
Abstract Aims/hypothesis Genome-wide studies have uncovered multiple independent signals at the RREB1 locus associated with altered type 2 diabetes risk and related glycemic traits. However, little is known about the function of the zinc finger transcription factor RREB1 in glucose homeostasis or how changes in its expression and/or function influence diabetes risk. Methods A zebrafish model lacking rreb1a and rreb1b was used to study the effect of RREB1 loss in vivo . Using transcriptomic and cellular phenotyping of a human beta cell model (EndoC-βH1) and human induced pluripotent stem cell (hiPSC)-derived beta-like cells, we investigated how loss of RREB1 expression and activity affects pancreatic endocrine cell development and function. Ex vivo measurements of human islet function were performed in donor islets from carriers of RREB1 T2D-risk alleles. Results CRISPR-Cas9-mediated loss of rreb1a and rreb1b function in zebrafish supports an in vivo role for the transcription factor in beta cell mass, beta cell insulin expression, and glucose levels. Loss of RREB1 reduced insulin gene expression and cellular insulin content in EndoC-βH1 cells, and impaired insulin secretion under prolonged stimulation. Transcriptomic analysis of RREB1 knockdown and knockout EndoC-βH1 cells supports RREB1 as a novel regulator of genes involved in insulin secretion. In vitro differentiation of RREB1 KO/KO hiPSCs revealed a dysregulation of pro-endocrine cell genes, including RFX family members, suggesting that RREB1 also regulates genes involved in endocrine cell development. Human donor islets from carriers of T2D-risk alleles in RREB1 have altered glucose-stimulated insulin secretion ex vivo , consistent with RREB1 regulating islet cell function. Conclusions/interpretation Together, our results indicate that RREB1 regulates beta cell function by transcriptionally regulating the expression of genes involved in beta cell development and function. Research in context What is already known about this subject? Human genetic variation in RREB1 is associated with altered diabetes risk, variation in glycemic, and anthropometric traits RREB1 is a transcription factor that binds to Ras-responsive elements and is expressed in multiple diabetes relevant tissues, including pancreatic islets What is the key question? How does altered expression or function of RREB1 influence diabetes risk? What are the new findings? Knockdown and knockout of RREB1 in mature human EndoC-βH1 cells reduces expression of insulin transcript and cellular content, as well as insulin secretion under prolonged stress Carriers of the T2D-risk RREB1 coding allele trend towards reduced insulin content, but have improved glucose-stimulated insulin secretion A loss-of-function zebrafish model suggests that RREB1 is required for insulin expression How might this impact on clinical practice in the foreseeable future? RREB1 controls beta cell function and whole-body glucose homeostasis by transcriptionally regulating the development and function of pancreatic beta cells
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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".