Zmiz1 is required for mature β-cell function and mass expansion upon high fat feeding
Bibliographic record
Abstract
ABSTRACT Genome-wide association studies have identified hundreds of signals for type 2 diabetes (T2D), most of which confer risk through effects on gene expression. We previously identified the transcription factor ZMIZ1 as a probable effector transcript in human islets, but how altered ZMIZ1 expression impacts T2D risk is unknown. We now show that islets from carriers of the T2D-risk alleles have reduced islet insulin content and glucose-stimulated insulin secretion. To elucidate the mechanism for islet-cell dysfunction, we generated β-cell-specific Zmiz1 knockout (Zmiz1 βKO ) mice. Male and female Zmiz1 βKO mice were glucose intolerant with impaired insulin secretion, compared with control littermates. Transcriptomic profiling of Zmiz1 βKO islets identified over 500 differentially expressed genes including those involved in β-cell function and maturity which we confirmed at the protein level. After high fat feeding, Zmiz1 βKO mice fail to expand β-cell mass and become severely diabetic. Thus, Zmiz1 is required for normal glucose homeostasis and may contribute to T2D risk by maintaining a mature β-cell state and allowing islet mass expansion upon metabolic stress.
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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 | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".