Mutated ATP synthase induces oxidative stress and impaired insulin secretion in β‐cells of female BHE/cdb rats
Bibliographic record
Abstract
BACKGROUND: Adenosine triphosphate (ATP) is a critical determinant of beta-cell insulin secretion in response to glucose. BHE/cdb rats have a mutation in ATP synthase that limits ATP production, yet develop mild diabetes only with ageing. We investigated the cellular basis for reduced insulin secretion and compensatory mechanisms that mitigate the effects of the ATP synthase mutation. METHODS: In vitro beta-cell function in isolated islets and expression of key regulatory genes was compared with in vivo oral glucose tolerance and insulin sensitivity in BHE/cdb and control rats. RESULTS: BHE/cdb rat islets had reduced responsiveness to glucose stimulation and ATP content was 35% lower than in control islets. Oral glucose tolerance was impaired at both 21 and 43 weeks of age because of a reduction in glucose-stimulated insulin secretion (GSIS). An increase in inducible nitric oxide synthase (INOS, 3-fold) and manganese superoxide dismutase (MnSOD, 1.6-fold), detection of nitrotyrosine, beta-cell apoptosis, and nucleocytoplasmic translocation of pancreas duodenum homeobox-1 (PDX-1) in beta-cells indicated increased oxygen radical formation. However, BHE/cdb rats partially compensated for low glucose responsiveness by increasing the number of small islets and beta-cell hypertrophy. There was also an increase in the proportion of mature insulin relative to proinsulin (PI) detected within beta-cell granules. Increased activation of AMP-dependent kinase (AMPK)-regulated pathways was consistent with increased oxidative stress and with induction of apoptosis and reduction of preproinsulin gene transcription. CONCLUSIONS: The findings are consistent with impaired but partially compensated mechanisms of insulin secretion early in life, but progressive non-compensated impairments due to oxidative stress occurs by age 43 weeks.
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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 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.003 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 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".