Dual mode of action of metformin on mitochondrial metabolism
Why this work is in the frame
A frame that forgets how it found something cannot be audited. These are the routes that admitted this work.
Bibliographic record
Abstract
Metformin is commonly used in the treatment of diabetes, however recently there is increasing interest in “repurposing” the drug for cancer prevention or treatment. Metformin is believed to act by inhibiting mitochondrial complex I, leading to activation of AMPK. Interestingly, metformin treatment is not associated with the serious health consequences that are seen with classic inhibitors of complex I. To address this apparent paradox, we investigated the impact of metformin on cellular bioenergetics using in-depth respirometry analyses coupled with stable isotope tracer experiments in both cells and isolated mitochondria. We show that cells treated with metformin display reduced respiration. Metformin reduces respiration by specifically inhibiting respiration coupled to ATP production, while increasing uncoupled respiration. Thus, cells treated with metformin devote a large fraction of their respiration for uncoupled reactions and become inefficient. The impact of metformin on cellular respiration can be attributed to direct action on mitochondria as metformin inhibits complex I-dependent respiration and citric acid cycle activity in isolated mitochondria. Overall, our study reveals global bioenergetic consequences of metformin exposure, and establishes mechanistic similarities between metformin and recently described liver-specific uncoupling agents that, like metformin, improve the metabolic consequences of obesity.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 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) | 0.001 | 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 it