1739-P: Insulin Rapidly Increases Skeletal Muscle Mitochondrial ADP Sensitivity, Mitigating HFD-Induced Mitochondrial Dysfunction
Bibliographic record
Abstract
Introduction: Causality of the association between impairments in mitochondrial function and insulin resistance remains debatable. We have previously demonstrated that mitochondrial ADP sensitivity is impaired in high-fat diet (HFD)-induced insulin resistance, which contributes to bioenergetic imbalance and higher reactive oxygen species (ROS) production. However, insulin regulates several metabolic processes within skeletal muscle, and we tested the hypothesis that insulin could rapidly improve mitochondrial ADP sensitivity, a phenomenon possibly lost in HFD-induced insulin resistance. Methods: Male and female C57Bl/6 mice were fed a control diet (10% fat) or HFD (60% fat) for 8 weeks. At the end of treatment, insulin was injected intraperitoneally (3 U/kg) twice (0 and 30 minutes). At 60 minutes red gastrocnemius muscle was excised to evaluate mitochondrial bioenergetics, ADP sensitivity, and ROS production. Results: In control mice, insulin increased respiration by ∼2-fold in the presence of submaximal (100-1000 μM ADP) but not maximal ADP-supported respiration. As a result, insulin decreased the apparent ADP Km from 700 to 380 μM ADP. Despite these respiratory changes, insulin had no effect on mitochondrial maximal succinate-supported ROS emission or the ability of ADP to suppress ROS emission. HFD consumption impaired whole-body glucose intolerance, skeletal muscle insulin resistance (decreased insulin-stimulated Akt Thr-308 and Ser-473 phosphorylation) and impaired mitochondrial submaximal ADP-supported respiration by ∼50% (ADP Km ∼1100 μM). However, despite the reduction in insulin signaling following HFD, insulin increased submaximal ADP-supported respiration by ∼2-fold, decreased the apparent ADP Km to ∼400 μM and improved the ability of ADP to suppress mitochondrial ROS emission. Conclusion: Insulin rapidly improves mitochondrial ADP sensitivity, mitigating the apparent HFD-induced mitochondrial dysfunction. Disclosure H. Brunetta: None. H.L. Petrick: None. E.A. Nunes: None. G. Holloway: None. Funding Natural Sciences and Engineering Research Council of Canada (400360); Coordination for the Improvement of Higher Education Personnel
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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) | 0.001 | 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 | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.014 | 0.003 |
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".