Hypothesis

The combined recovery time of glucose and ketone concentrations (GK‑RT) following a standardized mixed macronutrient challenge (30 g glucose + 20 g MCT oil) predicts the magnitude of VO₂max increase after a 12‑week aerobic‑interval program in healthy adults, and this relationship is mediated by exercise‑induced mitochondrial autophagy (mitophagy).

Mechanistic Rationale

1. Integrated glucose‑ketone sensing – Abbott’s glucose‑ketone CGM provides real‑time concurrent trajectories, allowing calculation of GK‑RT as the time for both metabolites to return to baseline after the challenge [1].
2. Metabolic flexibility proxy – Faster GK‑RT reflects a greater capacity to switch between glucose oxidation and ketolysis, a hallmark of mitochondrial plasticity [3].
3. Link to VO₂max – VO₂max gains depend on mitochondrial biogenesis and quality control; enhanced flexibility should prime mitochondria for adaptive remodeling during training [5].
4. Mediating pathway – We propose that the acute oxidative shift during GK‑RT activates AMPK‑ULK1 signaling, triggering Parkin‑dependent mitophagy, which removes damaged organelles and makes space for new, efficient mitochondria, thereby amplifying training adaptations.

Testable Predictions

• Prediction 1: Individuals in the fastest GK‑RT tertile will achieve ≥15 % VO₂max increase, whereas the slowest tertile will show ≤5 % change after the intervention.
• Prediction 2: Baseline GK‑RT will correlate positively with circulating LC3‑II/I ratio and phosphorylated ULK1 (Ser555) measured pre‑ and post‑exercise (r > 0.4, p < 0.05).
• Prediction 3: Pharmacological inhibition of autophagy (e.g., chloroquine) during the training period will attenuate the GK‑RT–VO₂max relationship, reducing the slope by at least 50 %.

Experimental Design

• Recruit 60 sedentary adults (age 20‑35, BMI 18‑25).
• Measure fasting glucose, ketone, insulin, HbA1c, and perform a mixed macronutrient challenge while wearing the integrated CGM‑ketone device; compute GK‑RT.
• Stratify participants into GK‑RT tertiles.
• Implement a 12‑week supervised HIIT protocol (4 × 4 min at 90 % HRmax, 3 sessions/week).
• Assess VO₂max via cardiopulmonary exercise testing pre‑ and post‑intervention.
• Collect blood pre‑, post‑acute exercise (week 0 and week 12) for LC3‑II/I, p‑ULK1, and mitophagy markers.
• In a substudy (n = 20), administer chloroquine (500 mg daily) vs placebo during weeks 6‑12 to test autophagy dependence.

Falsifiability

If GK‑RT shows no significant association with VO₂max gains (β ≈ 0, p > 0.05) or if autophagy inhibition does not diminish the GK‑RT–VO₂max slope, the hypothesis is falsified. Conversely, confirming the predictions would support GK‑RT as a mechanistic, CGM‑derived biomarker for prescribing personalized endurance training to enhance metabolic flexibility and longevity.

References

[1] Abbott’s integrated glucose‑ketone monitor https://tcoyd.org/2024/12/news-2025-diabetes-devices-and-advancements/ [2] AI‑enabled CGM predictive alarms https://diagnostics.roche.com/global/en/healthcare-transformers/article/future-diabetes-technology-predictive-cgm.html [3] Glucose Recovery Time to Baseline (GRTB) https://pmc.ncbi.nlm.nih.gov/articles/PMC12617953/ [4] Fasting insulin and HbA1c longevity biomarkers https://optimalhealth.co/resources/blood-testing/biomarkers-longevity [5] VO₂max as functional age metric https://cenegenics.com/2025-in-review-the-longevity-trends-that-redefine-healthspan/ [6] CGM meta‑analysis in T2D https://pubmed.ncbi.nlm.nih.gov/41309353/