SAT-649 - Dissociation between Muscle Mitochondrial Function and Insulin Sensitivity

Background:
Mitochondrial dysfunction has long been proposed as a contributing factor to insulin resistance. While reduced oxidative capacity is observed in aging, physical inactivity, and type 2 diabetes, emerging evidence indicates that mitochondrial defects are not consistently predictive of insulin sensitivity when controlling for physical activity, adiposity, and systemic metabolic status. The extent to which muscle mitochondrial function independently determines insulin-mediated glucose disposal remains uncertain.

Objective:
To associations between insulin sensitivity and muscle morphology, mitochondrial oxidative capacity, and physical performance in adults with a wide range of body composition.

Methods:
Thirty-five adults (age 32.9 ± 7.4 years, 65.7% female) were assessed. Of these, 24 had obesity and 11 did not, based on DEXA-defined criteria (>30% body fat in men and >42% in women). Participants completed thigh MRI to quantify muscle area, vastus lateralis biopsies to assess oxidative capacity and reactive oxygen species (ROS) production, VO₂max testing, knee extension strength and power assessments, a full-body DEXA scan, and a 6-hour hyperinsulinemic-euglycemic clamp to assess insulin sensitivity.

Results:
Muscle mitochondrial State 3 respiration was positively associated with aerobic capacity (VO₂ peak: R² = 0.26, p = 0.019) and total knee-extension work (R² = 0.20, p = 0.044), but not with insulin sensitivity (R² = 0.015, p = 0.23). ROS production was unrelated to metabolic outcomes (all p > 0.60). MRI-derived thigh muscle area showed only a weak trend toward association with insulin sensitivity (p = 0.078). As expected for two physiologic indices of insulin sensitivity, fasting HOMA-IR and clamp-derived GINF were moderately correlated (R² = 0.43, p = 0.0005), reflecting internal consistency of metabolic status across methods. Measures of adiposity—including BMI, percent body fat, and adipocyte size—were strongly interrelated (R² = 0.34–0.59) but were not significantly associated with insulin sensitivity (all p > 0.05).

Conclusions:
Mitochondrial respiration correlates with physical performance but not insulin sensitivity, and MRI-derived muscle size offers limited predictive value. These findings reveal a dissociation between skeletal muscle energetic capacity and whole-body insulin sensitivity and suggest that metabolic risk may be better indexed by systemic measures rather than by muscle morphology or mitochondrial biology.

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