The Role of Insulin Sensitivity in Changes in Lean Mass and Muscle Quality During Weight Loss

Obesity represents a major public health concern due to its rising prevalence and its strong association with increased risk of cardiometabolic diseases and functional decline. Weight loss is a primary treatment strategy, but it often results in the loss of lean mass (LM), including skeletal muscle, which can impair metabolic health and physical function. Insulin sensitivity (SI), a marker of metabolic health, may influence changes in muscle quantity and quality during weight loss, yet this relationship remains underexplored.

This dissertation investigated the role of baseline SI in predicting changes in LM and muscle quality during weight loss. Three analyses were conducted using data from two controlled feeding trials involving adults with overweight or obesity. One intervention included both men and women with obesity who underwent a 16-week dietinduced weight loss intervention. The other included women with overweight who were randomized to three groups: diet-only, diet plus aerobic exercise, or diet plus resistance exercise until they reached a body mass index (BMI) < 25 kg/m2 . SI was assessed using an intravenous glucose tolerance test (IVGTT), and body composition was measured using dual-energy X-ray absorptiometry (DXA) and computed tomography (CT).

In the first manuscript, higher baseline SI was associated with greater retention of total and appendicular LM during weight loss. The second manuscript found that this relationship was significant only in participants who did not exercise, suggesting that exercise may alter the influence of SI on LM loss. The third manuscript demonstrated that higher baseline SI predicted greater reductions in perimuscular adipose tissue (PMAT), but not intermuscular adipose tissue (IMAT), indicating depot-specific associations between SI and muscle fat infiltration.

These findings suggest that SI is a significant predictor of changes in both muscle quantity and quality during weight loss. Individuals with lower baseline SI may be at greater risk for LM loss and less favorable changes in muscle composition with weight loss. Incorporating baseline SI assessments into weight loss interventions could enable personalized strategies—such as increased protein intake and/or resistance training—to preserve muscle and improve metabolic outcomes.