Mitochondrial Dysfunction in Type 2 Diabetes Mellitus and Capacity for Fat Oxidation During Exercise

During prolonged moderate-intensity exercise, skeletal muscle gradually increases its metabolic reliance on fat oxidation. In healthy subjects, this adaptation is enhanced by aerobic training and is associated with increased mitochondrial capacity in muscle. Whether or not subjects with type-2 diabetes (T2DM) respond to exercise training with similar metabolic and mitochondrial adaptations is yet to be demonstrated. Skeletal muscle mitochondrial oxidative capacity has been shown to be deficient in T2DM, suggesting a compromised physiologic reserve that might have implications for the metabolic plasticity of muscle during exercise. This study will test the hypothesis that fat oxidation rates during exercise are poorly responsive to training in T2DM, being correlated to the degree of muscle mitochondrial adaptation. The effects of a 16-week intervention (8 weeks of exercise intervention followed by 10-12 weeks of weight loss intervention) on systemic fat oxidation during exercise and mitochondrial capacity will be compared between 3 sedentary subject groups; 15 lean subjects, 15 overweight subjects with T2DM, and 15 overweight subjects without diabetes. The first aim is to compare the degree of improvement in fat oxidation during submaximal exercise obtained by indirect calorimetry. The second and third aims are, respectively, to compare the degree of improvement in mitochondrial content and oxidative capacity in muscle biopsy samples. The fourth aim is to determine whether fat oxidation from non-plasma sources is increased by the intervention. The final aim is to examine whether improvements in fat oxidation predict degree off success in a subsequent weight loss program. The results of this study will be relevant to the understanding of the mechanisms by which exercise training confers metabolic improvements in T2DM. In addition, this study will address whether perturbations in mitochondria could explain why obese individuals with T2DM might have difficulty with fat disposal.