The activation of skeletal muscle AbMole Sarafloxacin HCl mitochondrial biogenesis pathways as determined by PGC-1a protein content. The change in free-fatty acid concentration was a major determinant of the change in glycemic control. Free-fatty acid accumulation in the circulation may be the result of an imbalance between skeletal muscle uptake and oxidation and defects in adipose tissue insulin signaling. Lipid oversupply to skeletal muscle may cause insulin resistance through accumulation of incompletely oxidized lipid species. In the present investigation, improved balance between muscle lipid storage and oxidation, as suggested by a decrease in serum FFA, may be an important contributor to the improvement in HbA1C. We observed a strong inverse relationship between the changes in adiponectin and the changes in HbA1C. Civitarese et al. recently uncovered a pathway by which adiponectin increases skeletal muscle PGC-1a, mitochondrial number and oxidative capacity. Adiponectin may also have beneficial effects, independent of PGC-1a, by enhancing ceramidase activity, thus reducing the amount of insulin desensitizing ceramides. Our results demonstrate a clinically relevant situation in which the change in serum adiponectin was associated with an improvement in HbA1C. A recent review called for more effective and sophisticated exercise prescriptions for the improvement of glucose control through increasing intramuscular PGC-1a. Studies demonstrate increased PGC-1a with aerobic training, while others show no effect or improvements with resistance training. We tested different exercise modalities and only resistance training had a tendency to increase PGC-1a content. Additionally, the change in PGC-1a was greater in those with longer duration of type 2 diabetes. In our final model, a greater increase in PGC-1a and a shorter duration of type 2 diabetes were independently associated with improved glycemic control. The main results from the HART-D trial together with this ancillary study suggest that: 1) a program of combined aerobic and resistance training has the greatest effect on HbA1C; 2) resistance training may potentiate a greater change in PGC-1a, and therefore, HbA1C; and 3) individuals who start an exercise program soon after diagnosis may see a larger effect on HbA1C levels. Our investigation is limited by a small sample size with almost 50% of the participants assigned to the resistance training group. However, we had adequate power to detect independent effects of substrate, hormone and muscle changes on glycemic control after collapsing the exercise groups. Drug changes were not controlled during the intervention period resulting in a limitation whereby a tendency to reduce diabetes medications after the combination intervention reduces the effect on change in HbA1C levels. Furthermore, dietary assessments were taken at baseline and follow-up by food frequency questionnaire thus limiting our ability to determine the impact of dietary modifications such as changes in caloric intake and dietary composition.