Why Might Thiazolidinediones Increase Exercise Capacity in Patients With Type 2 Diabetes?

Individuals with type 2 diabetes are insulin resistant and as a group have a lower exercise capacity (Vo_2max) than age- and weight-matched people without diabetes (1,2). In this issue, Regensteiner et al. (3) report that rosiglitazone (RSG), a thiazolidinedione (TZD) commonly used to treat insulin resistance, also improves exercise capacity in patients with type 2 diabetes. Following 4 months of treatment with 4 mg/day RSG, the authors observed expected improvements in insulin sensitivity as determined by homeostasis model assessment and a hyperinsulinemic-euglycemic clamp in 10 middle-aged men and women with type 2 diabetes. A novel finding was that RSG caused a modest but significant increase in Vo_2max (1.4 ml · kg⁻¹ · min⁻¹ or ∼7.1%). These observations raise three fundamental questions: 1) Why is type 2 diabetes associated with a decrease in exercise capacity? 2) How might TZDs, such as RSG, counteract this? and 3) Is the effect of RSG on exercise capacity likely to be clinically relevant?

Recent studies suggest several explanations for the decrease in Vo_2max in patients with type 2 diabetes. One of these is the presence of mitochondrial dysfunction. As reported by Kelley et al. and Ritov et al., (4–6) skeletal muscle of sedentary middle-aged individuals with established type 2 diabetes (HbA_1c 8.0 ± 0.2%) exhibits reduced mitochondrial oxidative enzyme (succinate dehydrogenase) activity and electron transport chain capacity (rotenone-sensitive NADH:O₂ oxido-reductase activity) (∼26 and 59%, respectively), smaller mitochondria, and higher intramyocellular triglyceride content than muscle of normal control subjects. Their data also suggested that subsarcolemmal mitochondria were especially affected. In addition to these …