Anti-inflammatory and angiogenic effects of exercise training in cardiac muscle of diabetic mice.

Background: Improved glycemic control and cardiovascular function are major benefits of regular exercise training (ET) in type 2 diabetes. Recent work has demonstrated that ET improves cardiac and vascular functions independent of obesity, inflammation, and glucose control in the diabetic db/db mouse. In this study, we determined whether ET can overcome the effects of elevated inflammatory cytokines and hyperglycemia on markers of cardiac angiogenesis and inflammation in the diabetic mouse. Methods: Male diabetic db/db mice were assigned to a sedentary and exercise-trained group. Sedentary lean control littermates were used as controls. ET was performed at moderate intensity on a treadmill 5 days a week for a period of 8 weeks. After ET, blood was collected for assay of glucose, hemoglobin (HB and HB1AC), C-reactive protein (CRP), and IL-6. Markers of inflammation and insulin resistance (IL-6, IL-1 beta, and tumor necrosis factor-alpha [TNF-alpha]) and angiogenesis (endothelial nitric oxide synthase [eNOS], vascular endothelial growth factor-A [VEGF-A], and hypoxia-inducible factor-1 alpha [HIF-1 alpha]) were measured in hearts. Results: Diabetic db/db mice remained obese and hyperglycemic after ET. Percent total HB and HB1AC were significantly higher in ET db/db mice compared to sedentary db/db mice, indicating further deterioration of glucose control with ET. Plasma levels of CRP and IL-6 were higher in sedentary db/db mice compared to control mice and were unaffected by ET. However, in the presence of hyperglycemia and elevated plasma cytokines, protein expression of eNOS, mRNA expression of VEGF-A, and HIF-1 alpha was increased in db/db hearts after ET. On the other hand, protein expression of TNF-alpha and mRNA expression IL-6 and IL-1 beta was significantly decreased by ET in hearts of db/db mice. Conclusion: Our results indicate that ET improves cardiac markers of angiogenesis, insulin resistance, and endothelial dysfunction in the db/db mouse. This was observed independently of obesity, hyperglycemia, and the systemic inflammatory state.