Diabetic cardiomyopathy is defined as cardiac dysfunction in diabetic patients that cannot be attributed to hypertension, coronary artery disease or valve abnormalities. The exact cause of cardiac dysfunction in diabetic cardiomyopathy is not fully elucidated and may involve impaired cardiac insulin-mediated Akt signaling. Evidence suggests that exercise training may improve cardiac function in models of diabetic cardiomyopathy. The pathways underlying exercise-induced improvements in cardiac function are not known and may involve changes in insulin-mediated Akt signaling. The purpose of the proposed study was to investigate the underlying mechanisms of diabetic cardiomyopathy as well as systemic and cardiac related adaptations to exercise training in db/db mice, a well-accepted model of diabetic cardiomyopathy. Hypotheses were tested to determine if cardiac tissue of db/db mice exhibited reduced insulin-mediated Akt signaling and if exercise training altered: a.) insulin-mediated Akt signaling in cardiac tissue; b.) systemic insulin resistance and maximal oxygen consumption (max VO2); and c.) cardiomyocyte function in db/db mice.
Methods: Three groups of mice were studied: C57BL6 (C57) sedentary; db/db sedentary; and db/db exercise. C57 mice served as the healthy control group. Glucose tolerance tests (GTTs) and maximal oxygen consumption tests were completed prior to the intervention. db/db mice were progressively trained on a treadmill 5 days/week for 8 weeks. Max VO2 was measured every two weeks to ensure proper training intensity. Following training, GTTs and max VO2 were repeated and the hearts were excised. Phosphorylation of Akt was assessed along with cardiac functional parameters of individual left ventricular myocytes.
Results: No differences (p>0.05) in systolic or diastolic function were found between exercise-trained db/db, sedentary db/db and healthy sedentary mice. We revealed differences (p<0.05) in insulin-mediated Akt signaling between healthy mice and both groups of db/db mice, however no significant differences (p>0.05) were noted between exercise-trained and sedentary db/db mice. Following the intervention, exercise-trained db/db mice exhibited greater (p<0.05) insulin sensitivity compared with sedentary db/db mice. Further, exercise training resulted in greater improvements (p<0.05) in max VO2 in db/db mice compared with sedentary counterparts.
Conclusion: For the first time, we have shown that impaired cardiac insulin-mediated Akt signaling is evident in db/db mice. We have also documented that short-term high intensity exercise training is effective at improving max VO2 in db/db mice. Further, we have illustrated that exercise-trained db/db mice exhibit better systemic glucose control compared with sedentary db/db mice. Investigations involving longer training regimens may be needed to determine if changes in cardiac Akt signaling mediate any exercise-induced improvements in cardiac function in subjects with diabetic cardiomyopathy.