In the present study, we investigated the roles of miR-21 in diastolic dysfunction of early diabetic cardiomyopathy in vitro and in vivo, and found that miR-21 protected against diastolic dysfunction and cardiac hypertrophy, by reducing ROS production via gelsolin in db/db mice, which suggested a new therapeutic strategy against diabetic cardiomyopathy. This evidence concerns the gene GSN and diabetic cardiomyopathy.