In conclusion, our in vitro and in vivo models clearly show that the presence of homocysteinemia in a diabetic environment, by increasing ROS levels and decreasing Timp1-MMP-9 interactions, functionally activates MMP-9, and by further facilitating alterations in the DNA methylation-hydroxymethylation process, increases MMP-9 transcription and represses Timp1 transcription. Here, TIMP1 is linked to hyperhomocysteinemia.