The main findings of the present study after 6 weeks of voluntary exercise, prior to IR injury (1) attenuation of the infarct size in the T2DM GK heart ex vivo; (2) higher cardiac and aortic cNOS activities; (3) higher cardiac HO activity; and (4) improved metabolic parameters, e.g. plasma leptin and blood glucose concentration. Here, NOS3 is linked to type 2 diabetes mellitus.