NOS3 and type 2 diabetes mellitus: Similarly, in manifest T2DM there will be an associated increase in aMt that will leak mtROS—superoxide, and there will be excessive oxidation of the eNOS enzyme cofactor tetrahydrobiopterin (BH4) that ultimately uncouples the eNOS production of NO (eNOS enzyme uncoupling) that will decrease endothelial-derived NO bioavailability [11,12,136,140].