Chronic nutrient excess state associated with prolonged diabetes triggers a switching off of AMPK, which results in impaired peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) activity and diminished mitochondrial14 and endothelial nitric oxide synthase (eNOS) activities15, leading to neurodegeneration in patients with DPN. Here, NOS3 is linked to diabetes mellitus.