PPARGC1A and diabetes mellitus: Further mechanism exploration shown that PGC-1α induces Notch signaling, blocks activation of Rac/Akt/eNOS signaling, and renders endothelial cells unresponsive to angiogenic factors, finally contributing to vascular dysfunction in diabetes.582 In addition, T2DM disrupts SIRT1/PGC-1α/SIRT3 pathway in the epididymal, which causes a decline of the antioxidant defenses and an increased oxidative damage in that tissue, ultimately leading to impaired male reproductive function.583