EDN1 and Hyperinsulinemia: During diabetes, selective inhibition of the PI3K-Akt-eNOS pathway, together with compensatory hyperinsulinemia leads to unmasking and stimulation of the MAPK-mediated production of endothelin-1 (ET-1) (36, 37), and vascular smooth muscle proliferation, which could contribute to atherosclerotic plaque development and peripheral artery disease (38, 39).