EDN1 and hyperinsulinism: This is why hyperinsulinemia, which is typically associated with IR in the attempt to maintain normal glucose levels, ends up hyper-stimulating the MAPK pathway, producing an imbalance of the two pathways with an increase in the MAPK effects of insulin, in particular overproduction of ET-1 and reduced NO production, resulting in vasoconstriction and endothelial dysfunction.