Oxidative stress and vascular disease in diabetes: is the dichotomization of insulin signaling still valid?

The current wisdom indicates that insulin's positive effects, normoglycemia, vasodilation, and anti-inflammation, are mediated by the canonical phosphoinositide 3-kinase (PI3K)/Akt pathway whereas the negative effects are mediated by the mitogen-activated protein kinase (MAPK)/extracellular regulated kinase (ERK) pathway. Much of the intracellular oxidant stress is mediated by the MAPK/ERK pathway which is a downstream signal also for other proatherogenic hormones such as angiotensin II. However, recent evidence links MAPK activation to antioxidant activity and vascular protection. We argue against a dichotomization of insulin signaling also in light of the concept that ERK-MAPK represents a critical node in the intracellular insulin network responsible for several positive effects related not only to vascular function but also to life span.