Figure 2.
Differential beneficial or adverse effects of insulin therapy on vascular endothelial cells depending on the level of metabolic control achieved. Insulin signaling in endothelial cells can be via the PI3K (causes vasodilation and is anti-thrombotic) and the MAPK pathway (causes vasoconstriction and is prothrombotic) such that there is a balance of beneficial and harmful effects. In response to an excess nutrient supply, as occurs in metabolically uncontrolled T2D, selective IR in the PI3K pathway will occur such that signaling through the MAPK pathway will be unopposed, increasing the risk of vascular events. Insulin treatment will either improve or worsen vascular health depending on whether it is effective or not at bringing blood nutrient levels under control. If high exogenous insulin therapy is successful at improving blood nutrient levels, then insulin signaling through the PI3K pathway will increase such that insulin therapy will be beneficial to blood vessel health. However, if high dose exogenous insulin therapy fails to control blood nutrients (i.e., in refractory patients), then the IR in the PI3K pathway will not be relieved and insulin signaling will predominate via the harmful MAPK pathway and increase the risk of vascular events.