Angiotensin II Shifts Insulin Signaling Into Vascular Remodeling From Glucose Metabolism in Vascular Smooth Muscle Cells

Insulin activates biaxial signaling pathways; the insulin receptor substrate (IRS)-1/Akt pathway, which mainly regulates glucose metabolism, and the mitogen-activated protein (MAP) kinase pathway, which induces cell growth, hypertrophy, and fibrosis in various cell types.1,2 Insulin regulates homeostasis of cellular functions and glucose metabolism by maintaining the balance between these signaling pathways.3 Insulin resistance is considered to occur when insulin signals are not transmitted to the glucose metabolic pathway, resulting in increased insulin concentration to maintain normal blood glucose levels.4 Therefore, patients with type 2 diabetes mellitus, which is often characterized by insulin resistance, usually show hyperinsulinemia. These patients also show proliferative and hypertrophic vascular changes, arteriosclerosis and finally, cardiovascular events.5 The molecular mechanism of insulin resistance is reportedly considered to occur via serine phosphorylation of IRS-1 or its degradation.2,6,7 However, in a state of insulin resistance, effects of insulin on hypertrophic change via MAP kinase activation, independently of IRS-1, have not been clarified yet. Angiotensin (Ang) II not only regulates vascular constriction, cell proliferation, and hypertrophy, but also is deeply involved in the onset and progression of type 2 diabetes mellitus.8-10 Clinical studies have shown Ang II type 1 (AT1) receptor blockers (ARBs) to reduce the incidence of new-onset type 2 diabetes mellitus and improve insulin resistance,8,9 indicating that Ang II affects insulin signaling. It is also reported that ARBs prevent arteriosclerosis in diabetes patients, independently of systemic glucose metabolism.10 We have evaluated how insulin signaling is affected by Ang II in vasculature, and have partially clarified the molecular mechanism of vascular insulin resistance.6 Ang II induces IRS-1 degradation, subsequently attenuates signal transduction, and finally inhibits glucose metabolism in vascular smooth muscle cells (VSMCs). However, systemic glucose metabolism is mostly regulated in skeletal muscle, adipose tissue and liver.11 Therefore, vasculature’s role in glucose metabolism is considered to be minor, and the role of insulin signaling in vasculature is still controversial. Considering the evidence mentioned above, we hypothesized that Ang II reduces glucose metabolic insulin signals via IRS-1 depletion, causing diversion of insulin signals into the cell hypertrophic pathway mediated by MAP kinase activation in VSMCs. To test this hypothesis, we examined the effects of Ang II on the VSMC insulin signaling pathways, including IRS-1-Akt and MAP kinase, glucose metabolism and hypertrophic changes.