New insights into insulin action and resistance in the vasculature

Abstract

Two-thirds of adults in the United States are overweight or obese, and another 26 million have type 2 diabetes. Decreased insulin sensitivity in cardiovascular tissue is an underlying abnormality in these individuals. Insulin metabolic signaling increases endothelial cell nitric oxide (NO) production. Impaired vascular insulin sensitivity is an early defect leading to impaired vascular relaxation. In overweight and obese persons, as well as in those with hypertension, systemic and vascular insulin resistance often occur in conjunction with activation of the cardiovascular tissue renin-angiotensin-aldosterone system (RAAS). Activated angiotensin II type 1 receptor and mineralocorticoid receptor signaling promote the development of vascular insulin resistance and impaired endothelial NO-mediated relaxation. Research in this area has implicated excessive serine phosphorylation and proteasomal degradation of the docking protein insulin receptor substrate and enhanced signaling through hybrid insulin/insulin-like growth factor receptor as important mechanisms underlying RAAS impediment of downstream vascular insulin metabolic signaling. This review will present recent evidence supporting the notion that RAAS signaling represents a potential pathway for the development of vascular insulin resistance and impaired endothelial-mediated vasodilation.

Keywords: cardiovascular disease; endothelium; insulin resistance; nitric oxide; obesity.

Figure 1

Insulin effects on endothelial cells. Under normal conditions, stimulation of IR results in activation of the PI3K–Akt pathway, eNOS phosphorylation, and vasodilation. Insulin resistance induced by RAAS activation and excess nutrients causes increased serine phosphorylation of insulin receptor substrate and metabolic signaling with uninhibited activation of mitogenic and growth pathways. Aldo, aldosterone; Ang II, angiotensin II; AT1R, angiotensin II type 1 receptor; eNOS, endothelial NO synthase; ET-1,endothelin-1; IGF1-R, insulin-like growth factor-1 receptor; IR, insulin receptor; mTOR, mammalian target of rapamycin; MR, mineralocorticoid receptor; MAPK, mitogen activated protein kinase; NO, nitric oxide; PI3K, phosphatidylinositol 3-kinase; p, phosphorylation; Akt, protein kinase B; Ser, serine; Ser K, serine kinase; thr, threonine; Tyr, tyrosine.