Metabolic actions of angiotensin II and insulin: A microvascular endothelial balancing act

Abstract

Metabolic actions of insulin to promote glucose disposal are augmented by nitric oxide (NO)-dependent increases in microvascular blood flow to skeletal muscle. The balance between NO-dependent vasodilator actions and endothelin-1-dependent vasoconstrictor actions of insulin is regulated by phosphatidylinositol 3-kinase-dependent (PI3K) - and mitogen-activated protein kinase (MAPK)-dependent signaling in vascular endothelium, respectively. Angiotensin II acting on AT₂ receptor increases capillary blood flow to increase insulin-mediated glucose disposal. In contrast, AT₁ receptor activation leads to reduced NO bioavailability, impaired insulin signaling, vasoconstriction, and insulin resistance. Insulin-resistant states are characterized by dysregulated local renin-angiotensin-aldosterone system (RAAS). Under insulin-resistant conditions, pathway-specific impairment in PI3K-dependent signaling may cause imbalance between production of NO and secretion of endothelin-1, leading to decreased blood flow, which worsens insulin resistance. Similarly, excess AT₁ receptor activity in the microvasculature may selectively impair vasodilation while simultaneously potentiating the vasoconstrictor actions of insulin. Therapeutic interventions that target pathway-selective impairment in insulin signaling and the imbalance in AT₁ and AT₂ receptor signaling in microvascular endothelium may simultaneously ameliorate endothelial dysfunction and insulin resistance. In the present review, we discuss molecular mechanisms in the endothelium underlying microvascular and metabolic actions of insulin and Angiotensin II, the mechanistic basis for microvascular endothelial dysfunction and insulin resistance in RAAS dysregulated clinical states, and the rationale for therapeutic strategies that restore the balance in vasodilator and constrictor actions of insulin and Angiotensin II in the microvasculature.

Introduction

Insulin resistance is frequently present in obesity, hypertension, coronary artery disease, dyslipidemias, and metabolic syndrome (DeFronzo and Ferrannini, 1991, Petersen et al., 2007). Insulin regulates glucose homeostasis by promoting glucose disposal in skeletal muscle and adipose tissue (Petersen et al., 2007). In addition to its direct actions on the skeletal muscle, insulin regulates nutrient delivery to target tissues by actions on microvasculature (Baron and Clark, 1997, Clark, 2008, Clark et al., 1995, Clark et al., 2003, Barrett et al., 2011). These vasodilator actions of insulin are nitric oxide (NO)-dependent and lead to increased skeletal muscle microvascular perfusion that further enhances glucose uptake in skeletal muscle (Muniyappa et al., 2007, Vicent et al., 2003, Vincent et al., 2004, Zhang et al., 2004). These actions of insulin on skeletal muscle microvasculature appear to be a rate limiting step for insulin-mediated glucose disposal. At the cellular level, balance between phosphatidylinositol 3-kinase- (PI3K)-dependent insulin-signaling pathways that regulate endothelial NO production and mitogen activated protein kinase (MAPK)-dependent insulin-signaling pathways regulating the secretion of the vasoconstrictor endothelin-1 (ET-1) determines the microvascular response to insulin. Insulin resistance is typically defined as decreased sensitivity or responsiveness to metabolic actions of insulin such as insulin-mediated glucose disposal. However, diminished sensitivity to the vascular actions of insulin also plays an important role in the pathophysiology of insulin-resistant states (Natali et al., 1997, Baron et al., 1991). Endothelial insulin resistance is typically accompanied by reduced PI3K-NO pathway and an intact or heightened MAPK-ET1 pathway (Muniyappa et al., 2007).

The Renin-angiotensin-aldosterone system (RAAS) plays a major role in microvascular function and remodeling. Ang II regulates endothelial NO production, arterial tone, skeletal muscle microvascular perfusion, and glucose metabolism in a receptor (AR)-specific manner (AT₁R vs. AT₂R) (Chai et al., 2011, Chai et al., 2010). In contrast to AT₁R, stimulation of AT₂R increases NO production, reduces vascular tone, and augments skeletal muscle microvascular perfusion (Chai et al., 2011, Chai et al., 2010). Activation of RAAS in insulin-sensitive tissues is known to induce insulin resistance (Cooper et al., 2007, Lastra-Lastra et al., 2009). In particular, chronic activation of RAAS impairs insulin signaling, increases oxidative stress, and reduces NO bioavailability (Cooper et al., 2007). However, insulin resistance also increases local RAAS activity triggering a vicious cycle that leads to endothelial dysfunction, atherosclerosis, inflammation, and dysmetabolic states associated with obesity, diabetes, and hypertension. Thus, the relative contributions of AT₁R and AT₂R activation and cross-talk between the signaling pathways of insulin and Ang II appear to modulate endothelial function. Herein, we discuss the cellular mechanisms and signaling pathways underlying the microvascular actions of insulin and Ang II, the metabolic consequences of an imbalance in these pathways, and potential therapeutic interventions that may improve microvascular function in insulin-resistant conditions.