Link between the renin–angiotensin system and insulin resistance: Implications for cardiovascular disease

Abstract

The incidence of metabolic syndrome is rapidly increasing in the United States and worldwide. The metabolic syndrome is a complex metabolic and vascular disorder that is associated with inappropriate activation of the renin-angiotensin-aldosterone system (RAAS) in the cardiovascular (CV) system and increased CV morbidity and mortality. Insulin activation of the phosphatidylinositol-3-kinase (PI3K) pathway promotes nitric oxide (NO) production in the endothelium and glucose uptake in insulin-sensitive tissues. Angiotensin (Ang) II inhibits insulin-mediated PI3K pathway activation, thereby impairing endothelial NO production and Glut-4 translocation in insulin-sensitive tissues, which results in vascular and systemic insulin resistance, respectively. On the other hand, Ang II enhances insulin-mediated activation of the mitogen-activated protein kinase (MAPK) pathway, which leads to vasoconstriction and pathologic vascular cellular growth. Therefore, the interaction of Ang II with insulin signaling is fully operative not only in insulin-sensitive tissues but also in CV tissues, thereby linking insulin resistance and CV disease. This notion is further supported by an increasing number of experimental and clinical studies indicating that pharmacological blockade of RAAS improves insulin sensitivity and endothelial function, as well as reduces the incidence of new-onset diabetes in high-risk patients with CV disease. This article reviews experimental and clinical data elucidating the physiological and pathophysiological role of the interaction between insulin and RAAS in the development of insulin resistance as well as CV disease.

The Novel Angiotensin II Receptor Blocker Azilsartan Medoxomil Ameliorates Insulin Resistance Induced by Chronic Angiotensin II Treatment in Rat Skeletal Muscle

“…Insulin resistance is widespread in the United States, with an estimated 70 million Americans presenting with this condition [3]. Systemic and tissue overactivation of the renin-angiotensin-aldosterone system (RAAS) can play an important role in the development of insulin resistance in skeletal muscle [3,4,5], the primary site for insulin-mediated glucose disposal in humans [6,7]. Several lines of evidence from animal model and human clinical investigations support a direct role of angiotensin II (Ang II) action to induce insulin resistance in skeletal muscle.…”

Changes in cardiac Na+/K+-ATPase expression and activity in female rats fed a high-fat diet

“…Similarly, in our study a HF diet augmented both RhoA and ROCK2 expression in obese female rat hearts. This may be related to the activation of the renin-angiotensin system, which is common in obesity and is characterized by increased level of Ang II [57]. This in turn induces a hypertrophic response in cardiomyocytes through various signal transduction pathways, including activation of RhoA [58,59].…”

Metabolic Syndrome: From Human Organ Disease to Fetal Programming

“…The action of aldosterone in cardiac cells is mainly related to the activation of mineralocorticoid receptors that can increase the cardiac Na+/H+ exchanger (pathway src-kinase phosphorylation and subsequent recruitment and activation of metalloproteinase receptor epidermal growth factor), contributing to hypertrophy of the heart. Moreover, the activation of aldosterone receptors can enhance the automaticity of the cardiomyocytes, generating atrial and ventricular arrhythmias through increases in the transcription of the voltage-gated T-type calcium channel [92][93][94][95][96].…”