Modulation of the action of insulin by angiotensin-(1–7)

Abstract

The prevalence of Type 2 diabetes mellitus is predicted to increase dramatically over the coming years and the clinical implications and healthcare costs from this disease are overwhelming. In many cases, this pathological condition is linked to a cluster of metabolic disorders, such as obesity, systemic hypertension and dyslipidaemia, defined as the metabolic syndrome. Insulin resistance has been proposed as the key mediator of all of these features and contributes to the associated high cardiovascular morbidity and mortality. Although the molecular mechanisms behind insulin resistance are not completely understood, a negative cross-talk between AngII (angiotensin II) and the insulin signalling pathway has been the focus of great interest in the last decade. Indeed, substantial evidence has shown that anti-hypertensive drugs that block the RAS (renin-angiotensin system) may also act to prevent diabetes. Despite its long history, new components within the RAS continue to be discovered. Among them, Ang-(1-7) [angiotensin-(1-7)] has gained special attention as a counter-regulatory hormone opposing many of the AngII-related deleterious effects. Specifically, we and others have demonstrated that Ang-(1-7) improves the action of insulin and opposes the negative effect that AngII exerts at this level. In the present review, we provide evidence showing that insulin and Ang-(1-7) share a common intracellular signalling pathway. We also address the molecular mechanisms behind the beneficial effects of Ang-(1-7) on AngII-mediated insulin resistance. Finally, we discuss potential therapeutic approaches leading to modulation of the ACE2 (angiotensin-converting enzyme 2)/Ang-(1-7)/Mas receptor axis as a very attractive strategy in the therapy of the metabolic syndrome and diabetes-associated diseases.

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

“…It is clear though that cross-talk between insulin and ANG II (285,1089) can modulate the final outcome of the action of insulin. Studies demonstrating a close connection between insulin resistance and cardiovascular disease support the notion that alterations within the RAS could be related to dysregulation of the action of insulin (240,538,1271). Mechanistically, ANG II negatively regulates several steps of the insulin-signaling cascade via AT 1 R (FIGURE 12), including insulin-induced phosphorylation of the insulin receptor (IR), IR substrate-1 (IRS-1), and activation of Akt by phosphoinositide 3-kinase (PI3K) (31,493,729).…”

Antagonism of angiotensin 1–7 prevents the therapeutic effects of recombinant human ACE2

“…Akt, a serine/threonine kinase, also appears to have a central role in Ang 1–7 signaling, and phosphorylation of eNOS at Ser1177 by Akt results in a twofold increase in eNOS catalytic activity [10]. The phosphorylation of Akt at the regulatory sites Ser473 and Thr308 is stimulated by Ang 1–7 in human endothelial cells in vitro, as well as in the rat heart, liver, skeletal muscle, and adipose tissue in vivo [11]. Ang 1–7 exerts its beneficial effects through a NO/ cGMP pathway [12, 13].…”

Angiotensin 1–7 mediates renoprotection against diabetic nephropathy by reducing oxidative stress, inflammation, and lipotoxicity

“…3, A-D). ANG 1-7-induced attenuation of ROS coupled with the insulin-sensitizing property of ANG 1-7 (12,17) reduced the elevated random blood glucose (Fig. 3E) and plasma TAG (Fig.…”