Modulation of insulin resistance by renin angiotensin system inhibitors: implications for cardiovascular prevention

Abstract

Insulin resistance (IR) and the related hyperinsulinamia play a key role in the genesis and progression of the continuum of cardiovascular (CV) disease. Thus, it is reasonable to pursue in primary and secondary CV prevention, the pharmacological strategies that are capable to interfere with the development of IR. The renin-angiotensin-aldosterone system (RAAS) plays an important role in the pathogenesis of IR. In particular, angiotensin II (Ang II) through the generation of reactive oxygen species, induces a low grade of inflammation, which impairs the insulin signal transduction. The angiotensin converting enzyme (ACE) inhibitors are effective not only as blood pressure-lowering agents, but also as modulators of metabolic abnormalities. Indeed, experimental evidence indicates that in animal models of IR, ACE inhibitors are capable to ameliorate the insulin sensitivity. The Ang II receptor blockers (ARBs) modulate the peroxisome proliferator-activated receptor (PPAR)-γ activity. PPAR–γ is a transcription factor that controls the gene expression of several key enzymes of glucose metabolism. A further mechanism that accounts for the favorable metabolic properties of ARBs is the capability to modulate the hypothalamic–pituitary-adrenal (HPA) axis. The available clinical evidence is consistent with the concept that both ACE inhibitors and ARBs are able to interfere with the development of IR and its consequences like type 2 diabetes. In addition, pharmacological inhibition of the RAAS has favourable effects on dyslipidaemias, metabolic syndrome and obesity. Therefore, the pharmacological antagonism of the RAAS, nowadays, represents the first choice in the prevention of cardio-metabolic diseases.

Relationship between the Plasma Proteome and Changes in Inflammatory Markers after Bariatric Surgery

“…Another interesting correlation was between reduction in IL6 and fold change in ACE. The role and importance of ACE inhibitors in cardiovascular disease related to obesity and diabetes is well known [40]. ACE inhibitors are effective not only as blood pressurelowering agents, but also as modulators of metabolic abnormalities.…”

“…ACE inhibitors are effective not only as blood pressurelowering agents, but also as modulators of metabolic abnormalities. Indeed, experimental evidence indicates that in animal models of insulin resistance, ACE inhibitors ameliorate the insulin resistance [40].…”

Hypertension in Patients with Insulin Resistance: Etiopathogenesis and Management in Children

“…It has been demonstrated that the ACEI do not only act as lowering agents, but also as modulators of metabolic anomalies [ 61 ]. Several mechanisms of function are involved in the treatment of the latter pathological condition.…”

“…First, ACEI interfere with the conversion of angiotensin I into AngII; furthermore, they increase the circulating level of the bradykinin by inhibiting the kininase II breakdown [ 62 ] and higher kinin levels are responsible for a major production of prostaglandins (prostaglandin E1) and NO, which improve exercise-induced glucose metabolism and muscle sensitivity to insulin [ 63 , 64 ], therefore insulin-mediated glucose uptake increased. Moreover, ACEI have the ability of causing peripheral vasodilation, leading to an increased surface area for glucose exchange between vessels and skeletal muscles [ 61 ]. A study conducted by Morel et al [ 65 ] demonstrated that IR was reduced in patients with high cardiovascular risk treated with enalapril for 12 weeks.…”

Angiotensin II Inhibits Insulin Receptor Signaling in Adipose Cells

“…In contrast, in human adipocytes and 3T3-L1 adipose cells, it has been reported that Ang II inhibits lipolysis and promotes lipogenesis [ 19 , 20 , 21 ], which are opposite to its reported catabolic actions [ 22 , 23 , 24 ] and similar to the insulin effects in this tissue [ 25 ]. Diverse investigations have been directed to clarify the association of Ang II with insulin resistance-linked obesity [ 26 , 27 ]. For example, there is evidence indicating that under obesity, the local adipose RAS tissue, particularly white visceral adipose tissue (VAT), is increased in humans and animals and clearly correlates with elevated local and systemic Ang II levels, which promotes hypertrophic adipose tissue because of lipid accumulation, adipocyte growth, and differentiation which in turn secrete adipokines [ 28 ].…”