The Role of the Angiotensin System in Cardiac Glucose Homeostasis: Therapeutic Implications

Resistance to the metabolic actions of insulin is thought to play a determining role in the aetiology of a great variety of disorders, including essential hypertension, accelerated atherosclerosis and cardiomyopathies. ACE inhibitors are recognised as being highly effective therapy for hypertension and cardiac insufficiency, and have a more beneficial effect on survival rate than expected on the basis of known mechanisms of action. The mechanism responsible for these extremely positive effects are just beginning to be understood and appear to be linked to the effects these drugs have on metabolism. The relationship between the insulin and angiotensin II (Ang II) signalling pathways needs to be fully clarified in order to prevent or correct the target organ damage resulting from changes in the cross-talk of these two hormonal systems. In recent years, Ang II has been shown to play a central role in cardiovascular and neuroendocrine physiology as well as in cellular cycle control. Moreover, the fact that Ang II utilises the insulin-receptor substrate (IRS)-1 to relay signals towards their intracellular destination, provides the biochemical explanation of how these two systems interact in a healthy organism and in a diseased one. Since it is overactivity of the renin-angiotensin system that seems to impair the intracellular response to insulin signalling, cardiovascular drugs that modulate the cellular transmission of Ang II have attracted particular interest. As well as the already widely-used ACE inhibitors, selective blockers of the Ang II type 1 receptor (AT(1)) have been shown to be clinically effective in the control of haemodynamic parameters, but with perhaps a less striking effect on glucose homeostasis. Many trials have investigated the effect of Ang II blockade on systemic glucose homeostasis. The inhibition of Ang II by ACE-inhibitors frequently showed a positive effect on glycaemia and insulin sensitivity, while information on the effects of AT(1) receptor antagonists on glucose homeostasis is more limited and controversial. An important limitation of these studies has been the short treatment and follow-up periods, even for the 'so called' long-term studies which were only 6 months. Several investigators have focused on the effects of the nuclear factors involved in gene transcriptions, especially with respect to the agonists/antagonists of peroxisome proliferator-activated receptors (PPARs) and their intriguing interconnections with the insulin and Ang II subcellular pathways. In fact, in vitro and in vivo experimental studies have shown that thiazolidinediones (selective PPAR-gamma ligands) are not only powerful insulin sensitisers, but also have anti-hypertensive and anti-atherosclerotic properties. In addition to conventional pharmacological approaches, attempts have been made to use genetic transfer in the treatment of cardiovascular and metabolic disorders. The development of powerful viral vectors carrying target genes has allowed us to restore the expression/function of specific proteins involved in the cellular mechanism of insulin resistance, and research now needs to move beyond animal models. Although a clearer picture is now emerging of the pathophysiological interaction between insulin and Ang II, especially from pre-clinical studies, there is much to be done before experimental findings can be used in daily clinical practice.