Insulin resistance and heart failure: underlying molecular mechanisms and potential pharmacological solutions.

Obesity, insulin resistance, and type 2 diabetes mellitus are prevalent worldwide in aging populations. Hypertension and ischemic heart disease are more common in these patients. Diabetes, impaired fasting blood glucose, and insulin resistance are also associated with alterations of left ventricular structure and function. Systemic insulin resistance exacerbated by metabolic and endocrine overload may lead to cardiac insulin resistance. Reduced cardiac insulin signaling is emerging as one of the major factors in the development of heart failure. Elucidating the underlying molecular mechanisms linking insulin resistance and heart failure may help to develop new and effective drugs to improve myocardial function. Although angiotensin II receptor blockers (ARBs) are widely used in type 2 diabetes, relatively little is known regarding their efficacy in heart failure associated with insulin resistance. Patients with essential hypertension often exhibit insulin resistance, and ARB improves insulin resistance, suggesting that endogenous angiotensin II is critically involved in the development of insulin resistance in patients with hypertension. Zaman et al focused on emerging molecular and metabolic pathways underlying cardiac dysfunction in obesity and insulin resistance. They hypothesized that inappropriate activation of the renin angiotensin aldosterone system may contribute to the development of cardiac dysfunction associated with insulin resistance and obesity. They characterized the effects of a novel angiotensin II receptor blocker (azilsartan medoxomil) on structural and functional alterations in mice rendered obese and insulin resistant by a high-fat diet and subjected to left ventricular pressure overload (aortic banding). Azilsartan reduced left ventricular wall thickness, hypertrophy, and concentrations of the profibrotic plasminogen activator inhibitor (PAI)-1. It also increased cardiac output after aortic banding compared with results in vehicle controls. Insulin resistance is an independent risk factor of cardiovascular diseases. When AT1 receptors are activated by angiotensin II, serine phosphorylation of insulin receptor substrate-1 (IRS-1) inhibits tyrosine phosphorylation IRS-1 induced by insulin, leading to eventual reduction of glucose uptake. In mice simulating type 2 diabetes azilsartan reduced the expression of tumor necrosis factor-a in skeletal muscle and adipose tissue. Azilsartan also increased the expression of adiponectin and peroxisome proliferator-activated receptor g in adipose tissue. The favorable effect of azilsartan observed in the study by Zaman et al may be because of reduction of increased renin angiotensin aldosterone system activity induced by phenomena such as metabolic syndrome, reduction of profibrotic PAI-1 molecule, and improvement of impaired insulin signaling. In an animal model with insulin resistance, obesity, and pressure overload, azilsartan was effective in improving cardiac function, suggesting that this agent can provide favorable heart protection. In a recent clinical study, azilsartan achieved rigorous control of blood pressure. Further elucidation of the underlying mechanisms should provide a better understanding of the various cardiac abnormalities associated with insulin resistance and obesity.