Insulin resistance and heart failure: molecular mechanisms

Abstract

This article addresses the issue of insulin resistance and associated reductions in cardiac insulin metabolic signaling, which is emerging as a major factor in the development of heart failure, and assumes more importance because of an epidemic increase in obesity and the cardiorenal metabolic syndrome in our aging population. The effects of cardiac insulin resistance are exacerbated by metabolic, endocrine, and cytokine alterations associated with systemic insulin resistance. Understanding the molecular mechanisms linking insulin resistance and heart failure may help to design new and more effective mechanism-based drugs to improve myocardial and systemic insulin resistance.

Figure 1. Overnutrition and impaired insulin metabolic signaling leading to cardiomyopathy

The major signaling pathway causing insulin resistance is the convergence of multiple stimuli leading to the activation of S6 kinase. Overnutrition results in increased levels of circulating fatty acids, amino acids and excess glucose that cause activation of mTOR/S6 kinase. Activation of RAAS results in oxidative stress due to activation of NADPH oxidase by Ang II and aldosterone. Oxidative stress induced activation of kinases including JNK and S6 kinase, results in serine phosphorylation of IRS-1 and inhibition of insulin metabolic signaling. Cytokine-induced insulin resistance also involves activation of S6 kinase. Oxidative stress and insulin resistance is also accompanied by impaired AMPK signaling which is a negative regulator of mTOR/S6 kinase. Persistent hyperactivation of mTOR/S6 kinase also leads to ER stress, oxidative stress and activation of JNK. Excess accumulation and enhanced oxidation of fatty acids concomitant with increased accumulation of lipid intermediates result in lipotoxicity and metabolic inflexibility. These four overnutrition-induced cellular events are further amplified by their feed-forward interactions.

Figure 2. Molecular mechanisms of cardiac insulin resistance and consequences of impaired insulin signaling and overnutrition leading to cardiac dysfunction

The major consequences of insulin resistance and oxidative stress causing cardiac dysfunction are impaired calcium handling, metabolic inflexibility, mitochondrial and ER dysfunction, and endothelial dysfunction. These events contribute to cardiac inefficiency, myocardial cell death and cardiac fibrosis and diastolic dysfunction. The progression of cardiac injury leads to contractile dysfunction and cardiac failure.