Myocardial Insulin Resistance: An Overview of Its Causes, Effects, and Potential Therapy

Abstract

Abstract: Insulin resistance ensues when normal physiological concentrations of insulin are unable to induce effective cellular insulin signalling and glucose uptake by insulin sensitive tissues. It is caused by several abnormalities that include; 1) an overabundance of circulating free fatty acids (and dyslipidaemia), 2) systemic inflammation caused by increased tissue and circulating pro-inflammatory cytokines, and, 3) over activation of the systemic and organ specific renin-angiotensin systems. Although usually associated with obesity, insulin resistance is not a condition that only afflicts obese individuals. Dyslipidaemia which is implicated in the aetiology of insulin resistance can be caused by adipose tissue expansion (obesity) or the increased consumption of lipogenic fructose which has profound effects on liver metabolism and serum lipid profiles. The primary reason fructose is implicated in insulin resistance is because it induces hepatic lipogenesis which would directly contribute to dyslipidaemia and increased lipid deposition in adipose tissue, muscle (heart and skeletal) and the liver. These changes in tissue lipid content and utilisation are thought to compromise tissue insulin signalling and induce insulin resistance. Myocardial insulin resistance not only influences myocardial metabolism and mechanical function in the normoxic heart but also compromises myocardial tolerance to ischaemia/reperfusion and post-ischaemic outcomes. Once insulin sensitive organs become insulin resistant, their substrate metabolism is altered and in the case of the heart, cardiac mechanical function is compromised which could potentially contribute to heart failure. Insulin resistance also decreases myocardial tolerance to ischaemia and reperfusion by compromising myocardial metabolism during ischaemic/reperfusion. Recently emerged evidence also suggests that insulin resistance reduces myocardial tolerance to ischaemia and reperfusion by altering the functionality of the intrinsic pro-survival Reperfusion Injury Salvage Kinase (RISK) pathways that protect against ischaemia/reperfusion injury. The authors and others have demonstrated strong links between reduced expression and activation (phosphorylation) of components of the RISK pathway and increased myocardial susceptibility to ischaemia/reperfusion injury. Lifestyle changes are known to improve insulin sensitivity while several pharmacological interventions using metabolic modulators and insulin sensitizer are currently being investigated and have shown promise in the treatment of animals and patients with myocardial insulin resistance. This review will identify and highlight some of the proposed causes of insulin resistance with particular reference to the role of dyslipidaemia, inflammation and the rennin-angiotensin system in the aetiology of this condition. We will also explore the possible effects of high dietary fructose consumption on circulating lipids and inflammation and the implications of these changes on skeletal and cardiac muscle insulin sensitivity. We will briefly reflect on the adverse effects of myocardial insulin resistance on myocardial metabolism and mechanical function and assess the effects of insulin resistance on myocardial tolerance to ischaemia and reperfusion. The proposed cellular causes of this decreased myocardial tolerance to ischaemia will be identified and current lifestyle and pharmacological interventions utilised to alleviate these adverse effects of insulin resistance will be reviewed. Keywords: Insulin resistance, Dyslipidaemia, Lipotoxicity, Adipocytokines, Renin-angiotensin system, Myocardial ischaemia/reperfusion.