Diabetic cardiomyopathy: a hyperglycaemia- and insulin-resistance-induced heart disease

Abstract

Diabetic cardiomyopathy is characterised in its early stages by diastolic relaxation abnormalities and later by clinical heart failure in the absence of dyslipidaemia, hypertension and coronary artery disease. Insulin resistance, hyperinsulinaemia and hyperglycaemia are each independent risk factors for the development of diabetic cardiomyopathy. The pathophysiological factors in diabetes that drive the development of cardiomyopathy include systemic metabolic disorders, inappropriate activation of the renin-angiotensin-aldosterone system, subcellular component abnormalities, oxidative stress, inflammation and dysfunctional immune modulation. These abnormalities collectively promote cardiac tissue interstitial fibrosis, cardiac stiffness/diastolic dysfunction and, later, systolic dysfunction, precipitating the syndrome of clinical heart failure. Recent evidence has revealed that dysregulation of coronary endothelial cells and exosomes also contributes to the pathology behind diabetic cardiomyopathy. Herein, we review the relationships among insulin resistance/hyperinsulinaemia, hyperglycaemia and the development of cardiac dysfunction. We summarise the current understanding of the pathophysiological mechanisms in diabetic cardiomyopathy and explore potential preventative and therapeutic strategies.

Keywords: Cardiac dysfunction; Heart failure; Hyperglycaemia; Insulin resistance; Review.

Fig. 1

Pathophysiological mechanisms of diabetic cardiomyopathy. Hyperglycaemia and insulin resistance induce increases in AGEs, cardiac lipotoxicity, activation of the RAAS, coronary endothelial dysfunction and dysregulation of exosomes, which, in turn, result in mitochondrial dysfunction, oxidative stress, ER stress and impairment of calcium homeostasis. These pathophysiological abnormalities are associated with cardiac hypertrophy, fibrosis, death, stiffness, diastolic dysfunction and heart failure

Fig. 2

Insulin metabolic signalling in diabetic cardiomyopathy. In cardiac muscle cells, overnutrition, NEFA mobilisation, aldosterone and angiotensin II impair cardiac insulin metabolic signalling of PI3K/Akt through activation of mTOR/S6K1 and phosphorylation of IRS-1/2. Reduction in NO increases the ratio of titin isoform N2B/N2BA, intracellular Ca²⁺, and Ca²⁺ sensitisation in cardiomyocytes by inhibition of cGMP/PKG. Impairment of insulin metabolic signalling also inhibits GLUT4 recruitment to the plasma membrane and subsequently glucose uptake into the heart, which decreases Ca²⁺ ATPase activity and thus increases intracellular Ca²⁺. These abnormalities cause cardiac stiffness and diastolic dysfunction. AT-1R, angiotensin II receptor 1; MR, mineralocorticoid receptor; [Ca²⁺]i, intracellular calcium; ATPase, adenosine triphosphatase