Molecular mechanisms of cardiac pathology in diabetes – Experimental insights

Abstract

Diabetic cardiomyopathy is a distinct pathology independent of co-morbidities such as coronary artery disease and hypertension. Diminished glucose uptake due to impaired insulin signaling and decreased expression of glucose transporters is associated with a shift towards increased reliance on fatty acid oxidation and reduced cardiac efficiency in diabetic hearts. The cardiac metabolic profile in diabetes is influenced by disturbances in circulating glucose, insulin and fatty acids, and alterations in cardiomyocyte signaling. In this review, we focus on recent preclinical advances in understanding the molecular mechanisms of diabetic cardiomyopathy. Genetic manipulation of cardiomyocyte insulin signaling intermediates has demonstrated that partial cardiac functional rescue can be achieved by upregulation of the insulin signaling pathway in diabetic hearts. Inconsistent findings have been reported relating to the role of cardiac AMPK and β-adrenergic signaling in diabetes, and systemic administration of agents targeting these pathways appear to elicit some cardiac benefit, but whether these effects are related to direct cardiac actions is uncertain. Overload of cardiomyocyte fuel storage is evident in the diabetic heart, with accumulation of glycogen and lipid droplets. Cardiac metabolic dysregulation in diabetes has been linked with oxidative stress and autophagy disturbance, which may lead to cell death induction, fibrotic 'backfill' and cardiac dysfunction. This review examines the weight of evidence relating to the molecular mechanisms of diabetic cardiomyopathy, with a particular focus on metabolic and signaling pathways. Areas of uncertainty in the field are highlighted and important knowledge gaps for further investigation are identified. This article is part of a Special issue entitled Cardiac adaptations to obesity, diabetes and insulin resistance, edited by Professors Jan F.C. Glatz, Jason R.B. Dyck and Christine Des Rosiers.

Mesenchymal stem cells ameliorate myocardial fibrosis in diabetic cardiomyopathy via the secretion of prostaglandin E2

“…Cardiovascular complications, including diabetic cardiomyopathy (DCM), represent the leading causes of morbidity and mortality in diabetic patients [1,2]. DCM is mainly characterized by myocardial fibrosis, chronic inflammation, and structural and functional cardiac changes caused by long-term glucose abnormalities [3][4][5]. In particular, cardiac fibrosis is often accompanied by increased pro-fibrotic factors such as transforming growth factor (TGF)-β, proliferation and dysfunction of cardiac fibroblasts, increased deposition, and decreased degradation of extracellular matrix proteins (ECM) such as collagen, leading to increased ventricular wall stiffness, abnormal cardiac filling, and diastolic and contractile cardiac dysfunction [6][7][8].…”

Kir6.1 improves cardiac dysfunction in diabetic cardiomyopathy via the AKT-Foxo1 signaling pathway

“…K ATP plays a key protective role in the heart through various signaling pathways. Speci cally, genetic manipulation of cardiomyocyte insulin signaling intermediates has demonstrated that partial cardiac function rescue was achieved by upregulation of the insulin signaling pathway in diabetic hearts [37]. Similarly, a previous study has reported that the cardioprotective effect of K ATP occurs at least partially by regulating the AKT-Foxo1 signaling pathway, which in turn in uences the expression of PGC-1α and its downstream target genes [38].…”

Diabetic Cardiomyopathy: Five Major Questions with Simple Answers

“…The hexosamine biosynthetic pathway, protein kinase C pathway, advanced glycation end-products pathway, and polyol flux pathway secondary to an increase of hyperglycemia can all produce contractile dysfunction, which can lead to systolic HF in a patient with DCM. 16,17 Can Diagnosis be Improved?…”