Contribution of Impaired Insulin Signaling to the Pathogenesis of Diabetic Cardiomyopathy

Abstract

Diabetic cardiomyopathy (DCM) has emerged as a relevant cause of heart failure among the diabetic population. Defined as a cardiac dysfunction that develops in diabetic patients independently of other major cardiovascular risks factors, such as high blood pressure and coronary artery disease, the underlying cause of DCMremains to be unveiled. Several pathogenic factors, including glucose and lipid toxicity, mitochondrial dysfunction, increased oxidative stress, sustained activation of the renin-angiotensin system (RAS) or altered calcium homeostasis, have been shown to contribute to the structural and functional alterations that characterize diabetic hearts. However, all these pathogenic mechanisms appear to stem from the metabolic inflexibility imposed by insulin resistance or lack of insulin signaling. This results in absolute reliance on fatty acids for the synthesis of ATP and impairment of glucose oxidation. Glucose is then rerouted to other metabolic pathways, with harmful effects on cardiomyocyte function. Here, we discuss the role that impaired cardiac insulin signaling in diabetic or insulin-resistant individuals plays in the onset and progression of DCM.

Icariin Ameliorates Diabetic Cardiomyopathy Through Apelin/Sirt3 Signalling to Improve Mitochondrial Dysfunction

“…Despite the introduction of antidiabetic drugs in the United States (US), deaths due to heart failure in diabetic patients have not declined from 1985-2015 (Cheng et al, 2018). Instead, diabetic cardiomyopathy (DCM) has become a proximate cause of heart failure among diabetic patients (Zamora and Villena, 2019), and is one of the primary causes for the reduced functioning of diabetic cardiomyocytes (Dillmann, 2019). To date, however, the mechanism of DCM remains uncharacterized.…”

Role of Oxidative Stress in Metabolic and Subcellular Abnormalities in Diabetic Cardiomyopathy

“…Although type I diabetes is generally characterized by hypoinsulinemia, whereas type II diabetes is characterized by hyperinsulinemia, it should be emphasized that similar alterations in cardiac function and subcellular organelles are known to occur in both of these forms of diabetes [6,7,13,[24][25][26][27][28]. While this review has focused on the occurrence of cardiac dysfunction in insulin-dependent (type 1) diabetes, impaired insulin signaling has been suggested as a contributory mechanism in the pathogenesis of both types of diabetic cardiomyopathy [74]. In fact, it is now evident that several factors, including Ca 2+ -handling abnormalities, neurohormonal activation and oxidative stress, are considered as mechanisms for the occurrence of cardiac dysfunction as a consequence of insulin resistance or depressed insulin signaling [74].…”

“…While this review has focused on the occurrence of cardiac dysfunction in insulin-dependent (type 1) diabetes, impaired insulin signaling has been suggested as a contributory mechanism in the pathogenesis of both types of diabetic cardiomyopathy [74]. In fact, it is now evident that several factors, including Ca 2+ -handling abnormalities, neurohormonal activation and oxidative stress, are considered as mechanisms for the occurrence of cardiac dysfunction as a consequence of insulin resistance or depressed insulin signaling [74]. Accordingly, several other therapeutic options have been reported.…”

Exercise as A Potential Therapeutic Target for Diabetic Cardiomyopathy: Insight into the Underlying Mechanisms

“…Impaired energy metabolism in the myocardium or "metabolic remodeling of the heart" can lead to structural changes in cardiomyocytes, eventually leading to cardiomyopathy [14]. Under normal physiological conditions, glucose transporter-4 (GLUT-4), an intracellular protein, is translocated to the cell membrane in response to insulin, where it facilitates glucose uptake and utilization [48,49]. However, in diabetes, the expression and function of GLUT-4 are compromised, leading to a marked reduction in glucose transport and impaired energy utilization in the myocardium [50].…”

“…Mitochondria are important for energy metabolism, and the cardiac mitochondria processes the highest amounts of oxygen to meet the energy required for proper functioning of the organ. Therefore, mitochondrial dysfunction can play an important role in the pathogenesis of DCM [49]. The ultrastructural changes of the cardiac mitochondria associated with DCM include reduction of mitochondrial density, mitochondrial swelling, damage to the inner membrane, and increased mitochondrial matrix [17].…”