Insulin receptor substrate signaling controls cardiac energy metabolism and heart failure

Abstract

The heart is an insulin-dependent and energy-consuming organ in which insulin and nutritional signaling integrates to the regulation of cardiac metabolism, growth and survival. Heart failure is highly associated with insulin resistance, and heart failure patients suffer from the cardiac energy deficiency and structural and functional dysfunction. Chronic pathological conditions, such as obesity and type 2 diabetes mellitus, involve various mechanisms in promoting heart failure by remodeling metabolic pathways, modulating cardiac energetics and impairing cardiac contractility. Recent studies demonstrated that insulin receptor substrates 1 and 2 (IRS-1,-2) are major mediators of both insulin and insulin-like growth factor-1 (IGF-1) signaling responsible for myocardial energetics, structure, function and organismal survival. Importantly, the insulin receptor substrates (IRS) play an important role in the activation of the phosphatidylinositide-3-dependent kinase (PI-3K) that controls Akt and Foxo1 signaling cascade, regulating the mitochondrial function, cardiac energy metabolism and the renin-angiotensin system. Dysregulation of this branch in signaling cascades by insulin resistance in the heart through the endocrine system promotes heart failure, providing a novel mechanism for diabetic cardiomyopathy. Therefore, targeting this branch of IRS→PI-3K→Foxo1 signaling cascade and associated pathways may provide a fundamental strategy for the therapeutic and nutritional development in control of metabolic and cardiovascular diseases. In this review, we focus on insulin signaling and resistance in the heart and the role energetics play in cardiac metabolism, structure and function.

Poor Renal and Cardiovascular Outcomes in Patients with Biopsy-Proven Diabetic Nephropathy

“…In the current study, we found that LVH was present in about one-third of patients with biopsy-proven DN and this incidence was significantly higher than NDRD patients. Several pathophysiological changes may explain the high incidence of LVH in DN patients, including insulin resistance [19], decreased metabolic flexibility [41], increased accumulation of advanced glycation end-products [42], and activation of systemic RAAS [43]. Therefore, the detection of LVH is important and may serve as an early indicator of cardiovascular damage, especially in DN patients.…”

Inhibition of galectin-3 ameliorates the consequences of cardiac lipotoxicity in a rat model of diet-induced obesity

“…A common additional feature of the obese heart is impaired insulin signaling, which represents an adaptation of the heart to an excess of calories, which promotes the development of diabetic cardiomyopathy ( Guo and Guo, 2017 ; Jia et al, 2016 ; Riehle and Abel, 2016 ). This condition not only alters cardiac metabolism but also increases myocardial oxygen consumption, reduces cardiac efficiency by affecting mitochondrial function and increases oxidative stress with the mitochondria being the main source of reactive oxygen species (ROS) ( Boudina et al, 2007 ; Elezaby et al, 2015 ; McMurray et al, 2016 ).…”

A susceptibility biomarker identification strategy based on significantly differentially expressed ceRNA triplets for ischemic cardiomyopathy

“…The ICM susceptibility genes enriched in four ICM-related functional classes could classify samples accurately, including cardiovascular disease, which was associated with coronary angiogenesis and vascular endothelial growth factor receptor [41]; inflammatory immune, which was capable of causing myocardial ischemic injury [42]; metabolism, which was related to the phosphorylation of PI3K and Akt in myocardial tissue of cardiomyopathy [43], and cell polarity, one of the fundamental causes of congenital heart disease [44].…”