Unraveling and Targeting Myocardial Regeneration Deficit in Diabetes

Abstract

Cardiomyopathy is a common complication in diabetic patients. Ventricular dysfunction without coronary atherosclerosis and hypertension is driven by hyperglycemia, hyperinsulinemia and impaired insulin signaling. Cardiomyocyte death, hypertrophy, fibrosis, and cell signaling defects underlie cardiomyopathy. Notably, detrimental effects of the diabetic milieu are not limited to cardiomyocytes and vascular cells. The diabetic heart acquires a senescent phenotype and also suffers from altered cellular homeostasis and the insufficient replacement of dying cells. Chronic inflammation, oxidative stress, and metabolic dysregulation damage the population of endogenous cardiac stem cells, which contribute to myocardial cell turnover and repair after injury. Therefore, deficient myocardial repair and the progressive senescence and dysfunction of stem cells in the diabetic heart can represent potential therapeutic targets. While our knowledge of the effects of diabetes on stem cells is growing, several strategies to preserve, activate or restore cardiac stem cell compartments await to be tested in diabetic cardiomyopathy.

Streptozotocin-Induced Type 1 and 2 Diabetes Mellitus Mouse Models Show Different Functional, Cellular and Molecular Patterns of Diabetic Cardiomyopathy

“…To further investigate the involvement of cellular senescence, inducing chronic inflammation, in diabetes, we evaluated the senescence-associated secretory phenotype (SASP) [ 22 , 29 , 30 ] in freshly isolated CMs obtained from T1DM, T2DM and CTRL mice. The SASP has been postulated as a pathophysiological link between diabetes and senescence in cardiovascular diseases [ 22 , 23 , 31 ].…”

Targeting the redox system for cardiovascular regeneration in aging

“…In diabetic patients, circulating high glucose and altered insulin signaling are associated with increased ROS generation and susceptibility to oxidative responses in the heart, leading to tissue remodeling, ventricular hypertrophy, and impaired systolic and diastolic function (Huo et al., 2023 ; Nishio et al., 2004 ). Analysis of heart‐resident CPCs in insulin‐resistant humans and rodents reveal that hyperglycemia‐induced oxidative stress impairs CM formation and growth (Molinaro et al., 2022 ; Rota et al., 2006 ). The CM formation‐death imbalance leads to premature CPC senescence and subsequent cardiac aging and HF in diabetic patients (Westermeier et al., 2016 ).…”

Association of epicardial fat volume with subclinical myocardial damage in patients with type 2 diabetes mellitus

“…Hyperglycemia damages the myocardium and aggravates mitochondrial dysfunction, and the release of inflammatory factors and oxidative stress ( 32 ). The microenvironment of diabetes triggers cellular senescence, leading to excessive release of free fatty acids by adipose tissue, causing lipotoxicity ( 33 ). Secondly, as an endocrine organ, EAT secretes various cytokines and pro-inflammatory chemokines, such as tumor necrosis factor-alpha (TNF-α), interleukins (ILs), and adiponectin, directly or indirectly acting on the myocardium and cardiac blood vessels ( 34 ).…”