Recent advances associated with cardiometabolic remodeling in diabetes-induced heart failure

Abstract

Diabetes mellitus (DM) is characterized by chronic hyperglycemia, and despite intensive glycemic control, the risk of heart failure in patients with diabetes remains high. Diabetes-induced heart failure (DHF) presents a unique metabolic challenge, driven by significant alterations in cardiac substrate metabolism, including increased reliance on fatty acid oxidation, reduced glucose utilization, and impaired mitochondrial function. These metabolic alterations lead to oxidative stress, lipotoxicity, and energy deficits, contributing to the progression of heart failure. Emerging research has identified novel mechanisms involved in the metabolic remodeling of diabetic hearts, such as autophagy dysregulation, epigenetic modifications, polyamine regulation, and branched-chain amino acid (BCAA) metabolism. These processes exacerbate mitochondrial dysfunction and metabolic inflexibility, further impairing cardiac function. Therapeutic interventions targeting these pathways-such as enhancing glucose oxidation, modulating fatty acid metabolism, and optimizing ketone body utilization-show promise in restoring metabolic homeostasis and improving cardiac outcomes. This review explores the key molecular mechanisms driving metabolic remodeling in diabetic hearts, highlights advanced methodologies, and presents the latest therapeutic strategies for mitigating the progression of DHF. Understanding these emerging pathways offers new opportunities to develop targeted therapies that address the root metabolic causes of heart failure in diabetes.

Keywords: cardiac metabolism; diabetes mellitus; heart failure mechanisms; metabolic therapies; mitochondrial dysfunction.

Figure 1.

Mechanisms of diabetes-induced heart failure (DHF). This schematic representation illustrates the potential causes of heart failure in diabetes. Obesity and pancreatic β-cell destruction are critical contributors to the development of diabetes. Elevated glucose levels in the bloodstream increase blood viscosity and glycosylated hemoglobin levels. Diabetes also induces mitochondrial dysfunction, leading to elevated production of reactive oxygen species (ROS), due to a metabolic remodeling in the heart. In nondiabetic hearts, glucose and fatty acids are used in a balanced manner for ATP production. However, in diabetic hearts, glucose uptake and oxidation are significantly reduced due to insulin inactivity and the downregulation of glucose transporters such as GLUT4. Meanwhile, there is an increased reliance on fatty acids, with heightened uptake facilitated by transporters such as CD36 and fatty acid transport proteins (FATP) , resulting in excessive fatty acid oxidation. This metabolic remodeling leads to the accumulation of toxic lipid intermediates, such as diacylglycerol (DAG) and ceramides, contributing to lipotoxicity, mitochondrial dysfunction, and impaired cardiac efficiency. These metabolic remodeling events alter regulatory molecules, including epigenetic modifiers, maintaining homeostatic gene levels in cells. These changes foster oxidative stress and pathological remodeling, ultimately leading to heart failure. Images were created with a licensed version of BioRender.com.

Figure 2.

Hallmarks of diabetes-induced heart failure (DHF). DHF is characterized by several distinctive features. The condition involves a reduced availability of glucose metabolic substrates, which results in mitochondrial dysfunction. This leads to increased reliance on fatty acid oxidation in the diabetic heart. Notably, females have a higher risk of developing heart failure compared with males. Moreover, the progression of diabetic heart failure typically advances from diastolic dysfunction to systolic dysfunction, contrasting with ischemic heart failure, where systolic dysfunction precedes heart failure. Images were created with a licensed version of BioRender.com.

Figure 3.

Therapeutic strategies targeting cardiac substrate metabolism in diabetes-induced heart failure (DHF). This schematic provides details on pharmacological and nonpharmacological interventions targeting cardiac substrate metabolism in DHF. Pharmacological strategies include sodium-glucose cotransporter 2 (SGLT2) inhibitors (e.g., empagliflozin), which enhance glycemic control and shift substrate utilization toward ketone bodies, as well as fatty acid oxidation inhibitors (e.g., trimetazidine), which promote glucose oxidation and reduce oxygen consumption. Mitochondrial-targeted therapies, such as coenzyme Q10 and MitoQ, are designed to improve mitochondrial function and mitigate oxidative stress. Nonpharmacological interventions, such as dietary modifications (e.g., Mediterranean diet) and exercise, help enhance metabolic flexibility, insulin sensitivity, and improve mitochondrial function. Images were created with a licensed version of BioRender.com.