Lipid Metabolism and Angiogenesis in Diabetic Cardiomyopathy: Mechanistic Links and Therapeutic Perspectives

Diabetic cardiomyopathy (DCM) is a major cardiovascular complication of diabetes, characterized by progressive myocardial structural and functional abnormalities that develop independently of coronary artery disease or hypertension. The pathogenesis of DCM has been a hot topic of research since its first description and is still under active investigation. Increasing evidence indicates that disturbances in myocardial lipid metabolism and coronary microvascular dysfunction are not independent features of DCM, but interconnected processes that contribute to disease initiation and progression. Excessive lipid uptake, altered fatty acid oxidation, and accumulation of bioactive lipid species, including ceramides and diacylglycerols, promote mitochondrial dysfunction, oxidative stress, inflammation, and impaired cardiomyocyte function. In parallel, diabetes-induced endothelial dysfunction, microvascular rarefaction, and defective angiogenic adaptation compromise myocardial perfusion and limit the capacity of the diabetic heart to respond to increasing metabolic demands. Importantly, lipid overload can directly impair endothelial angiogenic signaling, whereas endothelial metabolic dysfunction may further amplify myocardial injury, establishing a self-reinforcing metabolic-vascular cycle. In this review, we discuss the molecular mechanisms linking altered lipid metabolism to endothelial dysfunction and impaired angiogenesis in DCM, with particular emphasis on toxic lipid species, adipokine signaling, VEGF- and HIF-dependent pathways, and endothelial metabolic regulation. We further examine emerging therapeutic strategies targeting myocardial lipid handling, mitochondrial metabolism, coronary microvascular dysfunction, and angiogenic signaling, highlighting recent preclinical and clinical evidence.