Hyperglycaemia to heart failure: molecular pathophysiology, clinical manifestations, and novel therapeutic targets for diabetic cardiomyopathy

Context: Diabetic cardiomyopathy (DCM) is a chronic cardiac disorder that develops independently of coronary artery disease or hypertension in individuals with diabetes. Despite being identified over fifty years ago, it remains poorly recognized, and its management lacks standardization. The rising global prevalence of diabetes has amplified the incidence of DCM, underscoring the urgent need to clarify its molecular underpinnings and clinical progression. Objective: To provide a comprehensive review of the molecular and physiological mechanisms underlying diabetic cardiomyopathy, elucidating how metabolic dysregulation contributes to cardiac structural and functional alterations. This study also aims to highlight the potential therapeutic targets involved in the key signaling pathways of DCM pathogenesis. Methods: A systematic literature review was conducted using major scientific databases, including PubMed, Scopus, and Web of Science, covering studies published between 2000 and 2025. Keywords used included “diabetic cardiomyopathy,” “hyperglycemia,” “insulin resistance,” “oxidative stress,” “inflammation,” “mitochondrial dysfunction,” and “therapeutic targets.” Data Sources, Study Selection, and Data Extraction: Peer-reviewed articles, original research papers, and review articles focusing on molecular mechanisms, signaling pathways, and therapeutic interventions related to DCM were included. Studies involving both experimental models and human subjects were considered. Data were extracted regarding metabolic alterations, key signaling cascades (NF-κB, PARP1, GLUT4, AT1R), and their association with cardiac remodeling, fibrosis, and functional impairment. The information was synthesized to illustrate the progression from metabolic imbalance to clinical manifestations and to identify promising molecular targets for therapy.