Restorative Potential of Stevia Leaves Against Cardiomyopathy Associated with Type 2 Diabetes Through Multiple Interdependent Pathways

<b>Background and Objective:</b> Diabetic cardiomyopathy (DCM) is a serious complication of type 2 diabetes, characterized by metabolic imbalance, oxidative stress, inflammation and apoptosis, leading to impaired cardiac function. Despite available treatments, safer and more effective natural alternatives remain underexplored. This study investigated the active composition of <i>Stevia rebaudiana</i> leaf extract (SLE) and evaluated its prophylactic effects against diabetic cardiomyopathy in an experimental rat model. <b>Materials and Methods:</b> Twenty-four male rats were randomly divided into four groups: Control, SLE-treated (400 mg/kg Stevia glycosides for 30 days), STZ-induced diabetic (110 mg/kg Nicotinamide followed by 60 mg/kg Streptozotocin) and SLE+STZ co-treated. Biochemical assays were performed to assess glucose metabolism, insulin sensitivity, serum electrolytes, protein and cardiac enzymes (LDH, CK-MB). Oxidative stress markers, antioxidant levels, inflammatory cytokines, apoptotic markers and cardiac histopathology were evaluated. Data were analyzed using One-way ANOVA followed by <i>post hoc</i> tests, with p<0.05 considered significant. <b>Results:</b> The SLE significantly reduced serum glucose and insulin resistance while improving QUICKI and regulating electrolytes, total protein, LDH and CK-MB compared to diabetic rats. It restored redox balance by lowering PCO, NO and MDA, while enhancing SOD, CAT, GSH and TAC. Inflammatory cytokines (TNF-α, IL-6, IL-1β, VCAM-1 and ICAM-1) and apoptotic markers (Bax, P53, Cytochrome C, Caspase-9 and Caspase-3) were markedly downregulated, whereas anti-apoptotic Bcl-2 was upregulated. Histological analysis confirmed preserved cardiac structure, reduced fibrosis and diminished DNA fragmentation, further supported by decreased PARP levels. <b>Conclusion:</b> <i>Stevia</i> <i>rebaudiana</i> leaf extract exerts potent cardioprotective effects in diabetic rats by improving metabolic indices, attenuating oxidative stress, inflammation and apoptosis and preserving cardiac architecture. These findings highlight its therapeutic potential as a natural prophylactic agent against diabetic cardiomyopathy, warranting further clinical validation.