Abstract
INTRODUCTION: Type 2 diabetes mellitus (T2DM) is one of the most commonly diagnosed metabolic diseases. Notably, two-thirds of diabetic patients may develop diabetic cardiomyopathy (DCM), a life-threatening condition for which no curative treatment currently exists. METHODS: This study aimed to investigate the potential ameliorative effects of caffeine against DCM development, utilizing a novel oral sustained-release caffeine-loaded Pickering emulsion formula stabilized by calcium carbonate nanoparticles to enhance its pharmaceutical and pharmacological properties. Eighty-four rats were divided into seven groups: control, caffeine, nano-caffeine, diabetic, diabetic + rosuvastatin, diabetic + caffeine, and diabetic + nano-caffeine. RESULTS: Our findings demonstrated that the newly developed nano-caffeine formulation significantly downregulated myocardial injury markers (CK-MB, cTnI, ALT, AST, and LDH) and markedly ameliorated myocardial tissue injury and fibrosis, as confirmed by histopathological examination and desmin/α-SMA expression analysis. Additionally, the nano-caffeine treatment reduced inflammatory cytokines (TNF-α and IL-1β), attenuated hyperlipidemia, decreased iNOS and NO myocardial concentrations, and upregulated protective antioxidants (Nrf2, GSH, GSH-Px, SOD, and catalase) compared to the control group. Importantly, the cardioprotective effects of nano-caffeine were more pronounced than those observed in caffeine-treated diabetic rats. Furthermore, a novel, simple, and validated HPLC method was employed to quantify caffeine levels in cardiac tissues in all groups. The analysis revealed significantly higher caffeine concentrations in the nano-caffeine group compared to other groups, indicating improved tissue delivery. CONCLUSION: The formulation significantly enhances the cardioprotective effects of caffeine against myocardial injury in T2DM rats by optimizing its pharmacodynamic and pharmacokinetic properties.