Ginsenoside Rc inhibits diabetic cardiomyopathy by reducing lipotoxicity through the adiponectin and autophagy pathways.

Diabetic cardiomyopathy (DCM), a consequential cardiovascular complication of diabetes mellitus, drives progressive myocardial fibrosis and cardiac dysfunction, culminating in heart failure (HF). Ginsenoside Rc (Rc) has significant antidiabetic and cardiovascular protective properties, but its potential to improve DCM is unclear. The aim of this study was to explore the mechanism of Rc against DCM. The DCM model was established in db/db mice to evaluate the effects of Rc on metabolic and adipokine indicators in serum, and echocardiography and histological examinations were used to detect cardiac function in the mice. A lipotoxicity model of H9c2 cells was established using PA to verify the protective effect of Rc on cardiomyocytes, reduce lipotoxicity and improve mitochondrial function. The effect of Rc on adiponectin (APN) was demonstrated in 3T3 - L1 cells. Lipid metabolomics was used to explore the possible pathways by which Rc improves DCM. Quantitative reverse transcription polymerase chain reaction (qRT‒PCR) and western blot (WB) were used to detect gene and protein expression in mouse hearts and H9c2 cells. Rc reduced body weight, glycemia, dyslipidemia, and inflammatory mediator levels in db/db mice. It alleviated myocardial fibrosis and lipid accumulation and protected against lipotoxicity-induced damage in H9c2 cells. Furthermore, Rc enhanced mitochondrial function in lipotoxic H9c2 cells while suppressing reactive oxygen species (ROS) generation. Rc also reduced hepatic lipid accumulation in db/db mice while decreasing lipid droplet accumulation in 3T3-L1 cells. Critically, Rc elevated circulating APN levels in both db/db mice and 3T3-L1 cells, which increased the expression of APPL1, LKB1 and AdipoR1 in both the hearts of db/db mice and lipotoxicity-induced H9c2 cells. Lipid metabolomics analysis of db/db mouse serum and urine revealed that Rc primarily regulated autophagy-related pathways. Rc significantly increased the number of autophagic vesicles in H9c2 cells with lipotoxicity and promoted autophagy pathways in both the hearts of db/db mice and lipotoxic H9c2 cells. This increased AMPKα2 phosphorylation, Beclin1 expression and the LC3II/LC3I ratio while reducing p62 expression. Collectively, these data indicated that Rc could rectify glucose/lipid metabolic perturbations, attenuate oxidative stress and inflammation, and restore mitochondrial functionality. Rc promoted APN secretion and activated the AdipoR1/APPL1/LKB1/AMPKα2 signaling pathway, further enhancing autophagy, increasing the ratio of LC3II/LC3Ⅰ and the expression of Beclin1, and decreasing the expression of p62, which reduced lipotoxicity and demonstrated potential for preventing and treating DCM.