1-Deoxynojirimycin attenuates diabetic cardiomyopathy via PI3K/AKT-mediated mitochondrial protection and anti-apoptosis

ETHNOPHARMACOLOGICAL RELEVANCE: 1-Deoxynojirimycin (DNJ), a naturally occurring alkaloid derived from mulberry leaves (Morus alba L.), is a powerful α-glucosidase inhibitor that has notable hypoglycemic effects. Nonetheless, the fundamental molecular mechanisms-especially diabetic cardiomyopathy (DCM)-are still not fully understood. PURPOSE: This study sought to determine the cardioprotective effect of DNJ in diabetic cardiomyopathy and to elucidate the associated molecular mechanism. METHODS: A high glucose-induced DCM model was established in H9C2 cells and db/db mice. DNJ was administered by gavage or coculture with cells. The molecular mechanism of DNJ activity and changes in the activity of the PI3K/AKT pathway were evaluated by echocardiography, tissue staining, transmission electron microscopy, fluorescence probes, biochemical kits, Western blotting, and transcriptome sequencing, and the pathway was verified by the use of inhibitors. RESULTS: In vivo tests initially demonstrated that DNJ may lower body weight and fasting blood glucose levels; enhance glucose tolerance and cardiac performance; diminish myocardial fibrosis, myocardial hypertrophy, and lipid accumulation; and reduce myocardial cell death in db/db mice. DNJ therapy improved the HG-induced reduction in H9C2 cell viability, reduced ROS levels, mitigated oxidative damage, and inhibited cell death. DNJ can restore HG-mediated suppression of ATP5B expression and ATP levels, potentially enhancing mitochondrial energy utilization. The therapeutic efficacy of DNJ may be contingent upon the PI3K/AKT pathway, underscoring its regulatory significance, particularly in mediating cellular responses to oxidative stress and promoting cell survival in H9C2 cells. CONCLUSIONS: Our preliminary findings suggest that DNJ may alleviate diabetic myocardial injury, possibly by triggering the PI3K/AKT pathway. This work offers a preliminary rationale for DNJ as a prospective treatment agent for DCM.