Abstract

Severe hypoglycemia (SH) is associated with adverse cardiac outcomes in individuals with diabetes; however, the underlying mechanisms remain poorly understood. Our previous study demonstrated that the myocardium of diabetic mice, characterized by hyperglycemia and hyperlipidemia, exhibited greater susceptibility to SH than that of non-diabetic mice. This study aimed to investigate the effects of glucose deprivation on cardiomyocytes pretreated with high glucose and lipids. The results indicated that brief exposure to high glucose and lipid levels maintained cardiomyocyte viability and enhanced PTEN-induced kinase 1 (PINK1)/Parkin-related mitophagy. However, glucose deprivation following high glucose and lipid treatment significantly increased cardiomyocyte susceptibility to injury compared with glucose deprivation after high glucose treatment alone. This was evidenced by reduced cell viability, increased apoptosis, and mitochondrial dysfunction—characterized by disrupted mitochondrial structure, depolarization, decreased adenosine triphosphate production, and impaired PINK1/Parkin-related mitophagy in the cells. These adverse effects were reversed by treatment with the mitophagy activator urolithin A. Our findings suggest that glucose plays a critical role in maintaining lipid tolerance via mitophagy in cardiomyocytes, a mechanism that may contribute to the pathogenesis of SH-induced myocardial injury.