Hesperetin-Attenuated Diabetes-Induced Vascular Endothelial Injury, Associated with Gut Microbiota Modulation and Cholesterol Homeostasis

Cardiovascular complications arising from vascular endothelial injury are the main cause of mortality in individuals with diabetes. Hesperetin, a typical flavanone derived from citrus fruits, has shown various biological activities beneficial to health, yet its effects on diabetes-induced vascular endothelial damage remain unexplored. In the present study, hesperetin intervention improved serum lipid metabolism, ameliorated aortic endothelial pathology, reduced aortic adhesion factor expression, and enhanced glucose tolerance with attenuated insulin resistance in type 2 diabetes mellitus rats. Mechanism studies revealed that intervention with hesperetin regulated the structure of gut microbiota, resulting in lower levels of trimethylamine oxide, the metabolite of gut microbiota, which in turn reduced its damage to the vascular endothelium. Simultaneously, hepatic cholesterol homeostasis regulation by hesperetin contributes to attenuated atherogenesis. Our study indicated that hesperetin, as a dietary supplement, exhibited potential for inhibiting the development diabetes-associated vascular endothelial damage.