The study aimed to investigate the intervening role of Didang decoction (DDD) at different times in macrovascular endothelial defense function,focusing on its effects on the AMP-activated protein kinase (AMPK) signaling pathway.The effects of DDD on mitochondrial energy metabolism were also investigated in rat aortic endothelial cells (RAECs).Type 2 diabetes were induced in rats by streptozotocin (STZ) combined with high fat diet.Rats were randomly divided into non-intervention group,metformin group,simvastatin group,and early-,middle-,late-stage DDD groups.Normal rats were used as control.All the rats received 12 weeks of intervention or control treatment.Western blots were used to detect the expression of AMP-activated protein kinase α1 (AMPKα1) and peroxisome proliferator-activated receptor 1 α (PGC-1 α).Changes in the intracellular AMP and ATP levels were detected with ELISA.Real-time-PCR was used to detect the mRNA level of caspase-3,endothelial nitric oxide synthase (eNOS),and Bcl-2.Compared to the diabetic non-intervention group,a significant increase in the expression of AMPKα1 and PGC-1α were observed in the early-stage,middle-stage DDD groups and simvastatin group (P ＜ 0.05).The levels of Bcl-2,eNOS,and ATP were significantly increased (P ＜0.05),while the level of AMP and caspase-3 were decreased (P ＜ 0.05) in the early-stage DDD group and simvastatin group.Early intervention with DDD enhances mitochondrial energy metabolism by regulating the AMPK signaling pathway and therefore may play a role in strengthening the defense function of large vascular endothelial cells and postpone the development of macrovascular diseases in diabetes.