Metformin is a widely used antidiabetic drug that exerts cardiovascular 
protective effects in patients with diabetes. How metformin protects against 
diabetes-related cardiovascular diseases remains poorly understood. Here, we 
show that metformin abated the progression of diabetes-accelerated 
atherosclerosis by inhibiting mitochondrial fission in endothelial cells. 
Metformin treatments markedly reduced mitochondrial fragmentation, mitigated 
mitochondrial-derived superoxide release, improved endothelial-dependent 
vasodilation, inhibited vascular inflammation, and suppressed atherosclerotic 
lesions in streptozotocin (STZ)-induced diabetic ApoE-/- mice. In high 
glucose-exposed endothelial cells, metformin treatment and adenoviral 
overexpression of constitutively active AMPK downregulated mitochondrial 
superoxide, lowered levels of dynamin-related protein (Drp1) and its 
translocation into mitochondria, and prevented mitochondrial fragmentation. In 
contrast, AMPK-α2 deficiency abolished the effects of metformin on Drp1 
expression, oxidative stress, and atherosclerosis in diabetic ApoE-/-/AMPK-α2-/- 
mice, indicating that metformin exerts an antiatherosclerotic action in vivo via 
the AMPK-mediated blockage of Drp1-mediated mitochondrial fission. Consistently, 
mitochondrial division inhibitor 1, a potent and selective Drp1 inhibitor, 
reduced mitochondrial fragmentation, attenuated oxidative stress, ameliorated 
endothelial dysfunction, inhibited inflammation, and suppressed atherosclerosis 
in diabetic mice. These findings show that metformin attenuated the development 
of atherosclerosis by reducing Drp1-mediated mitochondrial fission in an 
AMPK-dependent manner. Suppression of mitochondrial fission may be a therapeutic 
approach for treating macrovascular complications in patients with diabetes.