OBJECTIVE: Autophagy is a critical cellular system for removal of aggregated 
proteins and damaged organelles. Although dysregulated autophagy is implicated 
in the development of heart failure, the role of autophagy in the development of 
diabetic cardiomyopathy has not been studied. We investigated whether chronic 
activation of the AMP-activated protein kinase (AMPK) by metformin restores 
cardiac function and cardiomyocyte autophagy in OVE26 diabetic mice.
RESEARCH DESIGN AND METHODS: OVE26 mice and cardiac-specific AMPK dominant 
negative transgenic (DN)-AMPK diabetic mice were treated with metformin or 
vehicle for 4 months, and cardiac autophagy, cardiac functions, and 
cardiomyocyte apoptosis were monitored.
RESULTS: Compared with control mice, diabetic OVE26 mice exhibited a significant 
reduction of AMPK activity in parallel with reduced cardiomyocyte autophagy and 
cardiac dysfunction in vivo and in isolated hearts. Furthermore, diabetic OVE26 
mouse hearts exhibited aggregation of chaotically distributed mitochondria 
between poorly organized myofibrils and increased polyubiquitinated protein and 
apoptosis. Inhibition of AMPK by overexpression of a cardiac-specific DN-AMPK 
gene reduced cardiomyocyte autophagy, exacerbated cardiac dysfunctions, and 
increased mortality in diabetic mice. Finally, chronic metformin therapy 
significantly enhanced autophagic activity and preserved cardiac functions in 
diabetic OVE26 mice but not in DN-AMPK diabetic mice.
CONCLUSIONS: Decreased AMPK activity and subsequent reduction in cardiac 
autophagy are important events in the development of diabetic cardiomyopathy. 
Chronic AMPK activation by metformin prevents cardiomyopathy by upregulating 
autophagy activity in diabetic OVE26 mice. Thus, stimulation of AMPK may 
represent a novel approach to treat diabetic cardiomyopathy.