Diabetic cardiomyopathy is associated with suppression of cardiac autophagy, and 
activation of AMP-activated protein kinase (AMPK) restores cardiac autophagy and 
prevents cardiomyopathy in diabetic mice, albeit by an unknown mechanism. We 
hypothesized that AMPK-induced autophagy ameliorates diabetic cardiomyopathy by 
inhibiting cardiomyocyte apoptosis and examined the effects of AMPK on the 
interaction between Beclin1 and Bcl-2, a switch between autophagy and apoptosis, 
in diabetic mice and high glucose-treated H9c2 cardiac myoblast cells. Exposure 
of H9c2 cells to high glucose reduced AMPK activity, inhibited Jun NH2-terminal 
kinase 1 (JNK1)-B-cell lymphoma 2 (Bcl-2) signaling, and promoted Beclin1 
binding to Bcl-2. Conversely, activation of AMPK by metformin stimulated 
JNK1-Bcl-2 signaling and disrupted the Beclin1-Bcl-2 complex. Activation of 
AMPK, which normalized cardiac autophagy, attenuated high glucose-induced 
apoptosis in cultured H9c2 cells. This effect was attenuated by inhibition of 
autophagy. Finally, chronic administration of metformin in diabetic mice 
restored cardiac autophagy by activating JNK1-Bcl-2 pathways and dissociating 
Beclin1 and Bcl-2. The induction of autophagy protected against cardiac 
apoptosis and improved cardiac structure and function in diabetic mice. We 
concluded that dissociation of Bcl-2 from Beclin1 may be an important mechanism 
for preventing diabetic cardiomyopathy via AMPK activation that restores 
autophagy and protects against cardiac apoptosis.