Question: What is the role of AMPK in diabetic cardiomyopathy?

Context:
We recently reported that diabetes depresses AMP-activated protein kinase (AMPK) activity, inhibits MAPK8/JNK1-BCL2 signaling
Activation of AMPK directly phosphorylates MAPK8, which mediates BCL2 phosphorylation and subsequent BECN1-BCL2 dissociation, leading to restoration of cardiac autophagy, protection against cardiac apoptosis, and ultimately improvement in cardiac structure and function.
studies were shown that p38 MAPK stimulates glucose uptake through the AMPK activation.
Taken together, it is suggested that the modulation of AT-1R/AMPK-MAPK pathway might play crucial roles for the pathogenesis of diabetic cardiomyopathy and it could become an important therapeutic target to ameliorate the diabetic cardiomyopathy.
We conclude that AMPK activation protects cardiac structure and function by increasing cardiac autophagy in the diabetic heart.
Genetic inhibition of AMPK in cardiomyocytes attenuates cardiac autophagy, exacerbates cardiac dysfunction and increases mortality in diabetic mice.
Oxidative stress and lipid deposition were markedly increased in the myocardium, concomitant with inactivation of AMPK and increased expression of peroxisome proliferator-activated receptor coactivator-1 alpha (PGC-1 alpha).
Trimetazidine also caused AMPK activation and reduced PGC-1 alpha expression in the hearts of db/db mice.
The data suggest that trimetazidine significantly improves cardiac function in db/db mice by attenuating lipotoxicity and improving the oxidation status of the heart. Activation of AMPK and decreased expression of PGC-1 alpha were involved in this process.
Our findings highlight a role of PP2C and AMPK in the derangements of cardiac lipid metabolism in obesity and provide new insights as to the mechanisms of the liporegulatory disorder leading to lipotoxic cardiomyopathy.
We conclude that dissociation of BCL2 from BECN1 through activation of MAPK8-BCL2 signaling may be an important mechanism by which AMPK activation restores autophagy, protects against cardiac apoptosis, and prevents diabetic cardiomyopathy.
Both the AMPK activator resveratrol and the antioxidant N-acetylcysteine mimicked the UCF-101-induced beneficial effect in STZ-induced diabetic cardiomyocytes.
UCF-101 protects against STZ-induced cardiomyocyte contractile dysfunction, possibly via an AMPK-associated mechanism.

Answer: AMPK activation protects cardiac structure and function by increasing cardiac autophagy in the diabetic heart.  Decreased AMPK activity and the subsequent reduction in cardiac autophagy are central to the development of diabetic cardiomyopathy.  In fact, 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. In addition, genetic inhibition of AMPK in cardiomyocytes attenuates cardiac autophagy, exacerbates cardiac dysfunction and increases mortality in diabetic mice. The modulation of AT-1R/AMPK-MAPK pathway might play crucial roles for the pathogenesis of diabetic cardiomyopathy and it could become an important therapeutic target to ameliorate the diabetic cardiomyopathy. Stimulation of AMPK by metformin or trimetazidine administration may represent a novel approach to treat diabetic cardiomyopathy.