Background: Resveratrol (RSV) has a wide range of diabetic cardioprotective effects. It is currently recognized as a dietary supplement. Aim of Study:To investigate the impact of RSV on the molecular expression pattern of AMP-activated protein kinase (AMPK) and the glycogen synthase kinase-3 (3 serine 9 (GSK-3 (3 S9) in diabetic cardiomyopathy. Methods:We investigated this point using three groups of Wistar albino rats; control group, diabetic cardiomyopathy rats (DCM) and diabetics treated with RSV (DM-RSV) for 20 weeks. Echocardiography was performed at base line, and every 4 weeks. At the end of the study, Ex-vivo assessment of myocardial contractility was performed. The molecular changes in the cardiac tissues were evaluated in all groups for assessment of the silent information regulator (SIRT1), GSK-3 (3 S9 and the AMPK levels. Histological assessment was done for all cardiac tissues. Apoptosis was assessed by measuring the modulation in the Bax/Bcl2 ratio and poly (ADP-ribose) polymerase-1 (PARP1) levels, trying to explore the RSV underlying mechanism of action.Results: Marked deterioration in the cardiac functions was detected in the diabetic non treated group. The decreased levels of SIRT1, AMPK and GSK-3 (3 S9 that was associated with increased apoptotic markers, may be the cause of deteriorated cardiac functions. Assessment of the myocardial functions showed improvement in the diabetic RSV treated group. RSV aimed to normalize the hyperglycemic state and the disturbed molecular pattern associated with diabetes.Conclusion: Prolonged RSV administration protects the diabetic hearts. This could be explained by the interplay between SIRT1, AMPK and the GSK-3(3 S9 levels.