Curcumin has been identified as a potent inducer of heme-oxygenase-1 (HO-1), protein that provides protection against various forms of stress. Diabetic cardiomyopathy characterized by cardiomyocyte hypertrophy, eventually leads to heart failure. Transcriptional co-activator p300 and its interaction with myocyte enhancer factor 2 (MEF2) play a major role in diabetes-induced cardiomyocyte hypertrophy. The aim of this work is to study the effect of a novel water soluble curcumin derivative (3% curcumin content) on signaling mechanisms involved in cardiomyocyte hypertrophy and dysfunction in myocardial contractility in diabetes. Rats were divided into control group, control group receiving curcumin derivative, diabetic group, diabetic group receiving curcumin derivative, diabetic group receiving pure curcumin, diabetic group receiving HO inhibitor, zinc protoporphyrin IX (ZnPP IX) and diabetic group receiving curcumin derivative and ZnPP IX. Type-1 diabetes was induced by injection of STZ. Curcumin was given orally (20 mg/Kg/day orally for 45 days). After 45 days, 6 animals from each group were used to study some cardiac physiologic parameters. Blood samples were withdrawn from the remaining animals for estimation of plasma glucose, plasma insulin and glycated hemoglobin. Animals were sacrificed; the pancreas and heart were excised for the HO-1expression, activity estimation. Also, cardiac muscle was studied for gene expression of p300 and molecular markers of cardiac hypertrophy: ANP, MEF2A, and MEF2C. The new water soluble curcumin derivative (20 mg/Kg/day orally for 45 days) had the ability to decrease plasma glucose and increase plasma insulin levels significantly in diabetic rats and its action may be partially mediated by induction of HO-1 gene in pancreatic tissue. HO-1activity and gene expression were significantly increased in diabetic heart and pancreas. Curcumin derivative improved left ventricular function and prevented diabetes-induced upregulation of cardiomyopathy markers (ANP, MEF2A and MEF2C) and p300. Curcuminʹs action on cardiomyopathy is not mediated through HO-1. The effect of the new water soluble curcumin derivative by its small dose (20 mg/Kg/day orally for 45 days was better than the same dose of pure curcumin.