The stimulatory G protein Gsalpha transmits signals from activated beta-adrenergic receptors via the cyclic AMP-PKA pathway, targeting the key regulatory protein phospholamban. We hypothesized that mice with intrinsic activation of cardiac Gsalpha are resistant to the development of the diabetic cardiomyopathy phenotype. Accordingly, streptozotocin (STZ)-diabetes mellitus was induced in genetically engineered mice with cardiac-specific Gsalpha overexpression and in nontransgenic (NTG) littermates. At 8 weeks, Gsalpha diabetic mice showed no impairment of LV contractility nor increase in myocyte apoptosis, whereas NTG diabetic mice showed a 30% decrease in +dP/dt and -dP/dt with sustained (3-fold) myocyte loss by apoptosis. To assess the level of myocardial reactive oxygen species, we measured malondialdehyde, a surrogate marker of oxidative stress, which was increased in the hearts of NTG and Gsalpha diabetic mice. In addition, chronic hyperglycemia also increased the activity of catalase and superoxide dismutase in the hearts of NTG and Gsalpha diabetic mice. Hearts of NTG diabetic mice, but not Gsalpha mice, showed increased expression of proapoptosis Bax, downregulation in Bcl2, and an increase in the Bax/Bcl2 ratio. Hearts of NTG diabetic mice showed 60% reduction in phosphorylation at the critical Ser16 residue of phospholamban, whereas phosphorylation at Ser16 was restored in hearts of Gsalpha-diabetic mice. We conclude that cardiac-specific overexpression of Gsalpha compensates for the loss of cardiac function in diabetes mellitus.