Since the mechanisms responsible for gender differences in cardiac contractile function have not been fully elucidated, we focused to determine the effect of gender difference on beta-adrenergic receptors (beta-ARs) signal transduction in ventricular cardiomyocytes from insulin-dependent diabetic (streptozotocin-induced) rats. Dose-response curves of left ventricular developed pressure (LVDP) to isoproterenol (ISO) in females showed that there was only a similar to 30% decrease in the maximum response without a significant shift in EC50 in diabetic females. On the other hand, diabetes induced a clear rightward shift in the potency (5-10 folds) without a significant change in the maximum response in the males. In order to further determine of the underlying mechanism for this difference, we measured cAMP production and obtained dose-response curves with ISO stimulation in isolated cardiomyocytes. In diabetic females, there was no obvious change in the cAMP dose-response curve. On the other hand, there was a significant decrease in the maximum response without any apparent change in the potency of diabetic males. Our findings indicate that male and female rats are affected differently by diabetes in terms of LVDP responses to beta-ARs stimulation. Also, the difference between their beta-ARs induced cAMP responses may underlie this disparity.