Abstract: AIM To observe the protective effects and mechanism of Helix B surface peptide (HBSP) for the injury of mouse diabetic cardiomyopathy. METHODS Eighty male Kunming mice (20-25 g) were randomly divided into four groups: the control group (n=20), the control+HBSP group 30 μg/(kg·d), n=20, the diabetic cardiomyopathy (DCM) group (n=20) and the DCM+HBSP group 30 μg/(kg·d), n=20. The mice were intraperitoneally injected with streptozotocin to induce type 1 diabetes. Mice with random blood glucose≥16.7 mmol/L were considered as diabetic mice and they were fed for 12 weeks. Mice with impaired cardiac functions evidenced by echocardiography were chosen as diabetic cardiomyopathy mice and twenty of them were randomly chosen to receive intraperitoneal injection of HBSP 30 μg/(kg·d) for 4 consecutive weeks, grouped as DCM+HBSP group. Cardiac functions were evaluated by echocardiography. Apoptosis of cardiomyocytes was detected by TUNEL and myocardial interstitial fibrosis was evaluated by Sirius red staining. Expressions of Akt, phospho-Akt, GSK3β and phospho-GSK3β were detected by Western blotting. RESULTS Compared with the DCM group, the values of LVEF and LVFS in the DCM+HBSP group were increased while the values of LVESV and LVEDV were decreased (P<0.05) and cardiomyocyte apoptosis was inhibited (P<0.05). Compared with the DCM group, myocardial interstitial fibrosis was reduced in the DCM+HBSP group (P<0.01) and expressions of phospho-Akt and phospho-GSK3β were increased (P<0.05 and P<0.01, respectively). CONCLUSION Helix B surface peptide alleviates myocardial apoptosis, reduces myocardial interstitial fibrosis and improves cardiac function in diabetic cardiomyopathy mice. These protective effects of HBSP may possibly be through the activation of Akt-GSK3β signaling pathway.