Co-administration of hydrogen and metformin exerts cardioprotective effects by inhibiting pyroptosis and fibrosis in diabetic cardiomyopathy

Hydrogen is a novel medical gas with several properties, including anti-oxidative, anti-inflammatory, anti-apoptotic, anti-allergic, and energy metabolism stimulating properties. Hydrogen therapy has been proven effective in the treatment of myocardial ischemia, myocardial infarction, and ischemia-reperfusion injury. Diabetic cardiomyopathy (DCM) is a serious cardiovascular complication of long-term chronic diabetes that is linked to increased heart failure and arrhythmia morbidity. The effect of hydrogen on the pathogenesis of DCM is yet to be determined. Metformin is a well-known pharmacological agent for the treatment of diabetes; however, the application of large doses of the drug is limited by its side effects. Therefore, this highlights the importance of developing novel therapies against DCM. In this regard, we investigated the effect of hydrogen on DCM and the mechanisms that underlie it. Furthermore, we also assessed the efficacy of co-administration of metformin and hydrogen. In this study, we found that hydrogen improved cardiac dysfunction and abnormal morphological structure in streptozotocin-induced diabetic mice. As a mechanism, it was confirmed that hydrogen mediated its action by reducing pyroptosis via inhibition of the AMPK/mTOR/NLRP3 signaling pathway and ameliorating fibrosis via inhibition of the TGF-β1/Smad signaling pathway. Furthermore, our findings suggested that co-administration of hydrogen and metformin shows potent protective effects, as evidenced by increased survival rates, reduced fasting blood glucose, and decreased cell injury when compared to a single application of metformin. In conclusion, our study demonstrated that hydrogen inhalation attenuates DCM by reducing pyroptosis and fibrosis and that hydrogen can be combined with metformin to exhibit a more potent cardioprotective effect in DCM.