BackgroundLong-term dysfunction of glucose metabolism causes cardiac dysfunction called diabetic cardiomyopathy (DCM). Material and methodsTo investigate the effect and underlying mechanism of RS on the process of DCM, mouse models induced by a high-fat diet (HFD) and streptozotocin (STZ) were fed RS (2 g/kg/day) and vehicle treatment (by oral gavage) for 14 weeks. Various analyses, including qRT-PCR, western blot, immunofluorescence staining, histology staining, cardiac function, and diversity detection of intestinal microbiota were performed. ResultsRS intervention could directly improve myocardial fibrosis, hypertrophy, apoptosis, and cardiac insufficiency in DCM. These beneficial effects may be achieved by elevating the expression of IGF-1, activating the ERK phosphorylation. Furthermore, by carrying out nano LC-MS/MS analyses and 16S rDNA sequencing, we found RS might primarily affect proteins in the cytoplasm involved in post-translational modification, protein conversion, and signal transduction mechanisms. RS altered intestinal microbiota and improved intestinal mucosal permeability towards a favorable direction in DCM. ConclusionThis multi-dimensional assessment of RS suggests that might be a promising approach towards the treatment of DCM.