Transcriptional Heterogeneity of Cardiac Remodeling Between Type 1 and Type 2 Diabetes

Background: Cardiovascular complications stemming from diabetes pose a grave threat to patients' survival. Both type 1 diabetes (T1D) and type 2 diabetes (T2D) significantly increase the risk of heart failure, yet no reports have clarified whether there are differences in the pathway alterations involved in these two conditions. Investigating the heterogeneity of the cardiac remodeling between these two types of diabetes is conducive to reducing the incidence of cardiovascular events in diabetic patients in clinical practice. Methods: T1D and T2D models were established in adult mice, and the hearts were collected for RNA sequencing. Differential expression analysis (DEA) was performed. Integrating functional enrichment analyses, we probed into gene and pathway heterogeneity. Subsequently, we compared single-cell RNA sequencing (scRNA-seq) data of hearts from T1D and T2D mice, focusing on three cell populations (endothelial cells, macrophages, and fibroblasts) to identify gene and pathway differences. Finally, we evaluated shared genes and common signaling pathway changes across these three cell populations in both diabetes types. Results: We have successfully established T1D and T2D models in mice. Compared with shared genes, the two types of diabetes had more consistent pathway changes. Further scRNA-seq analysis identified endothelial cells, macrophages, and fibroblasts as significantly associated with the diabetic phenotype. In shared pathway, endothelial cells were significantly enriched in pathways related to endothelial proliferation and angiogenesis; macrophages were enriched in immune response pathways; and fibroblasts were enriched in pathways involving fibrosis, cell proliferation, and apoptosis. In endothelial cells, inflammatory response and fatty acid metabolism pathways were predominantly enriched in T1D, while energy metabolism pathways were dominant in T2D. In macrophages, antiviral immune pathways were specifically enriched in T1D, whereas macrophages in T2D were additionally implicated in the regulation of cardiomyocyte function. In fibroblasts, immune-related pathways were characteristically enriched in T1D, while cell respiration and energy supply pathways were prominent in T2D. Common functional enrichment pathways across the three cell types in both diabetes types mainly involved innate immune responses and cardiac morphogenesis, with the proportion of shared pathways being significantly higher than that of shared genes. Conclusions: This study, by combining RNA sequencing and scRNA-seq, revealed that cardiac pathologies induced by T1D and T2D exhibit a higher degree of consistent pathway changes compared to shared gene changes. Interventions targeting these common pathways may hold greater value in preventing and treating diabetic cardiomyopathy.