In summary, we mapped the transcriptional alterations associated with HFD/STZ-induced diabetes in different cardiac subpopulations, and identified key ligand–receptor pair drivers of myocardial fibrosis in the diabetic heart, specifically the Pdgf(s)–Pdgfra and Efemp1–Egfr interactions, which are mediated by fibroblasts with macrophages, endothelial cells, and epicardial cells. Here, PDGFRA is linked to diabetes mellitus.