Patients with diabetes and COVID-19 are at a heightened risk of developing severe complications, such as acute respiratory distress syndrome, multi-organ failure, and death. This increased susceptibility may be attributed to the underlying inflammation associated with obesity, insulin resistance, and other comorbidities typically seen in patients. Patients with hyperglycemia exhibit elevated expression of angiotensin-converting enzyme 2 (ACE2), the cellular receptor for viral entry, which further facilitates viral infection. The pre-existing chronic inflammation, augmented inflammatory response, and increased viral load in diabetic patients contribute to a systemic immune response known as the "cytokine storm," which is strongly associated with the severity of COVID-19. Moreover, SARS-CoV-2 infection may also induce dysregulation of metabolic factors and trigger the onset of diabetes.

However, the molecular mechanisms underlying the bidirectional relationship between SARS-CoV-2 infection and diabetes are not fully understood. In this study, comparative transcriptomic analysis of peripheral blood mononuclear cell (PBMC) samples using publicly available scRNA-seq and bulk RNA-seq datasets from COVID-19 patients and type 1 and type 2 diabetes patients are used to elucidate the common molecular pathways that are involved in these conditions. Cluster elastic net models informed by cell composition, differential expression, and predicted miRNA interactions distinguish significant features in altered metabolic signaling and immune profiles across measures of SARS-COV-2 infection severity. Further, functional assessment with gene ontology (GO), identification of concordant and discordant gene expression signatures, and pathway analyses reveals common mechanistic links between longitudinal COVID-19, type I, and type II diabetes datasets paired with overlapping miRNA–mRNA–TFs regulatory networks through co-modulated genes involved in cytokine signaling across disease stage. Such insights may contribute to the development of targeted therapeutic strategies and improved clinical management for patients with diabetes and COVID-19 at heightened risk of severe complications.