With this background, we propose a hypothesis that, in COVID-19 patients presenting with diabetes, the overactivity of the “High Glucose-Osteopontin-Furin Axis” enhances the virulence of the SARS-CoV-2 virus by promoting the TMPRSS2-dependent cleavage of the SARS-CoV-2 Spike protein and facilitating SARS-CoV-2 entry into target cells as well as enhancing the replication of SARS-CoV-2 (Figure 4). Here, FURIN is linked to diabetes mellitus.