The Association Between COVID-19 and Patients with Diabetes

Editor: David L. Joffe, BSPharm, CDE, FACA

The SARS-CoV-2, or COVID-19, has unfairly affected comorbidities, specifically type 2 diabetes (T2D). A recent study may have the answer as to why this happens.

The primary innate immune cells are macrophages, responsible for the hyperinflammatory cytokine storm in persons severely infected with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), also known as COVID-19. Cytokine storm is a life-threatening systemic disorder that encompasses high circulating cytokine levels and immune cell hyperactivation stimulated by numerous autoimmune disorders, cancers, monogenic disorders, pathogens, and therapies. In individuals with diabetes, COVID-19 causes a powerful cytokine storm impacting increased mortality and morbidity. The clinical presentations of cytokine storm in the lungs are pneumonitis, pulmonary edema, dyspnea, hypoxemia, and ARDS (acute respiratory distress syndrome). In reaction to the COVID-19 infection, expression of SETDB2, the chromatin-modifying enzyme, decreases in macrophages, resulting in elevated transcription of inflammatory cytokines. Moreover, SETB2 is controlled by an interferon-beta (IFNβ)/JaK/STAT3 mechanism. Therefore, when exogenous IFNβ is administered, it allows inflammation reversal, especially in diabetic macrophages, by increasing SETDB2. Therefore, it has been suggested that focusing on the IFNβ/SETDB2 alliance in persons with T2D and infected with COVID-19 may reduce pathologic inflammation. 

The enzyme SETDB2 is vital for regulating macrophage facilitated inflammation in wound mending and diabetic wounds. The study by Melvin et al. assessed the inflammation in murine and human macrophages in murine hepatitis coronavirus (MHV-A59) and COVID-19. As a result of coronavirus, a reduction of histone methyltransferase SETDB2 in diabetic and normal macrophages was observed, which resulted in increased inflammatory cytokine production (TNFα, IL-6, IL-1β) through macrophage modification in H3K9me3 (trimethylation of histone 3 lysine ) at NFkB binding sites on inflammatory gene promoters after infection. Murine models lacking SETDB2 demonstrated that SETDB2 incited the inflammatory reaction to macrophages in responding to coronavirus infection. Moreover, SETDB2 expression in macrophages is controlled by IFNβ through the JaK1/STAT3 pathway. A reduction of IFNβ levels was observed in positive COVID-19 individuals with T2D compared to individuals without T2D and positive for COVID-19, along with murine diabetic macrophages. Thus, administering IFNβ to infected macrophages with coronavirus enhanced SETDB2 expression to a heightened level in diabetes and transcription reduction of inflammatory genes.  

The present study identified the vital role of SETDB2 for controlling macrophage-mediated inflammation during coronavirus infection. The down-regulation of SETDB2 after infection resulted in the loss of H3K9 trimethylation at NFkB binding sites on inflammatory gene promoters, which leads to transcription increase. During coronavirus infection, SETDB2 expression was reliant on the signaling of IFNβ through JAK1/STAT3, where disturbances to this route resulted in modified inflammatory gene transcription. IFNβ levels were observed to be lowered in plasma individuals with T2D and positive for COVID-19 and MHV infected mice with diabetes as opposed to non-T2D individuals infected with COVID-19 and MHV infected mice without diabetes. Thus, treating coronavirus macrophages with low doses of IFNβ decreased inflammation by upregulating SETDB2, specifically in patients with T2D. 

Interestingly, during influenza infection, upregulation of SETDB2 lessens inflammation, resulting in greater sensitivity to bacterial superinfections. In contrast, coronavirus triggers a decrease of SETDB2, ultimately leading to pathologic inflammation. This observation is vital because the reaction to coronavirus infection was amplified in diabetic macrophages, secondary to a reduction of SETDB2 in diabetic macrophages at baseline and an early insufficient T1IFN response. Thus, the coronavirus and diabetes concurrently signify a significant blow in reducing SETDB2 expression and activity in diabetic macrophages, inhibiting H3K9me3 at NFkB binding sites of inflammatory gene promoters and allowing unregulated inflammation. The limitation of the study was that numerous binding sites for NFkB on inflammatory gene promoters are present, even if the current analyses are associated with H3K9me3 and SETDB2-ChIP cytokine expression at vital proximal binding sites, perhaps that additional H3K9-targeting methyltransferases participate in controlling gene expression inflammation in coronavirus infection. Furthermore, during infection, IFNβ levels were measured at a single point, and levels may vary in the course of infection. In conclusion, the study implies that the exploitation of this pathway in macrophages and persons with diabetes may be a viable treatment to suppress pathologic inflammation and the emergence of cytokine storms in correlation with COVID-19.  

Practice Pearls:

  • During coronavirus infection, SETDB2 regulates macrophage-mediated inflammation, and the reduction of this enzyme results in unhindered inflammatory cytokine transcription.  
  • The JAK1/STAT3 pathway controls SETDB2 in macrophages during coronavirus infection. 
  • Administering coronavirus macrophages with low doses of IFNβ decreased inflammation by upregulating SETDB2, specifically in patients with type 2 diabetes. 


Melvin, William J et al. “Coronavirus induces diabetic macrophage-mediated inflammation via SETDB2.” Proceedings of the National Academy of Sciences of the United States of America vol. 118,38 (2021):  

Kimball, Andrew S et al. “The Histone Methyltransferase Setdb2 Modulates Macrophage Phenotype and Uric Acid Production in Diabetic Wound Repair.” Immunity vol. 51,2 (2019): 258-271.e5. doi:10.1016/j.immuni.2019.06.015.  

Fajgenbaum, David C., and Carl H. June. “Cytokine Storm.” New England Journal of Medicine, vol. 383, no. 23, 3 Dec. 2020, pp. 2255–2273, doi:10.1056/nejmra2026131 


Trina Maglalang RPh, 2022 PharmD Candidate University of Colorado 


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