Inflammation and vascular dysfunction: The negative synergistic combination of diabetes and COVID-19

Andrea Mario Bolla, Cristian Loretelli, Laura Montefusco, Giovanna Finzi, Reza Abdi, Moufida Ben Nasr, Maria Elena Lunati, Ida Pastore, Joseph V Bonventre, Manuela Nebuloni, Stefano Rusconi, Pierachille Santus, Gianvincenzo Zuccotti, Massimo Galli, Francesca D'Addio, Paolo Fiorina, Andrea Mario Bolla, Cristian Loretelli, Laura Montefusco, Giovanna Finzi, Reza Abdi, Moufida Ben Nasr, Maria Elena Lunati, Ida Pastore, Joseph V Bonventre, Manuela Nebuloni, Stefano Rusconi, Pierachille Santus, Gianvincenzo Zuccotti, Massimo Galli, Francesca D'Addio, Paolo Fiorina

Abstract

Aims: Several reports indicate that diabetes determines an increased mortality risk in patients with coronavirus disease 19 (COVID-19) and a good glycaemic control appears to be associated with more favourable outcomes. Evidence also supports that COVID-19 pneumonia only accounts for a part of COVID-19 related deaths. This disease is indeed characterised by abnormal inflammatory response and vascular dysfunction, leading to the involvement and failure of different systems, including severe acute respiratory distress syndrome, coagulopathy, myocardial damage and renal failure. Inflammation and vascular dysfunction are also well-known features of hyperglycemia and diabetes, making up the ground for a detrimental synergistic combination that could explain the increased mortality observed in hyperglycaemic patients.

Materials and methods: In this work, we conduct a narrative review on this intriguing connection. Together with this, we also present the clinical characteristics, outcomes, laboratory and histopathological findings related to this topic of a cohort of nearly 1000 subjects with COVID-19 admitted to a third-level Hospital in Milan.

Results: We found an increased mortality in subjects with COVID-19 and diabetes, together with an altered inflammatory profile.

Conclusions: This may support the hypothesis that diabetes and COVID-19 meet at the crossroads of inflammation and vascular dysfunction. (ClinicalTrials.gov NCT04463849 and NCT04382794).

Keywords: COVID-19; diabetes; inflammation; vascular dysfunction.

Conflict of interest statement

The authors have no conflicts of interest to disclose related to this manuscript.

© 2022 John Wiley & Sons Ltd.

Figures

FIGURE 1
FIGURE 1
Time to endpoint analysis (death/discharge) in patients with type 2 diabetes (n = 486) or not (n = 396) and admitted to the hospital for COVID‐19. Log‐Rank (Mantel‐Cox) analysis
FIGURE 2
FIGURE 2
Time to clinical endpoint (death/hospital discharge) in all patients grouped according to quartiles of in‐hospital mean blood glucose level (Q1 mean glycaemia  188 mg/dl). Log‐Rank (Mantel‐Cox) analysis
FIGURE 3
FIGURE 3
Differential plasma levels of peripheral cytokines in patients with type 2 diabetes (n = 10) or not (n = 38) and admitted to the hospital for COVID‐19. Analysis performed by a Bio‐Plex Pro Human Cytokine 17‐plex immunoassay on a Bio‐Plex 200 system (both from Bio‐Rad). Two‐tailed t‐student test. *p < 0.05, **p < 0.01
FIGURE 4
FIGURE 4
Electron microscopy of skin capillary sections in healthy control (Panels A and C) and in subject with COVID‐19 (Panels B and D). Panel C: blue arrows indicate Weibel‐Palade granules in endothelial cells. Panel D: red arrows indicate small vesicles within vacuoles
FIGURE 5
FIGURE 5
Excessive inflammation and vascular dysfunction are a key feature of both hyperglycemia and COVID‐19, making up the ground for a detrimental synergistic combination. The increase of IL1‐ra, IL‐6, IL‐8, MCP‐1, IFN‐γ, and IP‐10 observed in subjects with type 2 diabetes and COVID‐19 may contribute to explain the greater disease severity observed in diabetic patients

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