Type 2 Diabetes Coagulopathy Proteins May Conflict With Biomarkers Reflective of COVID-19 Severity

Abstract

Objective: Detailed proteomic analysis in a cohort of patients with differing severity of COVID-19 disease identified biomarkers within the complement and coagulation cascades as biomarkers for disease severity has been reported; however, it is unclear if these proteins differ sufficiently from other conditions to be considered as biomarkers.

Methods: A prospective, parallel study in T2D (n = 23) and controls (n = 23). A hyperinsulinemic clamp was performed and normoglycemia induced in T2D [4.5 ± 0.07 mmol/L (81 ± 1.2 mg/dl)] for 1-h, following which blood glucose was decreased to ≤2.0 mmol/L (36 mg/dl). Proteomic analysis for the complement and coagulation cascades were measured using Slow Off-rate Modified Aptamer (SOMA)-scan.

Results: Thirty-four proteins were measured. At baseline, 4 of 18 were found to differ in T2D versus controls for platelet degranulation [Neutrophil-activating peptide-2 (p = 0.014), Thrombospondin-1 (p = 0.012), Platelet factor-4 (p = 0.007), and Kininogen-1 (p = 0.05)], whilst 3 of 16 proteins differed for complement and coagulation cascades [Coagulation factor IX (p < 0.05), Kininogen-1 (p = 0.05), and Heparin cofactor-2 (p = 0.007)]; STRING analysis demonstrated the close relationship of these proteins to one another. Induced euglycemia in T2D showed no protein changes versus baseline. At hypoglycemia, however, four proteins changed in controls from baseline [Thrombospondin-1 (p < 0.014), platelet factor-4 (p < 0.01), Platelet basic protein (p < 0.008), and Vitamin K-dependent protein-C (p < 0.00003)], and one protein changed in T2D [Vitamin K-dependent protein-C, (p < 0.0002)].

Conclusion: Seven of 34 proteins suggested to be biomarkers of COVID-19 severity within the platelet degranulation and complement and coagulation cascades differed in T2D versus controls, with further changes occurring at hypoglycemia, suggesting that validation of these biomarkers is critical. It is unclear if these protein changes in T2D may predict worse COVID-19 disease for these patients.

Clinical trial registration: https://ichgcp.net/clinical-trials-registry/NCT03102801" title="See in ClinicalTrials.gov">NCT03102801.

Keywords: COVID-19; biomarkers; hypoglycemia; proteomics; type 2 diabetes.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Moin, Al-Qaissi, Sathyapalan, Atkin and Butler.

Figures

Figure 1

The protein-protein interaction tool STRING 11.0 (Search Tool for the Retrieval of Interacting Genes) was used to visualize the significantly different proteins in type 2 diabetes (T2D) compared to controls, and for all of the proteomic proteins in COVID-19 disease severity described by others (1) (https://string-db.org/). Interactions between proteins are evidence-based and collated from databases, experiments, neighborhood, gene fusion, co-occurrence, text mining, co-expression, and homology. Here, we determined the relationships between the platelet degranulation (A) and complement and coagulation cascade proteins (B) presented in the study by Shu et al. (1) that were significantly different between non-COVID infected T2D and control subjects. (A) Platelet degranulation proteins that differed significantly between T2D and control subjects, indicating their relationship to one another. (B) Complement and coagulation cascade proteins that differed significantly between T2D and control subjects, indicating their relationship to one another. (C) Combined platelet degranulation and complement and coagulation cascade proteins that differed significantly in T2D, indicating their relationships to one another.