Copyright ©The Author(s) 2021.
World J Diabetes. Mar 15, 2021; 12(3): 215-237
Published online Mar 15, 2021. doi: 10.4239/wjd.v12.i3.215
Table 1 Summary of studies describing potential linkages between diabetes mellitus and increasing propensity for coronavirus disease 2019 infection or diabetes mellitus triggered in response to viral infection, supporting sections 2 and 3
Pathway validation
Type of relation shown
Conclusion and overview derived from the study
Place added at the manuscript
1Abbas et al[59] (2020)EgyptPathway I, IVBidirectionalThe authors had concluded that there exists a bidirectional relationship between COVID-19 and DM. Furthermore, the authors also discussed the SARS-CoV-2 cellular entry using overexpression of ACE2 receptors in DM patients. Hence, DM is a risk factor for COVID-19. SARS-CoV-2 also uses additional ACE2, which is also observed on pancreatic beta cells. This leads to beta cell destruction that results in triggering of new-onset diabetes and worsening of pre-existing DMSection 2, page 9, and section 3, page 11
2Muniangi-Muhitu et al[60] (2020)The United Kingdom and SingaporePathway I-b, II, V, VI-aBidirectionalAuthors had concluded that DM worsens the COVID-19, and this is due to weakened immunity. Weak immunity support SARS-CoV2 to infect primarily monocytes and dendritic cells in DM patients. They showed that the use of common medications in DM and HTN can increase the expression of ACE2 levels, which favors SARS-CoV-2 viral binding. Additionally, the authors also mentioned that COVID-19 can trigger a cytokine storm, which results in insulin resistance and causes worsening in glycemic levelsSection 2, page 9 and section 3, page 11
3Mota et al[58] (2020)RomaniaPathway I, II, III, IVBidirectionalDrugs frequently used by patients with diabetes, like GLP-1 receptor agonists, thiazolidinediones, antihypertensives such as ACE inhibitors, and statins, up-regulate ACE2. Increased cellular furin in poor glycemic control can result in cellular viral entrySection 2, page 9 and section 3, page 11
4Kalra et al[68] (2020)United Kingdom, India, and KazakhstanPathway IIBidirectionalThe authors clearly mentioned that diabetes is known to be characterized by an impaired immune response, especially in those with uncontrolled glucose. This may increase the susceptibility to COVID-19 infectionSection 2, page 10
5Rubino et al[35] (2020)Australia, United Kingdom, GermanyPathway IV BidirectionalIn this study, the authors clearly mentioned that there is the possibility of glycemic alteration with the SARS-CoV-2 virus because it can directly affect the pancreatic beta cells, which results in new-onset DM or worsening pre-existing DMSection 3, page 10
6Balasubramanyam et al[88] (2020)Chennai (India)Pathway IVUnidirectionalCOVID-19 infection in diabetic patients aggravates morbidity and may be linked to increased mortality. The biological explanations for this could be virus exploitation of multiple organsSection 3, page 11
7Baracchini et al[66] (2020)GermanyPathway II, IVUnidirectionalThis study is clear evidence showing people with DM have a severe risk of SARS-CoV-2 because of the defective immune response. Secondly, this study also supported an overexpression of ACE2 receptors in DM patients facilitating cellular entry. At last, this study showed an increase in blood glucose levels due to the SARC-CoV-2-driven infection to the pancreatic beta cellsSection 3, page 11
8Fang et al[17] (2020)GreecePathway IUnidirectionalIn this study, the authors suggested that patients with cardiac diseases, hypertension, or diabetes, who are treated with ACE2 increasing drugs, are at higher risk for severe COVID-19 infection. Therefore, such patients should be monitored for ACE2-modulating medications, such as ACE inhibitors or ARBsSection 1, page 6
9Muniyappa et al[64] (2020)MarylandPathway IIUnidirectionalDM inhibits neutrophil chemotaxis, phagocytosis, and intracellular killing of microbes. Impairments in adaptive immunity characterized by an initial delay in the activation of Th1 cell-mediated immunity and a late hyperinflammatory response is often observed in patients with diabetesSection 2, page 9
10Chen et al[65] (2020)China and SwedenPathway IIUnidirectionalAuthors concluded that patients associated with DM have over-expression of ACE2, which will worsen the prognosis during a COVID-19 infectionSection 2, page 9
Table 2 Cardiovascular severity in diabetes and non-diabetes coronavirus disease 2019 patients
Pathophysiology of CVD
Hypoxia↑ ↑In COVID-19 patients compared with non-DM cases, DM reduced pulmonary function by reduced levels of FVC and FEV1 this condition further deteriorated in COVID-19 causing hypoxia[126-128,134] ongoing ischemia results in hypoxia causing CVD
Cytokine storm↑ ↑In COVID-19 patients compared with non-DM cases, DM increases the severity of the cytokine storm is due to exaggerated inflammatory response[138-141]. Thus, it increases the endothelial dysfunction causing a decrease in plaque stability, and an increase in plaque rupture results in CVD
RAAS Dysregulation↑ ↑DM patients using ACE inhibitors and ARBs have increased ACE2 expression is beneficial to vascular health by reducing profibrotic and proinflammatory function. But increased ACE2 levels increase the entry of SARS-CoV-2 infection, which potentially results in loss of ACE2 in blood vessels in diabetes patients causing vascular complications like CVD (see Obukhov et al[154])