Bidirectional link between diabetes mellitus and coronavirus disease 2019 leading to cardiovascular disease: A narrative review

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

SN	Ref.	Country	Pathway validation	Type of relation shown	Conclusion and overview derived from the study	Place added at the manuscript
1	Abbas et al[59] (2020)	Egypt	Pathway I, IV	Bidirectional	The 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 DM	Section 2, page 9, and section 3, page 11
2	Muniangi-Muhitu et al[60] (2020)	The United Kingdom and Singapore	Pathway I-b, II, V, VI-a	Bidirectional	Authors 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 levels	Section 2, page 9 and section 3, page 11
3	Mota et al[58] (2020)	Romania	Pathway I, II, III, IV	Bidirectional	Drugs 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 entry	Section 2, page 9 and section 3, page 11
4	Kalra et al[68] (2020)	United Kingdom, India, and Kazakhstan	Pathway II	Bidirectional	The 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 infection	Section 2, page 10
5	Rubino et al[35] (2020)	Australia, United Kingdom, Germany	Pathway IV	Bidirectional	In 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 DM	Section 3, page 10
6	Balasubramanyam et al[88] (2020)	Chennai (India)	Pathway IV	Unidirectional	COVID-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 organs	Section 3, page 11
7	Baracchini et al[66] (2020)	Germany	Pathway II, IV	Unidirectional	This 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 cells	Section 3, page 11
8	Fang et al[17] (2020)	Greece	Pathway I	Unidirectional	In 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 ARBs	Section 1, page 6
9	Muniyappa et al[64] (2020)	Maryland	Pathway II	Unidirectional	DM 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 diabetes	Section 2, page 9
10	Chen et al[65] (2020)	China and Sweden	Pathway II	Unidirectional	Authors concluded that patients associated with DM have over-expression of ACE2, which will worsen the prognosis during a COVID-19 infection	Section 2, page 9

ACE: Angiotensin-converting enzyme; COVID-19: Coronavirus disease 2019; DM: Diabetes mellitus; GLP-1: Glucagon-like peptide-1; HTN: Hypertension; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2.

Table 2 Cardiovascular severity in diabetes and non-diabetes coronavirus disease 2019 patients

Pathophysiology of CVD	Non-diabetes	Diabetes	Reason
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])

ACE: Angiotensin-converting enzyme; CVD: Cardiovascular disease; COVID-19: Coronavirus disease 2019; DM: Diabetes mellitus; FEV1: Forced expiratory volume in 1 sec; FVC: Forced vital capacity; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2.