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WJD https://www.wjgnet.com 215 March 15, 2021 Volume 12 Issue 3
World Journal of
Diabetes
W J D
Submit a Manuscript: https://www.f6publishing.com World J Diabetes 2021 March 15; 12(3): 215-237
DOI: 10.4239/wjd.v12.i3.215 ISSN 1948-9358 (online)
REVIEW
Bidirectional link between diabetes mellitus and coronavirus disease
2019 leading to cardiovascular disease: A narrative review
Vijay Viswanathan, Anudeep Puvvula, Ankush D Jamthikar, Luca Saba, Amer M Johri, Vasilios Kotsis,
Narendra N Khanna, Surinder K Dhanjil, Misha Majhail, Durga Prasanna Misra, Vikas Agarwal, George D
Kitas, Aditya M Sharma, Raghu Kolluri, Subbaram Naidu, Jasjit S Suri
ORCID number: Vijay Viswanathan
0000-0001-9116-3937; Anudeep
Puvvula 0000-0002-6367-4067;
Ankush D Jamthikar 0000-0002-3030-
7236; Luca Saba 0000-0003-2870-
3771; Amer M Johri 0000-0001-7044-
8212; Vasilios Kotsis 0000-0002-
3755-8097; Narendra N Khanna 0000-
0002-6935-0039; Surinder K Dhanjil
0000-0003-3892-8026; Misha Majhail
0000-0002-4173-601X; Durga
Prasanna Misra 0000-0002-5035-
7396; Vikas Agarwal 0000-0002-
4508-1233; George D Kitas 0000-
0002-0828-6176; Aditya M Sharma
0000-0003-1756-2504; Raghu Kolluri
0000-0002-4374-7513; Subbaram
Naidu 0000-0002-6284-399X; Jasjit S
Suri 0000-0001-6499-396X.
Author contributions: Viswanathan
V, Suri JS, Puvvala A, and
Jamthikar A contributed
conception and design; Dhanjil SK
and Khanna NN contributed
administrative support; Suri JS,
Puvvala A, and Jamthikar A
contributed manuscript writing;
Johri AM, Kitas GD, Agarwal V,
Misra DP, and Dhanjil SK
contributed critical evaluation;
Sharma A, Kolluri R, Dhanjil SK,
Khanna NN, Jamthikar A, and Suri
JS contributed vascular inputs; All
authors have read and approved
the final manuscript.
Conflict-of-interest statement:
Vijay Viswanathan, M Viswanathan Hospital for Diabetes, M Viswanathan Diabetes Research
Centre, Chennai 600013, India
Anudeep Puvvula, Annu’s Hospitals for Skin and Diabetes, Nellore 524101, Andhra Pradesh,
India
Ankush D Jamthikar, Department of Electronics and Communications, Visvesvaraya National
Institute of Technology, Nagpur 440010, Maharashtra, India
Luca Saba, Department of Radiology, University of Cagliari, Monserrato 09045, Cagliari, Italy
Amer M Johri, Department of Medicine, Division of Cardiology, Queen’s University, Kingston,
ON K7L 3N6, Canada
Vasilios Kotsis, 3rd Department of Internal Medicine, Hypertension Center, Papageorgiou
Hospital, Aristotle University of Thessaloniki, Thessaloniki 541-24, Greece
Narendra N Khanna, Department of Cardiology, Indraprastha APOLLO Hospitals, New Delhi
110020, India
Surinder K Dhanjil, Stroke Diagnosis and Monitoring Division, AtheroPoint™ LLC, CA 95661,
United States
Misha Majhail, Jasjit S Suri, Stroke Diagnosis and Monitoring Division, AtheroPoint™,
Roseville, CA 95661, United States
Durga Prasanna Misra, Department of Clinical Immunology and Rheumatology, Sanjay Gandhi
Postgraduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
Vikas Agarwal, Departments of Medicine, Sanjay Gandhi Postgraduate Institute of Medical
Sciences, Lucknow 226014, Uttar Pradesh, India
George D Kitas, Academic Affairs, Dudley Group NHS Foundation Trust, Dudley DY1 2HQ,
United Kingdom
George D Kitas, Arthritis Research UK Epidemiology Unit, Manchester University, Manchester
M13 9PL, United Kingdom
Aditya M Sharma, Division of Cardiovascular Medicine, University of Virginia, Charlottesville,
VA 22908, United States
Viswanathan V et al. Diabetes and COVID-19: A bidirectional link
WJD https://www.wjgnet.com 216 March 15, 2021 Volume 12 Issue 3
There is no conflict of interest
among the authors. Dr. Jasjit Suri is
affiliated with AtheroPoint™,
focused in the area of stroke and
cardiovascular imaging.
Open-Access: This article is an
open-access article that was
selected by an in-house editor and
fully peer-reviewed by external
reviewers. It is distributed in
accordance with the Creative
Commons Attribution
NonCommercial (CC BY-NC 4.0)
license, which permits others to
distribute, remix, adapt, build
upon this work non-commercially,
and license their derivative works
on different terms, provided the
original work is properly cited and
the use is non-commercial. See: htt
p://creativecommons.org/License
s/by-nc/4.0/
Manuscript source: Invited
manuscript
Specialty type: Endocrinology and
metabolism
Country/Territory of origin: India
Peer-review report’s scientific
quality classification
Grade A (Excellent): A
Grade B (Very good): B
Grade C (Good): 0
Grade D (Fair): 0
Grade E (Poor): 0
Received: November 6, 2020
Peer-review started: November 6,
2020
First decision: December 11, 2020
Revised: December 20, 2020
Accepted: February 11, 2021
Article in press: February 11, 2021
Published online: March 15, 2021
P-Reviewer: Li T
S-Editor: Gao CC
L-Editor: Filipodia
P-Editor: Wang LL
Raghu Kolluri, OhioHealth Heart and Vascular, Ohio, OH 43082, United States
Subbaram Naidu, Electrical Engineering Department, University of Minnesota, Duluth, MN
55812, United States
Corresponding author: Jasjit S Suri, PhD, Professor, Stroke Diagnosis and Monitoring Division,
AtheroPoint™, 208 Otter Glen Ct., Roseville, CA 95661, United States.
jasjit.suri@atheropoint.com
Abstract
Coronavirus disease 2019 (COVID-19) is a global pandemic where several
comorbidities have been shown to have a significant effect on mortality. Patients
with diabetes mellitus (DM) have a higher mortality rate than non-DM patients if
they get COVID-19. Recent studies have indicated that patients with a history of
diabetes can increase the risk of severe acute respiratory syndrome coronavirus 2
infection. Additionally, patients without any history of diabetes can acquire new-
onset DM when infected with COVID-19. Thus, there is a need to explore the
bidirectional link between these two conditions, confirming the vicious loop
between “DM/COVID-19”. This narrative review presents (1) the bidirectional
association between the DM and COVID-19, (2) the manifestations of the
DM/COVID-19 loop leading to cardiovascular disease, (3) an understanding of
primary and secondary factors that influence mortality due to the DM/COVID-19
loop, (4) the role of vitamin-D in DM patients during COVID-19, and finally, (5)
the monitoring tools for tracking atherosclerosis burden in DM patients during
COVID-19 and “COVID-triggered DM” patients. We conclude that the
bidirectional nature of DM/COVID-19 causes acceleration towards cardiovascular
events. Due to this alarming condition, early monitoring of atherosclerotic burden
is required in “Diabetes patients during COVID-19” or “new-onset Diabetes
triggered by COVID-19 in Non-Diabetes patients”.
Key Words: COVID-19; Diabetes mellitus; Bidirectional association; Cardiovascular
disease; Atherosclerotic burden; Imaging tools
©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
Core Tip: This narrative review hypothesizes that there is a bidirectional link between
diabetes mellitus (DM) and coronavirus disease 2019 (COVID-19). The first
bidirectional link is from COVID-19 to DM due to pancreatic damage or renin-
angiotensin-aldosterone system dysregulation or cytokine storm. This is caused by the
endocytosis of severe acute respiratory syndrome coronavirus 2. The second
bidirectional link is from DM to COVID-19 and is due to drug-induced or impaired
immunity or raised furin levels in DM. The review furthers explores the five pathways
leading to cardiovascular diseases.
Citation: Viswanathan V, Puvvula A, Jamthikar AD, Saba L, Johri AM, Kotsis V, Khanna NN,
Dhanjil SK, Majhail M, Misra DP, Agarwal V, Kitas GD, Sharma AM, Kolluri R, Naidu S,
Suri JS. Bidirectional link between diabetes mellitus and coronavirus disease 2019 leading to
cardiovascular disease: A narrative review. World J Diabetes 2021; 12(3): 215-237
URL: https://www.wjgnet.com/1948-9358/full/v12/i3/215.htm
DOI: https://dx.doi.org/10.4239/wjd.v12.i3.215
INTRODUCTION
Coronavirus disease 2019 (COVID-19) is a global pandemic and an ongoing
international public health emergency caused by severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2)[1]. Our understanding of the COVID-19 epidemic is
limited. However, the information gleaned from previous viral outbreaks may shed
Viswanathan V et al. Diabetes and COVID-19: A bidirectional link
WJD https://www.wjgnet.com 217 March 15, 2021 Volume 12 Issue 3
light on new approaches to prevent and cure this pandemic. As of November 5, 2020,
there are over 48.5 million laboratory-confirmed cases of COVID-19 in around 200
countries, with nearly 1.2 million deaths, mostly in comorbid and high-risk groups[1].
Diabetes mellitus (DM) is a highly prevalent metabolic disorder, affecting more than
400 million people globally[2-4]. It is now also considered an independent risk factor of
COVID-19[5-9]. Long-standing DM leads to macrovascular and microvascular
complications that ultimately affect patients’ quality of life[10]. DM has a long history of
being associated with several other infections[11], such as the 2008 epidemic SARS-CoV-
1[12], the 2009 pandemic influenza A (H1N1)[13], and the 2010 epidemic Middle East
respiratory syndrome-related coronavirus (MERS-CoV)[14]. Similarly, it has been shown
that DM is associated with the current COVID-19 pandemic[5,15-18]. A study of 20982
COVID-19 patients by the Chinese Centre for Disease Control and Prevention showed
a 5% prevalence of DM. Further, in an Italian study, Onder et al[6] reported that out of
355 COVID-19 patients, 36% had DM. Similarly, another study in the United States by
Bhatraju et al[8] reported that in 24 patients, 58% were diabetic. There is, therefore, an
extensive range (5.3%-58%) of reported prevalence of DM in COVID-19 patients[5],
which could be attributed to the fact that the studies were conducted in different
countries (or geographical locations), assessed significantly different sample sizes, and
had different objectives.
The majority of people suffering from COVID-19 escape major complications, but a
significant minority develops severe illness leading to death. Several factors have been
implicated in the development of severe illness, including (1) older age, (2)
comorbidities, (3) professional risk of exposure to SARS-CoV-2 at work, and (4)
socioeconomic and household conditions. People of any age can get the COVID-19
infection, including children, but typically, COVID-19 related serious complications
are present in those over 60 years[19,20]. A supporting study from the Centers for Disease
Control and Prevention, United States[21], consisting of 4226 people, reported that 80%
of deaths were in people aged ≥ 60 years that required intensive care unit admission
and long-term care. People of any age with a history of serious past chronic health
problems are more vulnerable to COVID-19, possibly because of a weak immune
system. Such comorbidities include long-standing heart and brain problems[22,23],
kidney impairment[24], cancer[19], immunological disorders[20], obesity[25,26], and diabetes
[27].
Obesity is a major risk factor for many diseases, and an increasing number of
reports show obesity as a risk factor for COVID-19[25,26], similar to what had been seen
with previous coronavirus infections such as SARS-CoV-1 and MERS[28]. Our
observations point to the reason for comorbidity (that includes diabetes) as one of the
highly probable causes of COVID-19 mortality. The top seven countries in diabetes
prevalence (India, United States, Pakistan, Bangladesh, Indonesia, Mexico, and Brazil)
are listed in the top 8% of countries contributing COVID-19 deaths globally. This
suggests that DM and its comorbid conditions may be a major contributor to COVID-
19-related mortality[1]. Front-line workers, including drivers, sanitation handlers,
police, security guards, doctors, and paramedics, come into contact with the public
more frequently and may have a higher chance of COVID infection[29,30]. In addition,
poor living conditions, discrimination, lifestyle, and low socioeconomic status are
associated with a higher risk of severe COVID-19 related infection, complications, and
death[31,32].
Recent studies have also indicated a plausible reverse association between DM and
COVID-19, which means that COVID-19 patients without a history of DM could
experience a new onset of diabetes[33-35]. To investigate this association, an international
group of diabetes researchers from the CoviDIAB Project (covidiab.e-dendrite.com)
has set up a global registry of patients with COVID-19–associated diabetes. Although
there is a high prevalence of DM in COVID-19, a possible bidirectional association and
the link between these two conditions are still unclear. Therefore, to prevent long term
cardiovascular events, it is essential to collect more evidence from different peer-
reviewed studies and validate this bidirectional mechanism between DM and COVID-
19.
We analyzed this possible bidirectional hypothesis by splitting it into two
unidirectional flows. We hope that this will lead to a better understanding of these two
global health emergencies. In section 2, we address the question “How does diabetes
increase the viral entry of SARS-CoV-2?”, while in section 3, we address the question
“How can COVID-19 infections lead to new-onset diabetes or the worsening of pre-
existing diabetes?” Table 1 provides an evidence-based summary of studies
supporting sections 2 and 3. Section 4 addresses the question “How can the interplay
between DM and COVID-19 increase the risk of cardiovascular disease (CVD)?”.
Further, it also discusses the role of vitamin D (Vit D) during the COVID-19 pandemic.
Viswanathan V et al. Diabetes and COVID-19: A bidirectional link
WJD https://www.wjgnet.com 218 March 15, 2021 Volume 12 Issue 3
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.
Finally, section 5 presents the role of atherosclerosis imaging for diabetes patients
during the COVID-19 pandemic and long term follow-up of survivors[36,37].
Viswanathan V et al. Diabetes and COVID-19: A bidirectional link
WJD https://www.wjgnet.com 219 March 15, 2021 Volume 12 Issue 3
HOW DOES DM INCREASE THE VIRAL ENTRY OF SARS-COV-2?
Three possible pathways that might increase COVID-19 susceptibility in patients with
DM are depicted in Figure 1. Increased susceptibility to COVID-19 infection may occur
through (1) medication-induced angiotensin-converting enzyme 2 (ACE2) expression
(pathway-I), (2) impaired immunity (pathway-II), and (3) increased furin levels
(pathway-III). In the first pathway, patients with DM exhibit a high prevalence of
increased blood pressure and CVD[38]. Hence, along with hypoglycemic agents, these
patients are mostly treated with antihypertensive medications like angiotensin-
converting enzyme inhibitors (ACE-I), angiotensin-II type I receptor blockers (ARB)[39],
and lipid-lowering drugs such as statins[40]. Hypoglycemic agents, such as (1)
glucagon-like peptide-1 agonists (e.g., liraglutide)[41] and (2) thiazolidinediones (e.g.,
pioglitazone)[42,43], facilitate viral entry following overexpression of ACE2. A new
hypoglycemic agent, sodium-glucose cotransporter 2 inhibitors (SGLT2i), has been
used for treating type 2 diabetes[44]. SGLT2i may also promote cellular viral entry by
increasing ACE2 levels indirectly, mainly when used alongside ACE-I. Moreover,
using SGLT2i in patients with COVID-19 may cause serious complications such as
dehydration and could increase the risk of diabetic ketoacidosis (DKA)[45-47].
Antihypertensive medications such as ACE-I and ARBs are also associated with an
increase in ACE2 expression[48-51]. Increased expression of ACE2 receptors by the
epithelial cells of the lung [alveolar type 2 (AT2) cells][52,53], intestine (enterocytes)[54],
kidneys (proximal tubule cells)[52], and heart (myocardial cells)[52] facilitates the human
cell entry of SARS-CoV-2[41-43,45,48-51]. Additionally, Hodgson et al[55] showed that patients
with DM and hypertension treated with ACE-I and ARB are more susceptible to
SARS-CoV-2 infection due to higher expression of ACE receptors. Furthermore,
experimental animal studies demonstrated increased expression of ACE2 receptors by
using statins[56,57]. In an experimental rabbit model, atorvastatin use resulted in
overexpression of ACE2 receptors in both the heart and the kidney[56]. A similar study
in diabetic rats treated with fluvastatin resulted in overexpression of ACE2 receptors
in the heart and blood vessels[57]. Recently Mota et al[57] reported in their study that
frequently used drugs in patients with DM, like glucagon-like peptide-1 receptor
agonist, thiazolidinediones, anti-hypertensives such as ACE-I, and lipid-lowering
drugs such as statins, hike ACE2 expression, increasing the risk of COVID-19. On the
other hand, it was shown that people who were on insulin had less ACE2 expression
(Table 1)[58]. Furthermore, Abbas et al[59] and Muniangi-Muhitu et al[60] also validated
that “Drug-induced” causes an increase in ACE2 expression in DM, which further
increases the possibility of SARS-CoV-2 viral entry. These studies suggest that a
medication-induced ACE2 overexpression may play a role in the pathophysiology of
COVID-19, as shown in pathway-I (Table 1).
The second pathway (marked as II in Figure 1) is related to the impaired immune
response in DM patients. Patients with DM have an increased susceptibility to
infections[61]. The presence of hyperglycemia and oxidative stress in DM inhibits (1)
neutrophil chemotaxis, (2) phagocytosis, and (3) macrophage activity[55,58,62-66].
Furthermore, in DM, impairment of natural killer cells and interferons (IFN-γ) has
been observed. Additionally, the SARS-CoV-2 virus primarily infects monocytes and
dendritic cells that results in a weakened immune system (Table 1)[60,67]. All these play a
vital role in increasing susceptibility to viral proliferation in COVID-19 patients,
especially those with poor blood glucose control[55,61-63]. Hence, with the above
explanation, we can conclude that there is a possible association between impaired
immune response and an increased risk of COVID-19 infection in diabetes patients.
Recently, Kalra et al[68] also supported the same pathway II in their newly published
article.
In the third pathway (marked as III in Figure 1), DM increases the presence of furin,
which is a type-1 membrane-bound protease belonging to the “proprotein convertase
subtilisin/Kexin” receptor family[55]. Interestingly, recent studies showed an increased
furin level in DM patients facilitating the cellular entry of SARS-CoV-2 (Table 1)[58,69,70].
Furthermore, furin is associated with the cleavage and priming of the spike protein of
SARS-CoV-2 (S1 and S2 proteins), thereby mediating viral entry in the host cell[71,72].
The presence of furin is likely associated with the replication of SARS-CoV-2 in
patients with DM[16,69]. Although pathway-III is well seen and better understood
compared with pathway-I and pathway-II, the cumulative effect of the three pathways
validates the possible link that indicates the increased cellular entry of SARS-CoV-2 in
patients with pre-existing DM.
Viswanathan V et al. Diabetes and COVID-19: A bidirectional link
WJD https://www.wjgnet.com 220 March 15, 2021 Volume 12 Issue 3
Figure 1 The plausible bidirectional link between diabetes mellitus and coronavirus disease 2019. ACE: Angiotensin-converting enzyme; COVID-
19: Coronavirus disease 2019; GLP1A: Glucagon-like peptide-1 receptor agonist; IL: Interleukin; RAAS: Renin-angiotensin-aldosterone system; SARS-CoV-2: Severe
acute respiratory syndrome coronavirus 2; SGLT2i: Sodium-glucose cotransporter 2 inhibitors; SIRS: Systemic inflammatory response; TNF: Tumor necrosis factor;
TZDS: Thiazolidinediones.
HOW CAN COVID-19 LEAD TO NEW-ONSET OR WORSENING OF PRE-
EXISTING DM?
This section illustrates the reasons causing “new-onset DM” or “worsening of pre-
existing DM” in post-COVID-19 cases. It has been observed that patients that were not
having a prior history of diabetes, but when infected by COVID-19, lead to severe
complications such as DKA[33-35]. It has been shown that DKA occurs mainly due to
total or subtotal insulinogenic (reduced insulin levels) and the overproduction of
counter regulators, which favors the production of ketones[34,73]. Further, DKA is most
commonly observed in patients with type 1 DM but may also occur in type 2
diabetes[74,75]. In an observational study, Li et al[33] reported that COVID-19 infection also
induces DKA in patients with diabetes. Henceforth, we hypothesized the three
plausible series of pathways of new-onset DM or worsening of pre-existing diabetes
after COVID-19 infection, which is depicted in Figure 1 (pathways-IV, V, and VI). A
zoomed version of Figure 1 indicating the bidirectional association between DM and
COVID-19 is provided in Supplementary Figure 1.
Pathway IV explains the effect of COVID-19 causing insulin-dependent DM. It is
well known that viral infections are associated with the development of pancreatic
autoantibodies leading to insulin-dependent DM or type 1 DM. These respiratory
viruses were identified as one of the potential causative pathogens in “the
environmental determinants of diabetes in the young” (TEDDY) study[76,77]. SARS-CoV-
2 uses the ACE2 receptor as an entry gate[78] into the pancreas. An interesting study by
Thaweerat et al[79] showed that the ACE2 receptors are more densely populated in the
endocrine area when compared with the exocrine area of the pancreas through ACE2
immunostaining of pancreatic tissue[79]. The main function of the exocrine area of the
pancreas is to facilitate blood glucose regulation[80]. SARS-CoV-2 enters into the
Viswanathan V et al. Diabetes and COVID-19: A bidirectional link
WJD https://www.wjgnet.com 221 March 15, 2021 Volume 12 Issue 3
pancreas thereby triggering autoimmunity and resulting in pancreatic cell destruction;
this is particularly prevalent in severe COVID-19 cases[81-84]. This pathway, activated
due to viral infection, may lead to the production of cross-reactive antibodies against
pancreatic cells (molecular mimicry hypothesis)[85,86]. Thus, the hypothesis of the
bidirectional involvement of DM-COVID-19 holds, which states that the SARS-CoV-2
infection results in direct damage to pancreatic islet cells, leading to the impairment of
insulin levels[79,87] and potentially triggering DM (shown in pathway-IV in Figure 1).
Recently Abbas et al[59] also validated the existence of this pathway (Table 1).
Additionally, Baracchini et al[66] and Mota et al[58] also mentioned this pathway in their
recent work on COVID-19 (Table 1). Balasubramanyam et al[88] and Rubino et al[35]
further asserted their views on this pathway, establishing its validation.
Pathway V suggests that endocytosis of SARS-CoV-2 decreases ACE2 levels that
causes the increase of angiotensin II (AngII) levels, which is a potent vasoconstrictor.
Constriction of vessel lumen may be due to inhibition of nitric oxide in the
endothelium of islet capillaries[89]. This results in a decrease in blood supply to the
pancreas. Islet cells receive 15% of the total blood supply to the pancreas, even though
they constitute only 1%-2% of pancreatic volume[90]. Hence, a decrease in the blood
flow to the pancreatic islets due to vasoconstriction may impair insulin secretion in the
pancreas[91] (see pathway V of Figure 1). This further confirms the bidirectional
association between COVID-19 and DM, also listed in Table 1.
In pathway VI, increased proinflammatory cytokines due to COVID-19 are higher in
patients with DM in comparison with patients without DM. This likely contributes to a
poorer prognosis when both diseases coexist[92]. The severe illness that accompanies
COVID-19 causes a systemic inflammatory response. This can be seen even with mild
COVID-19 infection, resulting in an increase of proinflammatory cytokines such as
interleukin (IL)-6, IL-1β, and tumor necrosis factor alpha (TNF-α)[93]. Increased
proinflammatory cytokines result in decreased insulin sensitivity, which then leads to
hyperglycemia. Further obesity, a significant coexisting condition associated with type
2 diabetes, is linked to the development of insulin resistance (IR). Obesity and type 2
diabetes further aggravate the proinflammatory cytokine response, which worsens the
IR[93] (see pathway VI in Figure 1). Wang et al[70] reported that SARS-CoV-2 infection in
patients with diabetes results in increased levels of stress hormones such as
glucocorticoids that can lead to a hyperglycemic state. An acute rise in glycemic levels
may result in life-threatening complications like ketoacidosis. Finally, the systemic
inflammatory state associated with COVID-19 may plausibly worsen the pre-existing
IR state in such individuals, manifesting as overt DM[94]. The long-term sequelae of this
process are currently unknown, and clinical studies are needed to validate the
hypothesis further. However, our hypothesis is supported by some recent studies that
also indicate a similar thought that “the association between COVID-19 and
hyperglycemia is because of metabolic inflammation and exaggerated cytokine
release” (Table 1)[60,95]. This thought emerged because of the potential role of SARS-
COV-2 in the impairment of insulin secretion, leading to hyperglycemia. Reddy et al[96]
presented a case study of two patients positive with COVID-19 and no personal
history of diabetes. The authors indicated precipitation of DKA, which can occur in
newly diagnosed diabetes patients. Pal et al[97] also provided an overview of this
bidirectional interaction between DM and COVID-19, where COVID-19 may lead to
diabetes and, in turn, further increases the severity of COVID-19. These studies
validate our thought process and indicate a need for a global study to investigate this
bidirectional hypothesis. The recent announcement of the CoviDIAB project will shed
light on this possible hypothesis of the bidirectional association between both of these
global healthcare emergencies[35,98].
HOW CAN THE INTERPLAY BETWEEN DM AND COVID-19 INCREASE
THE RISK OF CVD?
Throughout the world, DM is one of the leading causes of mortality and morbidity
due to its association with several microvascular and macrovascular complications,
which include CVD. Since there is a positive correlation between DM and COVID-19,
it is imperative to understand its implication on CVD risk. Several studies have found
that patients with COVID-19 and DM are at increased risk of vascular
complications[99,100]. Poor glycemic control with the presence of IR plays a vital role in
the worsening of CVD risk in DM patients[101]. As supporting evidence, the study by
Madjid et al[102] highlighted the identification of heart damage through high levels of
troponin in the blood due to COVID-19 leading to mortality of the patient. Further, it
Viswanathan V et al. Diabetes and COVID-19: A bidirectional link
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was shown that there is a role for inflammation of the heart due to COVID-19, e.g.,
myocarditis, vascular inflammation, and cardiac arrhythmias. Other supporting
evidence by Javanmardi et al[103] is a meta-analysis showing the prevalence of pre-
existing diseases in COVID-19 patients. The data in this study were pooled from 10
articles having 76993 patients and showed a prevalence of 7.87% [95% confidence
interval (CI) 6.57-9.28] diabetes, 16.37% (95%CI: 10.15-23.65) hypertension, 12.11%
(95%CI 4.40-22.75) CVD, and 7.63% (95%CI 3.83-12.43) smoking history, respectively,
in patients infected with SARS-CoV-2. Further, Azar et al[104] have shown that the
presence of pre-existing diseases such as DM, hypertension, and CVD are more likely
to be associated with an increased risk of mortality in COVID-19 patients. Azar et al[104]
focused on the cytokine storm concept that showed the connection between DM and
COVID-19. Further, they showed that the higher basal levels of proinflammatory
cytokines were seen in diabetic patients, which resulted in a cytokine storm with an
increase in viral infection. They demonstrated the link between high levels of IL-6 and
the AMP-activated protein kinase (AMPK)/mechanistic target of rapamycin signaling
pathway and their role in exacerbating diabetes-related complications and IR. Both
statements in the article support pathway VI of our article, which shows the possibility
of aggravating preexisting diabetes or new-onset diabetes in COVID-19 due to
cytokine storm. Additionally, they highlighted the role of the ACE2 receptor during
viral binding to the host cell, thereby causing an increased risk of viral uptake in
diabetes patients.
The work of Azar et al[104] is one of the bases of our hypothesis, where we discuss the
two-way relationship between DM and COVID-19, i.e. triggering of COVID-19 on the
new onset of DM and worsening glycemic levels of DM. Further, our study
demonstrated the importance of early imaging to prevent CVD among all patients
with COVID-19. On the contrary, the studies by Madjid et al[102] and Javanmardi et al[103]
did not directly support the concept of bidirectional relationship. Additionally, Sattar
et al[105] showed that there was worsening of cardiac events in COVID-19 patients with
preexisting cardiac conditions, such as coronary artery disease, hypertension, and
DM[105]. Furthermore, six different studies across various hospitals in China reported
the prevalence of comorbid conditions in COVID-19 patients. Out of 1527 COVID-19
admissions, 9.7% had diabetes, leading to increased CVD prevalence by 16.4%[7,106-110].
In the previous two sections, we have explained the possible bidirectional link
between DM and COVID-19. Current data from many countries such as China, Italy,
and the United States have shown that COVID-19 can lead to mild symptoms in most
individuals. However, a minority of individuals suffer from severe complications due
to underlying chronic complications (explained in detail in section I, page 3)[111].
Possible reasons for increased CVD risk in known DM patients infected with COVID-
19 are explained in five subsections (labeled as pathways A to E) of Figure 1. The first
two subsections discuss the possible connection between DM and CVD, which
includes (1) oxidative stress due to chronic hyperglycemia (subsection A) and (2)
increased coagulation activity (subsection B). Subsection C shows how COVID-19 and
DM jointly affect CVD due to hypoxia. In the last two subsections (D and E), we show
the possible pathways between COVID-19 and CVD. This includes the role of (1)
cytokine storm (subsection D) and (2) renin-angiotensin-aldosterone system (RAAS)
dysregulation along with endothelial dysfunction (subsection E).
Oxidative stress
Oxidative stress is defined as the pathology of hyper-production of “reactive oxygen
species” (ROS) and the counterbalancing part of the endogenous antioxidant defensive
system[106]. Chronic hyperglycemia and IR in DM result in the production of
proinflammatory cytokines and an increase of “advanced glycation end products”
(AGEs)[61,107]. High levels of AGEs increase CVD risk two-fold when compared with
low AGE levels[112]. A further increase in AGE levels results in ROS production, which
accelerates AGE production, producing a cyclic effect[113]. Increased ROS results in
oxidative stress as a systemic manifestation that plays a vital role in DM[108]. These
further result in endothelial dysfunction due to (1) nitric oxide inhibition in the
endothelial cells of the blood vessels and (2) increased inflammation and fibrosis[109],
eventually leading to increased risk of atherosclerotic CVD (marked as subsection A in
Figure 1). Interestingly, many studies found that AMPK has a protective role in cardiac
injury by acting against oxidative stress and turns into a potential therapeutic target in
patients with diabetes and COVID-19[110,114]. Besides this link between oxidative stress,
DM, and CVD, some recent studies have also pointed out a possible role of oxidative
stress in the pathogenesis of COVID-19 related infections[112,113,115,116]; however, this is
beyond the scope of this review.
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Increased coagulation activity
Increase in coagulation activity occurs due to the loss of fibrinolytic activity associated
with DM. In general, the fibrinolytic process helps to degrade clots and remove them
from blood vessels. It counters clot formation and risk occlusion in blood vessels by
eliminating fibrin from the vasculature. In patients with DM, there is an increase in
clotting factors and a relative reduction of the fibrinolytic system[117]. The impaired
coagulation in DM is associated with alterations of the fibrin network and increased
antifibrinolytic proteins[118]. Hence the reduced coagulation activity in patients with
DM causes endothelial dysfunction by triggering platelet activation and aggregation,
which further favors atherosclerotic plaque formation[119], increasing cardiovascular
risk (marked as subsection B in Figure 1).
Hypoxia
There is clear evidence that SARS-CoV-2 causes pulmonary as well as extrapulmonary
complications like CVD[120]. Primary SARS-CoV-2 enters through the respiratory route
and anchors to AT2 cells in the alveolar pulmonary epithelium[121]. This fusion is
occurring due to the presence of ACE2 receptors on the surface of AT2 cells and the
resulting development of respiratory symptoms as the most common clinical
presentation of COVID-19 patients[122]. Infected AT2 cells further initiate the immune
response by producing inflammatory mediators shown with SARS-CoV-1 and
stimulate the production of proinflammatory cytokines and chemokines[123].
Hyperproduction of chemokines and cytokines results in endothelial dysfunction,
causing vasodilation and an increase in sub-endothelial space's vascular permeability.
This further leads to diffused alveolar interstitial exudate[124] and causes pulmonary
edema resulting in an alveolar gas exchange disorder known as “acute respiratory
distress syndrome” (ARDS)[125]. Additionally, DM patients can have reduced lung
function indicated by decreased levels of “forced vital capacity” (FVC) and “forced
expiratory volume in one second” (FEV1). Generally, FVC and FEV1 are vital
parameters for accessing lung function[126-128]. Impending lung function is associated
with chronic hyperglycemia resulting in an increased risk of ARDS[126-128]. Decreased
lung function in DM can increase the risk of ARDS if infected with COVID-19. This
was further supported by Huang et al[129], where the authors showed that roughly 30%
of diabetes patients with COVID-19 developed impairment in lung function, shown as
a decline in FEV1/FVC ratio. Hence, ARDS risk is increased with the coexistence of
DM and COVID-19 and can further lead to depletion in the oxygen levels in the
blood[130-132].
Ongoing hypoxia in myocardial cells results in myocardial ischemia and heart
injury[132], and ongoing hypoxia in brain cells results in brain injury[133]. Nan et al[134]
showed that COVID-19 patients with comorbidity had an acute cardiac injury and
needed invasive mechanical ventilation, while Kwenandar et al[135] showed that
cardiovascular manifestations in COVID-19 patients like myocardial injury,
arrhythmias, sudden cardiac arrest, heart failure, and coagulation abnormality occur
in up to 33% of patients[135]. Zunyou, Wu et al[136], and Clerkin et al[137] submitted a
summary of the report to the Chinese center for disease control and prevention
indicating 1023 deaths in 44672 confirmed cases with COVID-19, i.e. a case-fatality rate
(CFR) of 2.3, and stating that patients with underlying CVD or hypertension had a
higher CFR compared with people without comorbidities[136,137].
Cytokine storm
Guo et al[92] reported a higher risk of pneumonia in COVID-19 patients with DM when
compared with patients without a history of DM. Patients with DM experience an
advanced stage of illness that causes multiple organ dysfunction, triggering an
exaggerated inflammatory response compared with non DM. This results in the
production of proinflammatory cytokines that include IL-6, IL-7, IL-12, IL-15, IL-22, C-
reactive protein, and TNF-α, leading to cytokine storm[138-141]. Another study by Guo
et al[142] showed that cardiac injury in patients with COVID-19 had elevated troponin
and C-reactive protein, suggestive of increased morbidity and mortality[122,142]. Zheng
et al[122] and Wu et al[143] exemplified that cardiac injury may happen due to cytokine
storms caused by the inflammatory response of T helper cells. Huang et al[129] also
supported that imbalance in T helper cells results in triggering cytokine storm leading
to destabilization of carotid plaque and micro thrombosis. Supporting evidence by
Kang et al[144] showed that significant risk of cardiac complications, such as arrhythmia,
heart failure, and myocardial infarction, in COVID-19 was due to a combination of (1)
hyper inflammation with cytokine release, (2) plaque instability, (3) myocardial
inflammation, (4) hypercoagulable state, and (5) direct myocardial injury. Vinayagam
Viswanathan V et al. Diabetes and COVID-19: A bidirectional link
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et al[145] concluded that chronic inflammation through cytokines and chemokines
promotes hypercoagulability, causing multiorgan dysfunction leading to heart and
brain injury.
RAAS dysregulation
RAAS plays an important role in maintaining cardiovascular health and electrolyte
balance[146] and has been well-described before. In COVID-19 patients, the SARS-CoV-2
gains entry into the cells by attaching to the ACE2 receptor of the cell. The anchoring
ability of the virus is due to its spike protein, which is present on its surface[71,147,148]. The
dysregulation of RAAS occurs due to the loss of a counter-balance between Ang II
levels and ACE2 levels after SARS-CoV-2 infection[149]. ACE2 levels degrade Ang II and
produce Ang (1-7), which opposes the negative impact of Ang II[132,150]. ACE2 and Ang
(1-7) are recognized as a cardio-cerebral protective factor[151]. The reduced levels of
ACE2 receptors and increased levels of Ang II after a SARS-CoV-2 infection can lead to
atherosclerotic CVD in two possible ways. First, an increased Ang II level causes
stimulation of the adrenal gland, triggering the production of the mineralocorticoid
hormone aldosterone[146], which causes Na (sodium) and water retention in the
collecting duct of the kidney[152]. This increases blood volume and blood pressure[153],
causing endothelial dysfunction that progresses to atherosclerotic CVD. Second,
excessive Ang II levels result in vasoconstriction, proinflammation, prothrombotic,
and proliferative effects[132,150]. This has a detrimental effect on the blood vessels,
thereby leading to endothelial cell damage and subsequent atherosclerotic
cardiovascular events. Additionally, DM patients using ACE inhibitors and ARBs have
increased ACE2 expression, which is beneficial to vascular health by reducing
profibrotic and proinflammatory function. But, increased ACE2 levels promote the
entry of SARS-CoV-2 infection that potentially results in a loss of ACE2 in blood
vessels in diabetes patients causing vascular complications like CVD[154]. Recently, Suri
et al[23] showed that COVID-19 is an independent risk factor for developing CVD due to
hypoxia, cytokine storm, and RAAS dysregulation.
Role of CVD risk factor in COVID-19 patients with/without DM
In Table 2, we briefly illustrated the difference in COVID-19 severity between patients
with DM and non-DM. We have shown that DM has an added risk in patients with
COVID-19. There are many reasons to explain why COVID carries a worse prognosis
in DM patients. They include age, culture, comorbidities like hypertension and pre-
existing CVD, higher body mass index, and proinflammatory and pro-coagulable
state, all of which may contribute to the risk of worse outcomes[155].
A meta-analysis by Santoso et al[156] showed a total of 2389 patients taken from 13
studies that had a cardiac injury and were associated with a higher risk of mortality
when affected by COVID-19. Further, the authors stated that these patients required
intensive care unit admission during the COVID-19 period[156]. In another meta-
analysis by the same group (see Huang et al[157]), which included 6452 patients with
DM from 30 studies, DM associated with the worst outcome and mortality when
affected by COVID-19. Additionally, Pranata et al[158] showed in a total of 4448 patients
from 16 studies that 77% of people had poor health outcomes due to cerebrovascular
disease, and 60% of people had poor health outcomes due to CVD.
Role of Vit D during COVID-19 pandemic
Vit D has many beneficial roles in the maintenance of musculoskeletal health, and its
deficiency causes calcium malabsorption resulting in fractures[159]. This can be
prevented by a daily intake requirement of 800-2000 IU of Vit D, co-administrated
with calcium, thereby reducing the risk of fracture by 15%-30%. This range of doses is
recommended by major organizations during pre-COVID times[160]. Interestingly in
recent publications on COVID-19 by Ilie et al[161] and Rhodes et al[162], the authors
showed that low Vit D levels are associated with higher mortality rates in SARS-CoV-2
infections. Further ecological studies have shown that major risk factors of low Vit D
levels are older age, higher latitudes, winter season, less sunlight exposure, and
dietary habits. Vit D is responsible for the modulation of innate and adaptive
immunity via Vit D receptor (VDR) and CYP27B1 (enzyme converting it to active
metabolite calcitriol), and both are expressed in immune cells[163,164].
Many studies showed that the major role of Vit D in COVID-19 is that it lessens the
cytokine production after SARS-CoV-2 infection including IL6, TNF-α, and IFN-β[165].
Other anti-viral properties include modulation of macrophage chemotactic protein1, IL
8, type 1 IFN, TNF-α, and lowering of ROS[166]. Ongoing clinical trials on pharma-
ceutical interventions of 2019 Novel Coronavirus Research Compendium[167] and
Viswanathan V et al. Diabetes and COVID-19: A bidirectional link
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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.
primary registry trials of World Health Organization[168] include trials of Vit D
supplementation in COVID-19 infection.
ROLE OF ATHEROSCLEROSIS IMAGING IN DIABETES PATIENTS
DURING COVID-19
Figure 2 shows the cytokine storm leading to atherosclerosis and pathway “E” leading
to endothelial dysfunction and atherosclerosis formation. Both DM and COVID-19 are
associated with vascular wall damage[169] (such as plaque erosion or atherosclerotic
plaque vulnerability), and this elevates the risk of atherosclerotic CVD events[170-172].
Vinciguerra et al[173] reported that atherosclerosis may be an ideal pathogenetic
substrate for high viral replication ability, leading to adverse cardiovascular outcomes.
Atherosclerosis is generally initiated by damage to the endothelial cells[174]. Recent
histological findings suggest the involvement of COVID-19 viral elements in
endothelial cell damage and the accumulation of inflammatory cells leading to
endothelial cell death[175]. The damage to endothelial cells and the hyperdynamic
circulation due to COVID-19 may lead to atherosclerotic plaque instability and
rupture[176].
Similarly, the formation of atherosclerotic thrombus in the arteries has been
reported in recent studies[177]. Lapergue et al[177] reported COVID-19 patients that
showed the development of large thrombus in the cervical carotid artery with
underlying mild non-stenosing atheroma. Indes et al[178] also reported an elevation of
risk for acute arterial thromboembolic complications in patients with COVID-19
infection. Esenwa et al[179] presented a radiology-pathology case series of three COVID-
19 patients and reported that a disproportionately high intra-luminal thrombus in the
carotid artery showing mild-to-moderate atherosclerotic disease with intimal
thickening and plaque calcification. Mohamud et al[180] presented a case study of six
COVID-19 patients that had atherosclerotic plaque vulnerability and the development
of thrombotic events. This was the result of the inflammatory response and cytokine
storm, which has also been considered as an important phenomenon for cardiac events
in our review (Figure 2). Similarly, Alkhaibary et al[181] reported complete occlusion of
the left common carotid artery and left middle cerebral artery of the COVID-19
patients.
These studies have also indicated the presence of vascular risk factors such as
hypertension and DM that exaggerate the risk of cardiovascular and stroke events in
COVID-19 patients. Since the COVID-19 driven cytokine storm is associated with
atherosclerotic plaque instability, it is essential to screen such patients for the presence
of arterial plaque burden. Imaging techniques have shown promising results in
screening, diagnosis, and patient management during this pandemic. COVID-19
symptoms of the patients and seriousness have helped to decide which imaging
technique is most appropriate: Portable and non-portable[23]. In COVID-19 patients,
non-invasive carotid ultrasound may be adopted for low-risk patients to investigate
the presence of carotid atherosclerotic plaque[182,183], which is also considered as a
surrogate marker CVD[184-186] and also used for CVD risk assessment in diabetic
Viswanathan V et al. Diabetes and COVID-19: A bidirectional link
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Figure 2 Pathways linking coronavirus disease 2019 to heart/brain injury. Pathway C: Hypoxia pathway. Pathway D: Cytokine storm. Pathway E:
Renin-angiotensin-aldosterone system pathway. ACE: Angiotensin-converting enzyme; ARDS: Acute respiratory distress syndrome; IL: Interleukin; SARS-CoV-2:
Severe acute respiratory syndrome coronavirus 2; TNF: Tumor necrosis factor.
patients[187-197]. Similarly, magnetic resonance imaging and X-rays can be useful for
screening of medium risk patients[198-200]. Most of the studies prefer the use of these
non-portable imaging techniques. For critical cases, intravascular ultrasound imaging,
computed tomography angiography, and ventriculography are generally followed for
arterial imaging[201-203]. Among all these techniques, ultrasound is a portable, less
expensive, and radiation-free imaging technique and, therefore, can be adopted for the
screening of atherosclerotic plaque in patients with COVID-19[204]. Several studies used
ultrasound to detect the rupture-prone atherosclerotic plaque and the tissue
characterization of such plaque for the prevention of future cardiac events[205-207].
Furthermore, studies have used ultrasound-based imaging techniques for CVD risk
assessment in patients with diabetes[187-189,191,193,195,196,208-212] and, thus, could also be
adopted for diabetic patients with COVID-19. Several other imaging-based studies
have shown the interaction of plaque measurements in diabetes patients[196,211,212]. In the
imaging category, plaque area was recently measured and correlated with hemoglobin
A1c in diabetes patients[213]. These further assert the role of atherosclerotic imaging and
phenotype measurements in post-COVID-19 patients. Image-based risk calculators can
be adapted for 10-year risk assessment on diabetes patients, which can be adapted for
post-COVID-19 follow-up[211,214].
In the current pandemic, it is also equally important for radiologists and medical
practitioners to follow the guidelines while conducting an imaging-based screening of
COVID patients. These include isolating the imaging equipment, taking the images
through the isolation room glasses, and using disposable sterile protection to imaging
probes[23].
Viswanathan V et al. Diabetes and COVID-19: A bidirectional link
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CONCLUSION
We showed clearly the six pathways between DM and COVID-19, establishing the
DM-COVID-19 loop. Three pathways were unidirectional from DM to COVID-19 and
vice-versa establishing the bidirectional flow. Further, we demonstrated the effect of
this DM-COVID-19 loop on CVDs, causing the acceleration towards cardiovascular
and cerebrovascular events. The mini-review also shows why only a minority group of
people develop severe complications, unlike the majority group of people who escape.
The review also sheds light on the role of Vit D during the COVID-19 pandemic.
Finally, the review presents the role of vascular imaging for tracking atherosclerotic
burden during COVID-19 and on long term follow-up patients. We conclude that (a)
DM/COVID-19 loop is detrimental to the patient’s heart and brain and (b) early
monitoring of atherosclerotic burden is required in “Diabetes patients during COVID-
19” or “new-onset Diabetes triggered by COVID-19 in Non-Diabetes patients”.
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