European Journal of Clinical Nutrition (2020) 74:864–870

https://doi.org/10.1038/s41430-020-0652-1

MINI REVIEW

Metabolism and metabolomics

Diabetes and COVID-19: evidence, current status and unanswered

research questions
Ritesh Gupta1 Akhtar Hussain2,3 Anoop Misra
● ●
1,4,5

Received: 19 April 2020 / Revised: 23 April 2020 / Accepted: 28 April 2020 / Published online: 13 May 2020
© Springer Nature Limited 2020

Abstract
Patients with diabetes who get coronavirus disease 2019 (COVID-19) are at risk of a severe disease course and mortality.
Several factors especially the impaired immune response, heightened inflammatory response and hypercoagulable state
contribute to the increased disease severity. However, there are many contentious issues about which the evidence is rather
limited. There are some theoretical concerns about the effects of different anti-hyperglycaemic drugs. Similarly, despite the
recognition of angiotensin converting enzyme 2 (ACE2) as the receptor for severe acute respiratory syndrome coronavirus 2
(SARS CoV-2), and the role of ACE2 in lung injury; there are conflicting results with the use of angiotensin converting
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enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) in these patients. Management of patients with diabetes
in times of restrictions on mobility poses some challenges and novel approaches like telemedicine can be useful. There is a
need to further study the natural course of COVID-19 in patients with diabetes and to understand the individual, regional and
ethnic variations in disease prevalence and course.

Background risk of infection with severe acute respiratory syndrome

coronavirus 2 (SARS CoV-2).
The high prevalence of diabetes globally makes it a frequent
comorbidity in patients with coronavirus-associated disease
2019 (COVID-19). Though diabetes increases the risk of Why patients with diabetes have increased
infection in general, most studies have reported prevalence severity and mortality?
of diabetes almost similar to that in general population in
patients with COVID-19. A meta-analysis of eight trials in Patients with diabetes who develop COVID-19 have been
China showed that diabetes was present in 8% of 46,248 seen to have a worse prognosis and increased mortality in
patients with COVID-19 [1]. Understandably, prevalence of most studies. In 201 Chinese patients with diabetes a hazard
diabetes in patients with COVID-19 varies by region, age ratio of 2.34 (95% CI, 1.35–4.05; p = 0.002) for acute
and ethnicity. It is not known whether patients with diabetes respiratory distress syndrome (ARDS) [2] has been repor-
with well-controlled blood glucose levels have an increased ted. Further, meta-analysis of nine studies from China (n =
1936) showed a significant correlation between severity of
COVID-19 and diabetes (OR, 2.67, 95% CI; 1.91–3.74; p <
0.01) [3]. Similarly, case fatality rate was 7.3% in patients
with diabetes as opposed to 2.3% in those without diabetes
* Anoop Misra in a report of 44,672 patients of COVID-19 by Chinese
anoopmisra@gmail.com Centre for Disease Control [4]. A recent study in 1122
1 patients with COVID-19 in 88 centres across the USA
Fortis CDOC Hospital, Chirag Enclave, New Delhi, India
2
found diabetes to be associated with more than fourfold
Chronic Disease—Diabetes, NORD University, Stjørdal, Norway
increase in mortality [5].
3
Medicine, Federal University of Ceara (UFC), Ceara, Brazil How diabetes increases severity of COVID-19 is unclear,
4
National Diabetes, Obesity and Cholesterol Foundation, though several factors may be responsible (Table 1). Poor
New Delhi, India glycaemic control impairs several aspects of the innate and
5
Diabetes Foundation (India), New Delhi, India adaptive immune response to viral infections and to the
Diabetes and COVID-19: evidence, current status and unanswered research questions 865

Table 1 Reasons of increased severity of COVID-19 in diabetes based downregulation might reduce the entry of virus into cells.
on various studies (mostly unadjusted analyses).
These issues are further discussed below in context of use of
Established anti-hyperglycemic and anti-hypertensive drugs.
(1) Glycaemic instability: hyperglycaemia and possibly
hypoglycaemia
(2) Immune defects especially impaired T-cell response Anti-hyperglycaemic drugs: correct selection
(3) Associated comorbidities like obesity, heart and kidney and potential problems
diseases
Postulated The precise effect of treatment with various oral anti-
(1) Chronic subclinical inflammation, increased interleukin 6 hyperglycaemic agents on the severity of COVID-19 is not
(2) Increased plasmin known, though there are some theoretical considerations.
(3) Reduced ACE2 Metformin has shown modest benefits in lower respiratory
(4) Increased furin (involved in entry of virus into cell) tract infections and pulmonary tuberculosis [16], though
gastrointestinal tolerability in sick patients is of concern.
Thiazolidinediones have been shown to increase ACE2
potential secondary bacterial infection in the lungs [6, 7]. levels [17]. However, propensity of thiazolidinediones to
Defects in immunity namely inappropriate T-cell action, cause fluid retention and the risk of congestive heart failure
impaired natural killer cell activity and defects in comple- in COVID-19 would make these agents unfavourable for
ment action could reduce viral clearance [8]. Interestingly, treatment. Glucagon-like peptide-1 agonists have has been
ARDS in patients with COVID-19 is driven by severe shown to increase ACE2 and increase surfactant in
hypoxaemia despite relatively well-preserved lung experimental animals [18]. Practical significance of changes
mechanics. Pre-existing proinflammatory state could in ACE2 levels with use of thiazolidinediones and
accentuate the cytokine storm, which is believed to be glucagon-like peptide-1 agonists is not known. Sulfony-
responsible for ARDS as well as multi-organ dysfunction in lureas are effective, but the risk of hypoglycaemia espe-
COVID-19 [9]. In this context, it is important to note that cially in the setting of irregular meals might preclude their
there is strong association between type 2 diabetes, obesity use. Nevertheless, sulfonylureas can be considered when-
and abnormal secretion of adipokines and cytokines like ever blood glucose monitoring is possible.
TNF-alfa and interferon, which may further impair immunity There is some data regarding use of dipeptidyl peptidase
and predispose to severe infection [10]. Further, diabetes is 4 (DPP4) inhibitors from previous viral epidemics. DPP4 is
associated with increased plasminogen levels which has been the prime receptor for Middle East respiratory syndrome
postulated to increase the virulence of SARS CoV-2 [11]. coronavirus responsible for its entry into cell [19]. Hence the
Presence of these inflammation and prothrombotic factors has possibility of DPP4 facilitating the entry of SARS CoV-2
been shown in a study in 174 patients hospitalised with into the cell cannot be ruled out. In that context, it is an
COVID-19 in Wuhan, China; significantly higher serum interesting postulation that widespread use of DPP4 inhibi-
levels of interleukein 6, erythrocyte sedimentation rate, C‐ tors in India and many other countries might be protecting
reactive protein, ferritin, fibrinogen and D‐dimer were repor- individuals with diabetes from this infection. On the other
ted in patients with diabetes compared with those without hand, DPP4 inhibitors can potentially interfere with immune
diabetes [12]. Increased viral replication in diabetes may also response which may be harmful, but clinical data from DPP4
due to an increase in furin, which is a type‐1 membrane‐ inhibitors has shown that this is generally not the case [20].
bound protease involved in the entry of coronaviruses into the There is increasing use of sodium glucose cotransporter 2
cell [13]. In addition, pre-existing comorbidities associated (SGLT-2) inhibitors worldwide and in India. Interestingly,
with diabetes like hypertension, coronary artery disease and SGLT-2 inhibitors could also activate ACE2 indirectly
chronic kidney disease further worsen the prognosis. Lastly, especially if used along with ACE inhibitors [21]. There is a
hypoglycaemia which could occur during treatment of dia- hypothetical possibility of SGLT-2 inhibitors reducing
betes may additionally worsen the clinical outcomes. lactate production because of reduction in oxygen demand
In this respect role of angiotensin converting enzyme 2 of tissues, which could reduce viral entry by raising cyto-
(ACE2) receptor in pathogenesis of COVID-19 in patients solic pH [22]. Further, caution about dehydration and the
with diabetes is intriguing. SARS CoV-2 enters the cell by possibility of euglycaemic ketoacidosis need to be observed
binding to ACE2, a process which involves many steps and when using SGLT-2 inhibitors in sick patients with
several enzymes and proteins [14]. There is experimental COVID-19. Insulin has also been shown to increase ACE2
evidence for downregulation of ACE2 in diabetes [15], expression by attenuating the effect of a disintegrin and
which may predispose to more severe lung injury. On the metalloprotease (ADAM-17) [23]. Practical relevance of
other hand, ACE2 is a receptor for SARS CoV-2 and this these findings is not known at present. In any case, insulin
866 R. Gupta et al.

remains the agent of choice to control sugars in hospitalised Scientific experimental data that support benefit
patients with COVID-19. This however necessitates fre- due to ACE inhibitors/ARB in COVID-19
quent monitoring of blood glucose and poses some practical
concerns in terms of increasing the exposure of healthcare Increased ACE2 might not result in increased viral entry
provider to the COVID-19 patient. Strategies like single because of the limited availability of the serine protease
dose of basal insulin and self-monitoring of glucose by TMPRSS2, which is required for viral binding [20].
patients are worth considering in that context. Further, Increased ACE2 and consequently angiotensin 1–7 have
technologies like remote continuous glucose monitoring vasodilatory and antifibrotic effects and have been shown to
and insulin pump could be useful. be protective against lung injury in animals [26]. Treatment
Thus, it appears safe to continue the usual anti- with ARBs was reported to reduce mortality in Ebola virus
hyperglycemic medications in most patients who have infection [27]. Previously, a small study in ten patients with
mild infection, good general condition and normal oral ARDS showed that recombinant ACE2 was well tolerated
intake. However, SGLT-2 inhibitors might need dis- and led to an increase in angiotensin (1–7) levels [28].
continuation due to the risk of dehydration and euglycaemic
ketoacidosis. Metformin may also need to be stopped if Clinical studies with ACE inhibitors/ARBs in
there is vomiting or poor oral intake. Doses of other anti- COVID-19
hyperglyacemic drugs like sulfonylureas and insulin may
have to be altered depending upon the blood glucose levels.
Hospitalised patients especially those requiring intensive (1) There are no controlled studies on the use of ACE
care would need insulin for glycaemic control. inhibitors and ARBs in patients with COVID-19.
(2) The clinical evidence is inconclusive. While one study
in China did not find any association of ACE inhibitor
Drugs for treatment of comorbidities in use with severity of disease, there was an increased
diabetes mortality in patients with COVID-19 receiving ACE
inhibitors and ARBs in another study [29, 30]. One
Angiotensin converting enzyme (ACE) inhibitors/ study in the USA did not find any significant
angiotensin receptor blockers (ARB) difference in mortality in patients who received
ACE inhibitors and ARBs and those who did not
These are commonly used drugs in patients with diabetes, [31]. A recently published study in 1128 patients
especially in those with hypertension and kidney dysfunc- hospitalised with COVID-19 in nine hospitals in
tion. There have been a lot of literature and debate whether Hubei, China showed significantly reduced all-cause
these drugs could benefit or harm patients having COVID- mortality with the use of ACE inhibitors or ARBs
19 infection. This issue is discussed below. compared with other anti-hypertensive drugs [32].
(3) Many patients with COVID-19 have shown hypoka-
Scientific experimental data that support potential lemia indicating activation of RAS [33], and ACE
harm duet to ACE inhibitors/ARB in COVID-19 inhibitors and ARBs may have a role [34].

There has been a lot of interest in ACE inhibitors and ARBs In this subject situation is far from clear and there are too
following the identification of ACE2 as the receptor for many unknown factors, which might be operative in the
SARS CoV-2. ACE inhibitors and ARBs increase the levels interaction between ACE2, diabetes, ACE inhibitors/ARBs
of ACE2 by inhibiting the conversion of angiotensin 1 to and lung injury. The lack of evidence for either benefit or
angiotensin 2. Increased ACE2 expression could theoreti- harm has prompted European Society of Cardiology Council
cally increase viral binding and entry into cell, though there on Hypertension, European Society of Hypertension and
is no clinical evidence to support this otherwise attractive American Heart Association to advise continuing with ACE
hypothesis. Reduced angiotensin 2 as a result of ACE inhibitors and ARBs in case a patient develops COVID-19
inhibition and increased angiotensin 1–7 as a result of [35]. A clinical trial is underway to study the ARB losartan
increased activity of ACE2 could reduce the cytosolic pH, and recombinant human ACE2 in patients with COVID-19.
which could result in more favourable environment for viral
endocytosis [24]. Also, angiotensin 1–7 has been shown to
increase sympathetic activity by acting on Mas receptors in Unanswered questions
the brainstem, which could contribute to cardiovascular
morbidity observed in these patients [25]. However, most of There have been several commentaries on the relationship
these concerns are hypothetical with minimal evidence. between diabetes and COVID-19 [36]. However, several
Diabetes and COVID-19: evidence, current status and unanswered research questions 867

Table 2 Contentious issues and unanswered questions regarding the efficacy of chloroquine is not proven; it has
diabetes and COVID-19.
been used in patients with COVID-19 [38].
(1) Are people with well-controlled diabetes at higher risk of getting Chloroquine has a weak anti-hyperglycaemic
COVID-19 infection than non-diabetic individuals? effect and there is a theoretical risk of hypogly-
(2) Is there any effect of obesity on the severity of COVID-19 in caemia when used in combination with other anti-
people with diabetes? hyperglycaemic drugs.
(3) Is there any specific diet or supplement which could help patients b. Corticosteroids, though neither effective nor
of diabetes and COVID-19?
recommended, are frequently used in ARDS and
(4) What is the role of renin angiotensin aldosterone system (RAAS)
sepsis and would worsen glycemic levels.
and inhibitors of RAAS in determining the predisposition to
COVID-19 and its severity?
(5) Do different anti-hyperglycaemic drugs have different effects on (3) COVID-19 and pancreatic beta cells: there is
the disease course in COVID-19? significant expression of ACE2 receptors in pancreatic
(6) Is the viral clearance slower in patients with diabetes (which islets and hyperglycaemia lasting up to 3 years has
could mean higher infectivity)? been reported in patients with SARS [39]. Direct
(7) Can COVID-19 lead to beta-cell dysfunction/destruction? injury to beta cells is a possibility and patients
(8) Is there an effect of COVID-19 directly on diabetes-related recovering from COVID-19 might need major
complications independent of glycaemic deterioration? changes in anti-hyperglycaemic regimen. Recently,
(9) What are the effects of ‘lockdown’ on glycaemia and diabetes- new-onset diabetes has been reported in patients with
related complications?
COVID-19 [11].
(10) Does reduction in air pollution because of restrictions on
(4) Suboptimal lifestyle measures and other issues during
vehicular movement and industries have a beneficial role in
control of blood glucose? lockdown:
(11) Can telemedicine help in management of diabetes in the times of
COVID-19? a. There are restrictions on movement of people and
(12) Is it useful and/or feasible to screen all people with diabetes for ‘lockdowns’ in several parts of the world in order
SARS CoV-2? to contain the pandemic. This poses some
(13) Are there any ethnicity-specific factors determining the different challenges in the evaluation and treatment of
risk of infection, disease severity and mortality rates in different patients with diabetes. There are limited opportu-
regions?
nities for exercise as regular walks and visits to
gyms or swimming pools are not possible. Dietary
irregularity could occur because of staying
unanswered questions remain, about which the knowledge at home.
and information is limited. Clearly, further research could b. There is considerable mental stress because of the
lead to important insights (Table 2). Some of these are unpredictability of the disease as well as social
discussed below. immobility as brought out in an excellent study in
healthy people in China at the time when there
(1) What is the natural history of COVID-19 in patients with was a huge burden of COVID-19 there [40].
diabetes? The natural course of the disease after infection c. Patients may find it difficult to procure healthy
of patients with diabetes with SARS CoV-2 has not been foods, medicines, insulin, needles and glucose
documented well. For example, we don’t know if the strips etc. because of partial or complete lock-
incubation period is different in people with diabetes. It downs. The problem becomes more pronounced
is also possible those patients of diabetes who are young, with elderly, poor and disadvantaged sections of
have short duration of diabetes, and well controlled may society.
have less severe COVID-19 infection. There is a d. There could be underreporting of symptoms
possibility of reduced viral clearance in diabetes as has because of the perceived need to avoid visiting
been reported in patients who are on corticosteroids [37]. hospitals.
This could have public health implications as the
patients with diabetes could remain infectious for a All these factors could cause glucose dysregulation and
longer period than those without diabetes. could predispose patients to complications like infections,
(2) Use of drugs in treatment of COVID-19 which could hyperosmolar coma, ketoacidosis and even acute cardiac
have effect on glycaemia: events. A prediction model of the effect of lockdown in
India on blood glucose showed a 3.6% increase in HbA1c at
a. Chloroquine has also been licensed for use in the end of 45 days of lockdown and future increase in
India for patients with type 2 diabetes. Although diabetes-related complications [41].
868 R. Gupta et al.

(5) Use of remote education and advice: Telemedicine a result of reduced industrial and vehicular
(also emails, texts) can be very helpful in these times emissions [46]. Increase in blood glucose has
to impart education and has been shown to improve been reported with short-term rise in pm10
glycaemia. Telemedicine guidelines for physicians in (particulate matter <10 microns in diameter)
India have been published [42]. Patients need to be and glycaemic improvement could occur with
educated about the need to visit the hospital urgently the fall in pollution [47].
in emergency situations like vomiting, drowsiness,
shortness of breath, chest pain, weakness of limbs,
altered sensorium, etc [43]. In view of the issues highlighted above, it is important to
(6) COVID-19 testing for all patients with diabetes? recognise the importance of diabetes as a vital comorbidity
Given the increased severity of COVID-19 in patients in patients with COVID-19. There are several contentious
with diabetes, a case could be made for testing of all issues and the ongoing research will hopefully shed more
people with diabetes for the presence of disease. That light on the behaviour of COVID-19 in patients with
would be a humongous task considering the high diabetes.
prevalence of diabetes. High-risk groups like those
with high HbA1c, those with comorbidities, long Author contributions RG and AM planned the outline of manuscript.
RG reviewed the literature and wrote the manuscript. RG, AM and AH
duration of diabetes or elderly could be chosen for
edited the manuscript.
testing, however, utility of this approach remains to be
proven, There are frequent false negative tests and
Compliance with ethical standards
repeated testing may be required in asymptomatic
individuals. Since there is no treatment currently Conflict of interest The authors declare that they have no conflict of
recommended for asymptomatic people, therefore interest.
apart from isolating them, detecting these patients
might not prove meaningful clinically. Publisher’s note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.
(7) Ethnic variations in severity of COVI19 in patients
with diabetes? In the United States, the disease has
caused disproportionately more fatalities in Blacks
and Asians compared with Whites [44]. South Asia, References
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