Bangladesh Journal of Medical Science Vol. 21 No.

01 January’22

Review article/Meta analysis

“Elucidation of the Shared Pathophysiology between Diabetes and COVID-19”
Nagalakshmi CS1, Shaheen B Shaikh2, Santhosh NU3
Abstract
Background: COVID-19 is a rapidly spreading communicable disease worldwide. It varies widely in its
spectrum of manifestations, from being mild self-limiting disease, to fulminant disease, often leading to
complications and death. Diabetes is an important co-morbidity linked to severity of infection by SARS-
CoV-2, which predisposes them to severe pneumonia. Poor glycaemic control is associated with worse
outcomes. The disease burden of COVID-19 is continuously increasing, and with a high prevalence of
diabetes, it is all the more important to understand the vital aspects of COVID-19 infection in diabetic
population. Hence, we try to provide close insights into its pathophysiology, clinical characteristics,
recommendations on management and prevention and possible avenues for improving disease outcomes.
Methods: PubMed database and Google Scholar were searched using the key terms ‘COVID-19’, ‘SARS
CoV- 2’, ‘Corona’ and ‘diabetes’. Full texts of the retrieved articles were accessed and referred. Three
main mechanisms which influence COVID-19 disease manifestation in diabetics include: (a) Entry
of virus via ACE-2 receptors (b) Action through Dipeptidyl-peptidase-4, and (c) Elevation of glucose
concentration in airways by elevated blood glucose.ACE-2 is expressed in alveolar epithelial cells, heart,
renal-tubular and intestinal epithelia and pancreas. S-Glycoprotein on the surface of SARS-CoV-2 binds
to this ACE-2 and undergoes a conformational change. This allows its’ proteolytic digestion by host
cell proteases TMPRSS2 and Furin, leading to internalization of virus. Viral entry into cells triggers an
inflammatory response by T-helper-cells and at times, a ‘cytokine storm’, resulting in organ damage.
Apart from diminishing neutrophil chemotaxis and reducing phagocytosis, by which diabetes predisposes
individuals to infections, there are several specific factors with respect to SARS-CoV2: (i) Increased
ACE-2 expression (ii) Raised Furin (iii) Diminished T-cell functioning, and (iv) Increased IL-6 levels.
Movement restrictions, increased stress due to social isolation and lack of physical activity further
complicates the issue. It is therefore, much essential to raise awareness among front-line workers. Finally,
the current situation emphasizes the need for more clinical investigation and define best practices for
optimum outcomes.
Keywords: COVID-19; Diabetes; Epidemics; Pandemics; outcome; glycaemic control; ACE-2; DPP-4;
cytokine storm; comorbidity; prevention

Bangladesh Journal of Medical Science Vol. 21 No. 01 January’22 Page : 19-23

DOI: https://doi.org/10.3329/bjms.v21i1.56323

Introduction: from mild self-limiting flu-like illness, to fulminant

COVID-19 (Coronavirus Disease-2019), a disease pneumonia, respiratory failure and death. 1,2
The
caused by Coronavirus (SARS-CoV), has emerged as spread of this novel virus has reached pandemic
a rapidly spreading communicable disease affecting proportions and it represents a threat by its increased
almost all countries. The disease severity varies morbidity and mortality, globally.3

1. Dr Nagalakshmi CS, Professor and Head, Department of Biochemistry, Akash Institute of

Medical Sciences and Research Center, Devanahalli, Bangalore Rural, Karnataka, India.
Email: [email protected], [email protected]
2. Dr. Shaheen B Shaikh, Associate Professor, Department of Biochemistry, Yenepoya Medical College
Hospital, Mangaluru, Karnataka, India.
3. Dr Santhosh NU, Consultant Neurosurgeon (Endovascular), Aster CMI Hospital, Sahakarnagar, Hebbal,
Bangalore North, Karnataka, India.

Correspondence: Dr Nagalakshmi CS, Professor and Head, Department of Biochemistry, Akash

Institute of Medical Sciences and Research Center, Devanahalli, Bangalore Rural, Karnataka, India.
Email: [email protected], [email protected]

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 Bangladesh Journal of Medical Science Vol. 21 No. 01 January’22

Increased incidence of COVID-19 in patients with Methods

Diabetes: PubMed database and Google Scholar were searched
In most regions, increased morbidity and mortality using the key terms ‘COVID-19’, ‘SARS CoV- 2’,
associated with COVID-19 is particularly seen ‘Corona’ and ‘diabetes’. Full texts of the retrieved
in older individuals and in those presenting with articles were accessed and referred.
one or the other co-morbidities, such as diabetes,
obesity, hypertension, cardiovascular disease, Observations And Discussion
cerebrovascular disease, chronic kidney injury, Link between Diabetes and COVID-19 infection:
chronic liver disease. 6–9 High prevalence of diabetes Three main mechanisms are thought to influence the
makes it a very important co-morbidity among these interplay between diabetes and Covid-19 infection:
in patients with COVID-19.1-5 (a) Initial entry of SARS-CoV-2 virus into host cells
through its spike protein, via ACE-2 receptors (plays
Importance of glycaemic control in diabetic crucial role in blood pressure regulation, metabolism
patients with Covid-19 infection: and inflammation 14, where it attacks the endocrine
pathway (b) It’s action through Dipeptidyl peptidase-4
Diabetes is a primary risk factor and is one of (DPP-4) enzyme (one of the pharmacological targets
the most important co-morbidities linked to the in those with type 2 diabetes). DPP4 are tissue
severity of infectious disease caused by respiratory oligopeptides that control the activityof growth
pathogens. Depending on the global region, 20–50% factors, chemokines, bioactive peptides and T-cell
of patients in COVID-19 pandemic had associated activation besides regulating glucose metabolism 15
diabetes. It predisposes individuals to infections and (c) Elevation of glucose concentration in airways
such as influenza and severe pneumonia.10,11,1 Similar by elevated blood glucose 16This hyperglycaemia
evidence of high risk among diabetic patients have may increase viral replication 17, by disrupting the
also been reported for Severe Acute Respiratory defensive capacity of airway epithelia and suppressing
Syndrome (SARS) and Middle East Respiratory anti-viral immune response. Hyperglycaemia might
Syndrome3 (MERS-CoV).12Poor glycaemic control exacerbate virus induced respiratory dysfunction too.
in patients with COVID-19 and pre-existing diabetes Diabetes in animal models is associated with several
is associated with worse outcomes, due to increased structural changes in lung, such as increased vascular
need for medical interventions, ARDS, multiple permeability and a collapsed alveolar epithelium 16.
organ injuries and high rate of mortality.2,4 COVID-19
Special aspects of Pathophysiology of diabetes
infected diabetic individuals are at an increased risk
for complications because of suppressed immune As mentioned above, CoV utilises ACE-2 as receptor
functions. The disease burden of COVID-19 has for cellular entry.18 ACE-2 is expressed in type I and II
been continuously increasing,13 and with a high alveolar epithelial cells of lungs and upper respiratory
prevalence of diabetes, it is important to understand tract, heart, endothelium, renal tubular epithelium,
the vital aspects of COVID-19 infection in people intestinal epithelium and pancreas. S-Glycoprotein
with diabetes.3,5 on the surface of SARS CoV-2 binds to this ACE-
2 and undergoes a conformational change in itself,
Hence, in this review, we try to provide close which allows its’ proteolytic digestion by host cell
insights, by revealing the possible mechanistic links, proteases TMPRSS2 and Furin, ultimately leading
into the biochemical basis and pathophysiology to internalization of the virus particle.19 Viral entry
behind increased susceptibility of patients with co- into the cell triggers an inflammatory response
morbidities, especially diabetes mellitus, for infection by T-helper cells by producing interferon gamma
and severity of the disease caused by this novel and then other inflammatory cells, thus leading to
corona virus. We also present clinical characteristics a ‘cytokine storm’, resulting eventually in organ
of COVID-19 patients with pre-existing diabetes, damage and multi-organ failure.
practical recommendations on its management / Diabetes is associated with poor outcomes in
prevention, an insight into the differing needs of COVID-19. Apart from the common mechanisms
several patient groups and possible avenues for of diminished neutrophil chemotaxis and reduced
improving the disease outcomes. phagocytosis, by which diabetes predisposes

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 Bangladesh Journal of Medical Science Vol. 21 No. 01 January’22

individuals to infections, there are several specific during prolonged periods of hospitalization.
factors liable for increased risk and severity of SARS
CoV2 infection in patients with diabetes such as: (i) Measures in Diabetic Patients infected with
Increased expression of ACE-2 (ii) Raised Furin, the COVID-19:1,4
host cell protease (iii) Diminished functioning of • Majority of patients have mild disease and can
T-Cells, and (iv) Increased levels of Interleukin-6. be managed at home
Special considerations on the use of Anti-diabetes • If the patient develops fever, cough, running
drugs: nose or dyspnoea, notify the appropriate health
authority and seek immediate medical help
Although optimising glycaemic control to reduce
the risk of severe COVID-19 disease is important, • Isolate the patient for 14 days or till the symptoms
specific considerations around treatment modality resolve (whichever is longer)
should be made. Lactic acidosis associated • Hydration should be well maintained
with metformin usage, or euglycemic/moderate
hyperglycaemic diabetic ketoacidosis associated • Symptomatic treatment with acetaminophen,
steam inhalation etc. will be helpful
with SGLT-2 inhibitors are rare instances; however,
it is recommended that these drugs Should be • Patients with type 1 diabetes should measure
discontinued in patients with severe symptoms of blood glucose and urinary ketones frequently
COVID-19 in an attempt to reduce the risk of acute
• Avoid Anti-hyperglycaemic agents which can
metabolic decompensation.20 cause volume depletion or hypoglycaemia
Management of hyperglycaemia and associated • Adjust the dose of oral anti-diabetic agents
Metabolic conditions: • Severely diseased and hospitalised patients need
People with diabetes should intensify their metabolic frequent blood glucose monitoring.
control by adopting suitable lifestyle modification • Oral Anti-diabetic agents like metformin and
protocols in addition to pharmacologic therapy. Most SGLT-2 inhibitors need to be stopped to reduce
patients with type 2 diabetes have other components the risk of acute metabolic decompensation.20
of Metabolic Syndrome i.e., hypertension (using
drugs not acting through ACE-2), dyslipidaemia, • Insulin is the preferred agent for control of
hyperglycaemia in sick patients
etc. Hence, continued treatment using an appropriate
antihypertensive and lipid-lowering agent is highly
Unproven therapies and future directions:
recommended. Treatment with ACE inhibitors orAT2
blockers is discouraged since they could increase the • In the absence of specific antiviral drug, anecdotal
expression of ACE2 and facilitate viral entry into use of drugs like lopinavir, ritonavir, interferon-
cells.21, 22 1b, Remdesivir (RNA polymerase inhibitor) and
chloroquine has been reported
Challenges associated with achieving optimal • Regular supplementation with Zinc and Vitamin
metabolic control in COVID-19 affected diabetic C is quite essential
patients:
• A definitive vaccine can be a major tool to
In spite of knowing the importance of maintaining contain this viral epidemic 23
optimal blood glucose levels in current situation of
COVID-19 pandemic, certain hindrances have to Preventive Measures
be overcome to achieve it practically. It is therefore
important to raise awareness regarding the significance Following measures are suggested for prevention of
of glycaemic control among the front-line workers. this disease in patients with diabetes:1,5
The optimal treatment of these patients should
consist of a multidisciplinary approach by doctors A. Specific Measures in Patients with Diabetes
from emergency medicine, infectious diseases, • More frequent monitoring of blood glucose
pulmonary medicine, endocrinology, nutritionists levels (to lessen chances of superadded
and exercise rehabilitation specialists, especially bacterial pneumonia as well) using Glucometer

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 Bangladesh Journal of Medical Science Vol. 21 No. 01 January’22

preferably(to lessen the exposure) Due to the challenges associated with restriction on
• Regular intake of antidiabetic medication – movement, an increasing number of diabetic patients
Telemedicine can be very helpful are cancelling their routine visits to diabetes clinics.
This development along with the increased stress
• Stabilise the co-existing cardiac/renal disease
associated with social isolation and lack of physical
• Balanced and adequate nutrition with good intake activity provides a fertile ground for worsening of
of proteins and fibre, together with limited intake glycaemic status and blood pressure control, further
of saturated fats is very much recommended
predisposing these vulnerable patients to COVID-19
• Home based Exercise (cycling, treadmill, infections.
stationary jogging and resistance exercise with
small weights) has been shown to improve As suggested by American Diabetes Association
immunity (ADA) and American Association of Clinical
Endocrinologists (AACE), it is much essential that
• Care of feet should be emphasized
we alert the health care community and the public
• Patients need to be educated about the need to regarding the increased risks of this progressing
visit the hospital immediately in emergency pandemic in diabetic patients. Also, adherence to
situations like vomiting, drowsiness, shortness CDC (Centers for Disease Control and Prevention)
of breath, chest pain, weakness of limbs, altered
guidance regarding social isolation is very important
sensorium etc.
in persons with diabetes. Finally, the current situation
emphasizes the need for more clinical investigation
B. General Preventive Measures:
as the pandemic unfolds to fully characterize the
• Thorough handwashing with soap and water problem and define best practices for optimum
• Practise proper respiratory hygiene withcovering outcomes.
of mouth and nose
• Contact with an affected person needs to be Source(s) of fund: None
minimised – Usage of face mask is highly Conflict of interest: None
recommended
Ethical Clearance: Not applicable
• Non-essential travel to affected areas to be
avoided Authors’ Contribution: 
• Data gathering and idea owner of this study: Dr
Conclusion
Nagalakshmi CS
Diabetes is associated with increased incidence
• Study design: Dr Nagalakshmi CS
and severity ofCOVID-19. There is experimental
evidence on the effect of diabetes on viral entry into • Data gathering: Dr Nagalakshmi CS, Dr Shaheen
cell and inflammatory response to the infection. B Shaikh, Dr Santhosh NU  
It is therefore important to control blood glucose
• Writing and submitting manuscript: Dr
in patients infected with COVID-19. As a result,
Nagalakshmi CS
increased vigilance and testing in diabetes and
general medicine clinics for COVID-19 and a lower • Editing and approval of final draft: Dr
threshold for hospitalization of these patients is Nagalakshmi CS, Dr Shaheen B Shaikh, Dr
imperative. Santhosh NU  

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 Bangladesh Journal of Medical Science Vol. 21 No. 01 January’22

References: 13. World Health Organization. Coronavirus disease

2019 (COVID-19) Situation Report - 73 https://
1. Gupta R, Ghosh A, Singh AK, Misra A.. Clinical
considerations for patients with diabetes in times of www.who.int/docs/default-source/coronaviruse/
COVID-19 Epidemic. Diabetes and Metabolic Syndrome: situationreports/20200402-sitrep-73-covid-19.
Clinical Research and Reviews 2020:14 (2020) 211e212 pdf?sfvrsn¼5ae25bc7_2
https://doi.org/10.1016/j.dsx.2020.03.002 14. Hoffmann M, Kleine-Weber H, Schroeder S, et
2. Zhu et al. Association of Blood Glucose Control and al. SARS-CoV-2 cell entry depends on ACE2
Outcomes in Patients with COVID-19 and Pre-existing and TMPRSS2 and is blocked by a clinically
Type 2 Diabetes 2020, Cell Metabolism 2020; 31, 1068- proven protease inhibitor. Cell 2020; published
1077, June 2, 2020 ª 2020 Elsevier Inc. online March 4. DOI: 10.1016/j.cell.2020.02.052
https://doi.org/10.1016/j.cell.2020.02.052
3. Hill MA, Mantzoros C, Sowers JR.. Commentary:
COVID-19 in patients with diabetes. Metabolism 15. Mentlein R. Dipeptidyl-peptidase IV
Clinical and Experimental 2020;107: 154217 (CD26) Role in the inactivation of regulatory
https://doi.org/10.1016/j.metabol.2020.154217 peptides. Regul Pept 1999 Nov 30;85(1):9e24.
4. Bornstein SR, Rubino F, Khunti K, Mingrone G, Hopkins D, https://doi.org/10.1016/S0167-0115(99)00089-0
Birkenfeld AL et. al., (2020). Practical recommendations 16. Philips BJ, Meguer JX, Redman J, Baker EH.
for the management of diabetes in patients with Factors determining the appearance of glucose
COVID-19. Lancet Diabetes Endocrinol 2020; 8: 546-50 in upper and lower respiratory tract secretions.
https://doi.org/10.1016/S2213-8587(20)30152-2 Intensive Care Med 2003; 12(2):204-2210.
5. Singh AK, Gupta R, Ghosh A, Misra A. . Diabetes https://doi.org/10.1007/s00134-003-1961-2
in COVID-19: Prevalence, pathophysiology, 17. Morra ME, Van Thanh L, Kamel MG, et al.
prognos (2020)is and practical considerations. (2018). Clinical outcomes of current medical
Diabetes and Metabolic Syndrome: Clinical approaches for Middle East respiratory syndrome: a
Research and Reviews 2020; 14:303e310 systematic review and meta-analysis. Rev Med Virol
https://doi.org/10.1016/j.dsx.2020.04.004 2018;28: e1977. https://doi.org/10.1002/rmv.1977.
6. Yang X, Yu Y, Xu J, et al. (2020). Clinical course https://doi.org/10.1002/rmv.1977
and outcomes of critically ill patients with SARS- 18. Vaduganathan M, Vardeny O, Michel T, McMurray
CoV-2 pneumonia in Wuhan, China: a single-centered,
JJV, Pfeffer MA, Solomon SD. (2020). Renin
retrospective, observational study. Lancet Respir Med
angiotensin aldosterone system inhibitors in
2020. https://doi.org/10.1016/S2213-2600(20) 30079-5
patients with covid-19. N Engl J Med March 30,
Feb 24. pii: S2213-2600(20)30079-5.
2020. https://doi.org/10.1056/NEJMsr2005760
7. Guan W, Ni Z, Hu Y, et al.. Clinical characteristics https://doi.org/10.1056/NEJMsr2005760
of coronavirus disease 2019 in China. N Engl J Med  
2020. https://doi.org/10.1056/NEJMoa2002032 Feb 28. 19. Hoffmann M, Kleine-Weber H, Krüger N, Müller M,
https://doi.org/10.1056/NEJMoa2002032 Drosten C, P€ohlmann S. The novel coronavirus 2019
8. Zhang JJ, Dong X, Cao YY, et al. Clinical characteristics (2019-nCoV) uses the SARS-coronavirus receptor
of 140 patients infected by SARS-CoV-2 in Wuhan, ACE2 and the cellular protease TMPRSS2 for entry
China. Allergy 2020. https://doi.org/10.1111/all.14238. into target cells. bioRxiv 2020:2020. 01.31.929042
https://doi.org/10.1111/all.14238 https://doi.org/10.1101/2020.01.31.929042
9. Li B, et al. Prevalence and impact of 20. Hartmann-Boyce J, Morris E, Goyder C, et al. Managing
cardiovascular metabolic diseases on COVID-19 diabetes during the COVID- 19 epidemic. 2020. https://
in China. Clin Res Cardiol 2020. https://doi. www.cebm.net/ covid-19/managing-diabetes-during-
org/10.1007/s00392-020-01626-9 Mar 11. the-covid-19-pandemic/ (accessed April 15, 2020).
https://doi.org/10.1007/s00392-020-01626-9 21. Fang L, Karakiulakis G, Roth M. Are patients with
hypertension and diabetes mellitus at increased risk for
10. Hespanhol VP, Barbara C. (2019). Pneumonia mortality,
COVID-19 infection? Lancet Respir Med 2020; 8: e21
comorbidities matter? Pulmonology 2019; published
https://doi.org/10.1016/S2213-2600(20)30116-8
online Nov 28. DOI:10.1016/ j. pulmoe.2019.10.003.
22. Li XC, Zhang J, Zhuo JL. The vaso protective axes of the
11. Zou Q, Zheng S, Wang X, et al. (2020). renin-angiotensin system: physiological relevance and
Influenza A-associated severe pneumonia in therapeutic implications in cardiovascular, hypertensive
hospitalized patients: risk factors and NAI and kidney diseases. Pharmacol Res 2017; 125:21e38.
treatments. Int J Infect Dis 2020; 92:208-13. https://doi.org/10.1016/j.phrs.2017.06.005
https://doi.org/10.1016/j.ijid.2020.01.017 23. DRAFT landscape of COVID-19 candidate vaccines d
12. Memish ZA, Perlman S, Van Kerkhove 18 february 2020. Geneva: World health organization.
MD, Zumla A. Middle East respiratory https://www.who.int/blueprint/prioritydiseases/ key
syndrome. Lancet 2020; 395:1063-77. action/list-of-candidate-vaccines-developed-against-
https://doi.org/10.1016/S0140-6736(19)33221-0 ncov.pdf. opens in new tab.

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