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 Table of Contents  
REVIEW ARTICLE
Year : 2022  |  Volume : 13  |  Issue : 4  |  Page : 322-330

A systematic review approach in understanding the COVID-19 mechanism in diabetes and its progression to diabetic microvascular complications


1 Department of Biochemistry, King George’s Medical University, Lucknow, Uttar Pradesh, India
2 Department of Biosciences, Integral University, Lucknow, Uttar Pradesh, India
3 Department of Medicine, King George’s Medical University, Lucknow, Uttar Pradesh, India

Date of Submission16-Aug-2022
Date of Decision13-Oct-2022
Date of Acceptance19-Oct-2022
Date of Web Publication21-Dec-2022

Correspondence Address:
Dr. Gyanendra Kumar Sonkar
Department of Biochemistry, King George’s Medical University, Shah Mina Rd, Chowk, Lucknow 226003, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jod.jod_87_22

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  Abstract 

Introduction: In uncontrolled hyperglycemia, lungs, tongue, oropharyngeal and nasopharyngeal airways having increased glycosylated angiotensin-converting enzyme 2 (ACE2) can serve as good viral binding sites for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leading to a greater tendency and considerable risk of prolonged life-threatening disease. This review was written with the objective to extract the recent advances, updates, and discoveries about the effects of coronavirus disease-2019 (COVID-19) on patients with diabetes and its microvascular complications. It was further written with the aim to discuss the current state of knowledge that has not yet been confirmed or unconfirmed, leading to various debatable issues about COVID-19-associated with microvascular complications in diabetes mellitus. Materials and Methods: We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and searched scientific sites related to our review article such as Web of Science, Embase, PubMed, Scopus, Google Scholar, and MEDLINE of last nearly two and half years. Results: The individuals who are suffering from type 2 diabetes mellitus experience more organ damage by SARS-Cov-2 due to cytokine storm. The pro-inflammatory state, lower primary immune system response, and increased ACE2 level with dysregulation of vascular function and the prothrombic state in patients with diabetes may increase the vulnerability for COVID-19 and worsened prognosis. The patients have reduced prognosis leading to microvascular complications such as diabetic nephropathy, neuropathy and retinopathy. In diabetes retinopathy, it induces the changes in the vasculature of the retinal veins. These viruses can directly affect the nervous tissue and/or can indirectly via activating the immune system-mediated mechanisms leading to diabetic neuropathy as well. Conclusions and Implications: During the cytokine storm the amount of D-dimer in the serum gets significantly increased, due to increased activating plasmin at the early stage of inflammation. Uncontrolled hyperglycemia leads to diabetic complications leading to increased mortality rate in patients with COVID-19. Thus, diabetes and its associated microvascular complications may lead to the severity and mortality in the patients with COVID-19. More of clinical practice and further studies should be implicated through this review article. Laboratory findings and clinical records are of much help in patients with diabetes and COVID-19. Worldwide studies from different countries apart from China should be considered to reach a conclusion about the conditions of patients with diabetes and microvasculature complications around the world.

Keywords: Covid-19, diabetic nephropathy, neuropathy, retinopathy, SARS-CoV-2, type 2 diabetes


How to cite this article:
Sonkar GK, Singh S, Sonkar SK. A systematic review approach in understanding the COVID-19 mechanism in diabetes and its progression to diabetic microvascular complications. J Diabetol 2022;13:322-30

How to cite this URL:
Sonkar GK, Singh S, Sonkar SK. A systematic review approach in understanding the COVID-19 mechanism in diabetes and its progression to diabetic microvascular complications. J Diabetol [serial online] 2022 [cited 2023 Jan 28];13:322-30. Available from: https://www.journalofdiabetology.org/text.asp?2022/13/4/322/364639




  Introduction Top


Type 2 diabetes mellitus (T2DM) is having a gradual increasing prevalence all over the world. In 1988 it was first described as a component of metabolic syndrome. It is characterized by insulin resistance and high blood glucose level in blood.[1] It seems that presence of hyperglycemia and T2DM are independently linked with coronavirus disease-2019 (COVID-19) severity and increased fatality.[2] In December 2019, Wuhan, in China reported several cases of pneumonia of mysterious etiology. After further investigation and close monitoring, Chinese scientists had confined a novel corona virus in 2019 and termed as nCoV-19 by World Health Organization (WHO) on January 7, 2020.[3] Later the Coronavirus Study Group renamed it as severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) and the disease caused by this pathogen was named as coronavirus disease 2019 (COVID-19).[3],[4] Due to the accelerated spread of COVID-19, on March 11, 2020, WHO declared COVID-19 as a global pandemic.[5] Li et al.[6] suggested that diabetes is known to increase the risk for COVID-19 infection. A Chinese study using six different studies from China using meta-analysis showed that the occurrence of diabetes was 9·7% in the whole COVID-19 cohort (n = 1527), which is close to 10.9% of diabetes in China. Various factors and mechanism such as hyperglycemia, efficient virus entry but its decreased clearance, high cellular binding affinity, diminished cellular response, high inflammation, cytokine storm and presence of cardiovascular disease have been proposed by several workers which may enhance the susceptibility in diabetes patients with COVID-19.[7] However, the exact mechanisms and interrelationships between diabetes and its complications with COVID-19 have not yet been fully illustrated.


  Materials and Methods Top


Search strategy

We did all-inclusive literature search following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guide [Figure 1]. A systematic electronic database search with PubMed, Embase, MEDLINE, Cochrane, Web of Science, Google Scholar, and Scopus was done using keywords “COVID-19” OR “coronavirus” OR “Diabetes” OR “SARS-CoV-2 infection” OR Type 2 Diabetes Mellitus AND COVID-19 complications” AND/OR “Immunobiology” OR “Pathophysiology” OR “COVID-19 AND Mechanism” OR “transmission” OR “ACE Receptor” OR “Cytokine Storm AND COVID-19”. Search was conducted for relevant studies published from January 1, 2020 to May 31, 2022.
Figure 1: PRISMA study flow chart

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Study selection and data extraction

Two reviewers (GKS and SS) screened the studies independently and any discrepancies were resolved by discussion with other researcher (SKS) to reach a consensus. Titles and abstracts were scanned and relevant full texts were assessed for eligibility. Only articles in English language were eligible for inclusions. Exclusion criteria included study type, non-research/original articles such as summaries of meetings or discussions or letter to the editor, duplicate or overlapping data.


  Discussion Top


General characteristics of COVID-19

SARS-CoV-2 belongs to the family Coronaviridae and order Nidovirales. Coronavirinae and Torovirinae are two subfamilies of Coronaviridae. Coronavirinae has four genera: (i) Alphacoronavirus (α) containing HCoV-229E and HCoV-NL63 (human coronavirus 229E and NL-63, respectively), (ii) Betacoronavirus (β) includes HCoV-OC43, SARS-HCoV, HCoV-HKU1, and MERS-CoV (Middle Eastern respiratory syndrome coronavirus, (iii) Gammacoronavirus (γ) present in whales and birds, and (iv) Deltacoronavirus (δ) isolated from pigs and birds.[8] Among these four genera humans are infected with only α and β-coronaviruses.[9]

Structure of corona virus

The genetic composition of coronavirus is a positive RNA strand having four different proteins viz. envelope (E), membrane (M), spike (S), and nucleocapsid (N). Of these four proteins, the most important one required for viral attachment, entry and fusion is the S protein.

The S protein has S1 subunit which is targeted by antibodies, entry inhibitors and vaccines. It also helps the entry of virus into the host cell by binding to its receptor through RBD (receptor binding domain) of the S1 subunit. After that S2 subunit of the same, catalyze the fusion of viral and the host membrane.[10] ACE2 is recognized by SARS-CoV-2 as its host receptor binding to viral S protein.[11] Analysis of RBD fragment in S protein of SARS-CoV-2 showed that the recombinant RBD protein binds strongly to human ACE2 (hACE2) as well as bat ACE2 (bACE2) receptors which blocks the entry of the virus into their respective hACE2 expressing cells. It suggests that recombinant RBD can act as viral attachment inhibitor that may inhibit SARS infection.[10]

Mode of transmission and diagnosis

Transmission of Corona virus is reported through direct contacts, aerosols and by droplets. The respiratory droplets in the cough and sneeze produced by an infected person may be inhaled by a nearby person (within 6 feet). It has also been seen that touching virus contaminated surface or object and subsequently touching eyes, nose or mouth can also spread the disease.[12] However, experimentally it has been shown that the virus can survive at least for 3 h in aerosols.[13] For diagnosis of COVID-19, the real-time polymerase chain reaction (RT-PCR) has been used as a current standard diagnostic method. It detects the positive strand mRNA in throat swabs, sputum and secretions from lower respiratory tract samples in persons infected with SARS-CoV-2.[14],[15]

Life cycle of SARS-CoV-2

Infection with SARS-CoV-2 initiates with the S1 subunit of S protein of virus binding to the ACE2 receptor present on the surface of host cell. As S1 subunit of S protein of virus binds with the ACE2 receptor of the host cell, there is cleavage of S1/S2 protein and S2’regions by TMPRSS2 (transmembrane serine protease). This process is called priming which facilitates the fusion of viral membrane with the host membrane. This is followed by direct entry of the virus into the host cell’s cytoplasm and finally into respiratory tissues.[16] As the host cell is invaded by the SARS-CoV-2, the genomic RNA (30 Kb) of the virus is translated into polypeptides corresponding to the open reading frames (i.e., ORF1a and ORF1b). These viral peptides include the non-structural proteins (nsps) such as nsp3 and nsp5, viral protease that process the polypeptides into 15–16 nsp subunits. Most of the viral proteins (nsps) are responsible for replicating the complete genome of the virus. The sub genomic promoters are used for the transcription of structural proteins that include spike proteins, nucleocapsids, envelop proteins and the membrane proteins. This translation takes place in the endoplasmic reticulum of the host cells[17] [Figure 2].
Figure 2: Life cycle of SARS-CoV-2

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Mechanism of action

S1 subunit Spike protein-ACE2 receptor complex is formed which gets internalized (receptor mediated endocytosis) by the host cell.[18],[19] A serine protease enzyme TMPRSS2, which is usually shown in the lungs and the gastro-intestinal tissues split and triggers the spike protein of SARS-CoV and MERS-CoV, after which fusion of membranes takes place. A study suggested that the if TMPRSS2 in mice is genetically inactivated, leads to less lungs damage and inflammation induced by MERS-CoV and SARS-CoV infection. An inhibitor of TMPRSS2, camostat mesylate reduces the rate of infection in the human lungs cells cultured in vitro.[20] Infections, diseases and use of glucocorticoids decreases insulin sensitivity leading to increase in more deaths in patients with diabetes. Lim et al.[21] in their review has proposed pathogenic mechanism that emphasizes infection with SARS-CoV-2 leads to inflammation and increased level of lipopolysaccharides[22] inflammatory cytokines,[23],[24] and toxic metabolites leading to alteration of immune responses and difficulty in glycemic control. Increased or decreased activity of natural killer cells and elevated levels of IFNγ and reactive oxygen species (ROS)[25] leads to lung fibrosis[26] and acute respiratory distress syndrome (ARDS).[27] This causes activation of RAAS system, causing insulin resistance, hyperglycemia, and vascular endothelial damage.[28],[29],[30] These combined effects contribute to disseminated intravascular coagulation (DIC), thromboembolism and cardiovascular events. D-dimer and clotting factors also increases due to SARS-CoV-2 infection leading to increase in blood viscosity and vascular endothelial damage.[31],[32] However, reasons are still being looked into COVID-19 mortality combined with diabetes. The duration, age, gender, race and blood glucose control of diabetes may have effect on the mortality of COVID-19.[32] Zheng et al.[33] reported from his meta-analysis study in more than three thousand confirmed cases of COVID-19 that there was significantly higher frequency of type 2 diabetes, cardiovascular disease and hypertension in affected group than in non-affected group. Hence, patients with preexisting diseases showed higher death rates. A study by Guo et al.[34] suggested that patients who were suffering from diabetes were more likely to be severely ill with an advanced prevalence of organ damage, hypercoagulability and amplified levels of inflammatory factors.

Immunobiology of SARS-CoV-19

The blood cell count in patients with COVID-19 suffers from leukopenia (low level of white blood cells) to leukocytosis (high level of white blood cells) and lymphopenia (low lymphocyte count), although the lymphopenia is more common in these patients. The lymphocyte count is associated with the severity of disease with lower count associated with the poor prognosis in the COVID-19 infected patients. The lymphocyte count of intensive care unit (ICU) patients suffering from COVID-19 having lymphocyte count of 800 cells/μL reduces the chances for survival.[35] The Ca2+ and K+ homeostasis perturbation by COVID-19 induces the activation of NLRP3 inflammasome.[36] The cytosolic Ca2+ increases whereas the cytosolic K+ gets decreased, leading to imbalance in these ions and the production of superoxides. These superoxides are recognized as DAMPs (damage-associated molecular patterns) which activates NLRP3 inflammasome.[37] The virus- infected cell secretes the IL-1β and IL-18 which recruits the leukocytes at the site of infection.[38] The first cells that are recruited in response to the chemokines and the cytokines are the neutrophils. These neutrophils start the virus clearance by different processes like neutrophil extracellular traps (NETs), oxidative burst, degranulation as well as phagocytosis[39] with release of IL-6 and IL-12, tumor necrosis factor alpha (TNF-α), prostaglandin E2 (PGE2), transforming growth factor beta (TGF β), and leukotriene B4. These molecules further recruit immune cells. The macrophages and the epithelial cells are activated by IL-1β via IL-1R signaling pathway, and stimulate the production of IL-6 and IL-12.[40] IL-1β stimulates the activation of dendritic cells which increases the expression of interferon (IFN) in response to viral infection.[41] The early stage of inflammation stimulates the IL-1β and IL-18 which influence the multiplication of the T-helper cells during the infection. IL 1β inhibits the TH1 activities and stimulates the Th17 response. These responses are advantageous for the replication of virus as it stimulates the production of Bcl-xL and Bcl-2 by the virus infected cell. Hence, it inhibits the apoptosis of virus infected cell.[42] Th17 enhances the inflammatory response by stimulating the production and release of IL-17 which induces the production of TNF-α, IL-1, IL 6 and IL-15.[43] Patients infected with SARS-CoV-2 have been reported to have a high number of Th17 in their blood samples.[44] Another pro-inflammatory cytokine, IL-18 modulates the activity of immune cells like T cell, DC, B cell, macrophage and natural killer cell (NK). It also induces the prostaglandin, TNF-α, and nitric oxide. IL-18 and IL-12 together induces TH1 cell response and IL-18 alone induces TH2 cell response.[45] The type of which T cell gets activated, is determined by the cytokine profile which is generated during the infection. TH cell response is stimulated by various pro-inflammatory cytokines such as IL-1, IL-2, IL-12, TNF-α and IFN-γ.[41]

COVID-19 in association with type 2 diabetes and its microvascular complications

Both the micro and macrovascular complications are responsible for much of the burden of diabetes. Neuropathy, nephropathy and retinopathy are the most common microvascular complications resulting from metabolic disturbances in axons and Schwann cells in peripheral nerves, mesangial cells in the renal glomeruli and endothelial cells in the retinal vessels.[46],[47] A French nationwide multicentric observational study was carried out in patients with diabetes hospitalized with COVID-19 showed early mortality on day seventh, which was associated with microvascular complications such as diabetes retinopathy and nephropathy.[48] Another similar study in patients with diabetes infected with COVID-19 reported retinopathy to be significantly (OR = 5.81, P < 0.001) associated with increased risk of intubation.[49] Data from Mexican Open Registry of COVID-19 in 2834 patients with diabetes nephropathy showed higher chances of developing COVID-19 pneumonia, hospitalization and intubation.[50] Similarly, a very large cohort study in Scotland also showed that patients with diabetes nephropathy and diabetes retinopathy infected with COVID-19 needed for intense treatment and had worst outcome in such patients compared with those with only diabetes.[51] It has been hypothesized that diabetic neuropathy, another microvascular complication could be a significant risk factor for severe COVID-19 due to an impairment of the autonomic nervous system and the inflammatory reflex resulting in a pro-inflammatory state in diabetic patients with COVID-19.[52] An observational study showed widespread sensory neuropathy with loss of smell and taste and abnormal temperature threshold in patients without prior diabetes neuropathy.[53] T2DM increases the risk of respiratory tract infection by viruses such as H1N1 strain and influenza and bacteria.[54],[55] A study on 500 patients in China reported that high mortality is associated with increased fasting glucose level.[56] COVID-19 infected patients with elevated blood glucose level shows high glycosylated ACE2 in nasopharyngeal and oropharyngeal airways and tongue and this serves as increased SARS-CoV-2 viral binding sites leading to more severe form of the disease. The expression of ACE2 takes place in type I and II alveolar epithelial cells in the lungs, renal tubular epithelium, heart, endothelium, upper respiratory tract, pancreas, intestinal epithelium, gall bladder and testis.[57],[58] It is a membrane bound monomeric 805 amino acid long[59] zinc and chloride dependent peptidyl dipeptidase specifically a carboxypeptidase which removes preferentially the hydrophobic and basic amino acid residues from the carboxy-terminal of the peptide.[60],[61] The function of ACE2 is to catalyze the hydrolysis of angiotensin II (1–8), a vasoconstrictor peptide and convert it into angiotensin (1–7) (a vasodilator). Hence, it helps in lowering the blood pressure (39). Some preclinical studies suggested that gain and loss of ACE2 function can provoke the actions of angiotensin II during the control and cell function, blood pressure, renal physiology, atherosclerosis and amelioration of experimental diabetes.[62],[63] The expression of ACE2 in islet is increased during the early T2DM but get decreased in late T2DM. Similarly, in kidney of diabetic patient it was suggested that ACE2 act as adjusting mechanism for hyperglycemia-induced activation of RAS. It was experimentally found that over expression of ACE2 in a 8 week old db/db mouse model enhance glucose insensitivity, improved islet function, elevated β-cell proliferation and insulin level and prevented β-cell apoptosis.[64] In the lungs it was seen that expression of ACE2 may increase in type 2 diabetes.[65] It was found that the deficiency of ACE2 in pancreas may cause the reduced insulin secretion.[66] A meta-analysis of 16003 patients (33 independent studies) by Kumar et al.[67] suggested that diabetes independently increases the mortality and severity of COVID-19 by two-fold as compared to the non-diabetics. The occurrence of diabetes in patients with COVID-19 was 9.8%.[67] Onder et al.[68] reported a prevalence of diabetes to be about 35% in fatal cases of randomly selected SARS-CoV-2 patients; however, Grasselli et al.[69] in his retrospective study found T2DM occurrence in 17% of COVID-19 ICU-admitted patients.

Cytokine storms in COVID-19 associated T2DM

T2DM and uncontrolled hyperglycemia alters both the humoral as well as the innate immunity (i.e., the cell mediated),[70] resulting in diminished first line of defense against any pathogens. A pro-inflammatory stage is caused by T2DM with a hyperbolic cytokine response. When the SARS-CoV-2 enters into the host cell it activates the inflammatory response, producing IFN-γ (interferon gamma) and activation and recruitment of T-cells leading to cytokine storm.[71] Reports suggest that T2DM individuals infected with COVID-19 had amplified CRP and IL-6 serum level compared to non-diabetics.[34] Hence, there are more chances of organ failure in individuals with T2DM and contracted the SARS-CoV-2. The pro-inflammatory cytokines (IL-6, TNF-α, IFN-γ) and anti-inflammatory cytokines released by Th2 cells (IL-4, IL-10) are then secreted by activated CD4+ T-cells. It has been proposed that cytokine storm together with extreme inflammation has a critical role in the pathogenesis of COVID-19 infection that may be similar to pathogenesis of SARS and MERS.[72] It was observed in the pulmonary pathology that the lungs of severe patients with COVID-19 have large amount of inflammatory cell infiltration.[73] A recent study, after analyzing hospitalized 138 patients of COVID-19 reported that neutrophilia is associated with the cytokine storm which is induced by viral infection, inflammatory response related coagulation activation and acute kidney injury. This increases the mortality rate in the COVID-19 infected individuals.[74]

COVID-19 and its association with diabetic nephropathy

There are valid reports which suggest that there is a complex pathophysiology between COVID-19 and diabetic nephropathy. One of the complications of SARS-CoV, that is, AKI (acute kidney injury) was first recognized in 2003.[75] Many studies reported that about 6.7% of patients suffering with viral infection have developed AKI in a median time of 20 days, of which about 30% required renal replacement therapy.[76] It has been reported that about 70% of the patients suffering with AKI die.[75] Studies shows that the AKI is most commonly prevalent in elder peoples, males and those who have high body mass index (BMI). The patients who are suffering with co-morbidities like CKD (chronic kidney disease), hypertension, CAD (coronary artery disease), heart failure, and T2DM have higher risk for AKI.[77] The etiology of SARC-CoV-2 associated with the AKI is similar, that is, it can directly attack the renal cells through the cell surface receptor (ACE2). A cross-sectional analysis in 3802 patients with COVID-19 by Lusignan et al.[78] suggested that the patients with CKD have higher risk for SARS-CoV-2 infection. Cheng et al.[79] in his prospective study in 701 patients of COVID-19 suggested that the patients with increased serum creatinine and leukocyte count, higher D-dimer levels, increased procalcitonin, increased lactose dehydrogenase (LDH), lower lymphocyte count, lower platelet count, prolonged partial thromboplastin time, the occurrence of AKI was significantly greater in patients with increased baseline serum creatinine. Autopsy and biopsy reports in AKI suggest acute tubular injury as the most common etiology. It was reported that in group of patients with COVID-19, the proximal tubules were not functioning properly which cause hypouricemia and uricosuria that is correlated with respiratory decompensation and disease severity.[80] A biopsy study[81] conducted in 85 deceased Mexican patients concluded severe AKI (54%). There were 29% findings of focal segmental glomerulosclerosis (FSGS), which could be associated with comorbidities and not necessarily with COVID-19 infection, 27% diabetic nephropathy, and 81% arteriosclerosis and acute tubular injury (ATI) in nearly half the deceased cases. Their histopathological characteristics were not associated with severe AKI but presence of pigmented casts in biopsy were significantly associated with poor kidney function recovery. COVID-19 also causes hypercoagulability, stroke, venous thromboembolism and pulmonary microangiopathy. The C5b-9 (terminal complement activation) has been seen in the kidney, lung, and skin, although the exact mechanism of activation of complement system is not known.[80] The authors confirmed that there is an independent association of various risk factors like age, sex, ethnicity, and socioeconomic deprivation with the mortality rate of the patients with COVID-19. A study by Leon-Abarca et al.[50] concluded in their study that patients with diabetes nephropathy had two-fold chances of getting infected with COVID-19 pneumonia, higher rate of hospitalization, increased probability of intubation and worst outcome in patients with CKD alone.

COVID-19 and its association with diabetic retinopathy

Another microvascular complication in diabetes is diabetic retinopathy (DR) causing eye blindness, however it is preventable. The occurrence of DR among patients with diabetes is approximately 35% worldwide.[81] Usually it is caused by the damage to blood vessels of the eyes. Those patients infected with COVID-19 have five times higher risk of having DR. The vasculature of the retinal veins are altered in the retina when infected with SARS-CoV-2. Greater changes in vasculature are associated with severity of COVID-19 disease at the early stage of infection.[82] It is not known that whether these retinal changes were caused by virus or by the host’s immune response. However, the endothelial damage and inflammatory response can be assessed by measuring the diameter of the retinal veins.[49] These finding suggests that if the patient is suffering with diabetes related vascular complications affecting both the large and small blood vessels, may increase the risk and susceptibility towards the respiratory failure by severe COVID-19 infection.[83]

COVID-19 and its association with diabetes neuropathy

Diabetes neuropathy in patients and also suffering from SARS-CoV-2 infection develop more severe complications. It was seen in a CORONADO study that the microvascular complications were independently associated with mortality of the severe patients with COVID-19 within 7 days.[49] This is characterized by neuropathic symptoms, anosmia, and dysfunction of large and small fiber in feet and face. Another study showed that the 50% of the diabetic population is affected by diabetic polyneuropathy (DPN) and also affects the large and small nerve fibers.[48] The viruses can directly affect the nervous tissue and/or can indirectly via activating the immune system-mediated mechanisms. Evidences of toxic encephalopathy, post infectious demyelinating diseases and encephalitis can harm the function and anatomy of the nervous system. The SARS-CoV-2 attacks on the neurons, activates the innate immune cells and cause damage to nerve cells by various mechanisms.[53] Mao et al.[84] categorized 36.4% diabetes patients of their study suffering with neurological manifestations into 3 classes, that is, 1. central nervous system which included symptoms such as headache, acute cerebrovascular disease, dizziness, impaired consciousness, seizure, and ataxia 2. peripheral nervous system which included symptoms like smell impairment, taste impairment, nerve pain, and vision impairment, and 3. muscular-skeletal. Some of the autopsy studies suggested that in most of the COVID-19 infected patients there were signs of cerebral edema and meningeal vasodilation. About one fourth number of patients and around 9% of patients developed mental illness and seizures when they were affected by MERS-CoV in the year 2012.[85],[86] A case report by Gagarkin et al.[87] have reported from United States that the COVID-19 disease is associated with acute inflammatory demyelinating polyneuropathy (AIDP, i.e., the progressive symmetric muscle weakness) or Guillain–Barré syndrome (a collection of immune-mediated polyneuropathies).


  Conclusions Top


Diabetes can lead to the multiple complications and increases the risk for complications of COVID-19 and associated mortality. The evidence suggests that T2DM patients are more prone to severe complications as compared to the patients without T2DM. One of the hypotheses suggests that high blood glucose favors the viral entry as both viruses as well as the ACE2 requires glucose for their functions. Although the exact way of interaction/mechanism of action requires more research. During the cytokine storm the amount of D-dimer in the serum gets significantly increased, due to increased activating plasmin at the early stage of inflammation. However, increased inflammation and the hypoxia induced molecule can activate the thrombin which further leads to hypercoagulation. The activated monocyte-macrophage secretes a number of tissue factors that activates the exogenous pathway of coagulation making the patients more prone to hypercoagulation as compared to patients with COVID-19 without diabetes. Viral load increases the inflammation, islet damage, and treatment with glucocorticoids could lead to hyperglycemia, that results dysregulation of blood glucose control in the SARS-CoV-19 patients who have comorbid diabetes leading to severe pneumonia. Uncontrolled hyperglycemia leads to diabetic complications leading to increased mortality rate in patients with COVID-19. The mechanism of this correlation is still not clear. Although the pro-inflammatory state, weakening of the primary immune response, vascular dysfunction with amplified level of ACE2 and the prothrombic condition in patients with diabetes may increase the vulnerability for COVID-19 and worsened prognosis. After analyzing a number of articles, it was concluded that the diabetes and its associated complications may lead to the severity and mortality in the patients with COVID-19.

Limitations of the study

Although our articles search was unbiased, and tried to maintain a complete strategy in searching literatures which have assessed both diabetes and COVID-19, it may be possible that unpublished data may have been missed. Secondly our review article did not include patients’ clinical records and laboratory findings which may underestimate the cases of microvascular disease in various population. Thus, the severity of underlying microvascular complications could not be taken into consideration and also, the type of treatment given to diabetes subjects was not so well known.

Acknowledgement

We are also thankful to all the researchers whose articles were included in the current review. We are also thankful to Ms. Shweta Parashar for typing this article and making the figure.

Financial support and sponsorship

This review writing is part of the project work sanctioned by Science and Engineering Research Board (SERB), New Delhi, India (File No. EEQ/2019/000250).

Conflicts of interest

There are no conflicts of interest.

Criteria for inclusion in the authors’/contributors’ list

All authors were involved in conception and design of the work. GKS, SS, and SKS performed screening and selection of articles. GKS and SS drafted the manuscript. All authors were involved in editing and revision of the manuscript and final approval of the version submitted for publication. All authors agree to be accountable for all aspects of the work and in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.



 
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