|Year : 2021 | Volume
| Issue : 1 | Page : 39-46
Clash of the two titans - COVID-19 and type 2 diabetes mellitus
Priya Kaushik1, Mithlesh Kumari1, Sanjiv Kumar Bansal1, Naveen Kumar Singh1, Rajni Dawar2, Mukesh Sharma3, Arpita Suri1
1 Department of Biochemistry, Faculty of Medicine and Health Sciences, SGT University, Gurugram, Haryana, India
2 Department of Biochemistry, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India
3 Department of Microbiology, Faculty of Medicine and Health Sciences, SGT University, Gurugram, Haryana, India
|Date of Submission||28-Sep-2020|
|Date of Decision||04-Dec-2020|
|Date of Acceptance||06-Jan-2021|
|Date of Web Publication||19-Feb-2021|
Dr. Arpita Suri
B-607/A, Sushant Lok, Phase-I, Gurugram - 122 009, Haryana
Source of Support: None, Conflict of Interest: None
COVID-19 has infected more than 32 million people globally in more than 100 countries. Diabetes mellitus (DM) has emerged as an important factor involved in the fatal outcomes of COVID-19. Accumulating evidence suggests that that reciprocal relationship may exist between these two raging pandemics, thus making COVID-19 more challenging for people with diabetes. Furthermore, poorly managed glycaemia in diabetes patients leads to increased risk of severe complications and higher mortality rate. The association between COVID-19 severity and DM can be supported by several pathophysiological mechanisms, such as compromised innate immune system, deranged cell-mediated immunity and adipose tissue infiltration of pro-inflammatory macrophages. Exaggerated coagulation and pro-thrombotic milieu in diabetes can predispose to thromboembolic complications associated with fatal outcomes in diabetic patients with COVID-19. Impaired pulmonary function and elevated levels of furin associated with diabetes can increase the chances of COVID-19 infection in patients with diabetes. In addition, SARS-CoV-2 infection can trigger stress hyperglycaemia leading to augmented viral replication and severity of infection associated with poor clinical outcomes in diabetic patients with COVID-19. Endothelial dysfunction associated with virus-induced endothelialitis can lead to organ ischaemia and life-threatening complications associated with COVID-19 with underlying DM. Vitamin D deficiency and insulin resistance worsened by SARS-CoV2 can lead to higher mortality and morbidity observed in diabetic patients with COVID-19. Therefore, COVID-19 patients should be adequately monitored for the development of new-onset diabetes, due to deranged glycaemic control, owing to underlying COVID-19 disease, and diabetic patients with COVID-19 should be kept under strict glycaemic control to avoid life-threatening complications.
Keywords: COVID-19, endothelial dysfunction, insulin resistance, type 2 diabetes mellitus, Vitamin D
|How to cite this article:|
Kaushik P, Kumari M, Bansal SK, Singh NK, Dawar R, Sharma M, Suri A. Clash of the two titans - COVID-19 and type 2 diabetes mellitus. Curr Med Res Pract 2021;11:39-46
|How to cite this URL:|
Kaushik P, Kumari M, Bansal SK, Singh NK, Dawar R, Sharma M, Suri A. Clash of the two titans - COVID-19 and type 2 diabetes mellitus. Curr Med Res Pract [serial online] 2021 [cited 2021 Mar 9];11:39-46. Available from: http://www.cmrp.org/text.asp?2021/11/1/39/309915
| Introduction|| |
In December 2019, hospitals in Wuhan, China, reported unusual high number of cases with severe pneumonia with mysterious aetiology. On further investigation, the causative agent in these cases was detected as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)., It belongs to the family of coronaviruses which are enveloped single-stranded viruses that affect human respiratory system. This deadly virus has infected more than 32 million people globally killing 990,000 people in more than 100 countries. Genetic sequence of COVID 19 shows 80% similarity to SARS CoV1 (2002) which was first emerged in China with a fatality rate of 11% and 50% similarity with MERS-CoV (2012) which was first reported in Saudi Arabia and then spread quickly to other countries with 37% fatality rate.,,,,
Genome sequencing has demonstrated that SARS-CoV-2, previously known as novel coronavirus 2019, belongs to β-coronavirus of order Nidovirales, subfamily Orthocoronaviridae and family Coronaviridae., They are spherical or pleomorphic particles of 150–160 nm in size with positive-sense single-stranded RNA as the genetic material. In addition to this, they are composed of four structural proteins (spike surface glycoprotein, membrane protein, envelope protein and nucleocapsid protein), five accessory proteins (ORF3a, ORF6, ORF7, ORF8 and ORF9) and other 15–16 non-structural proteins. The coronavirus attaches to host cell via spike protein which has two subunits such as N-terminal S1 and C-terminal S2., The host proteases such as furin enter the space between S1 and S2 and separate them, further leading to a formation of claw-like structure (pinchers of the S-spike). As a result, S1 part attaches to the Angiotensin converting enzyme 2 (ACE2) receptor and S2 part attaches to the cell membrane, leading to endocytosis of the virus particle. It is important to note that SARS-CoV2 binds to ACE2 receptor with 10 times more affinity due to the disordered structure of spike protein which exposes a crack between S1 and S2, facilitating the entry of human proteases in the same.
Studies have shown that Avian Influenza, SARS-CoV and MERS-CoV patients with old age and comorbidities had poor clinical outcomes. Xie et al. in their study on 168 patients from 21 hospitals in Wuhan reported that 25% of the patients had diabetes and it was the second most commonly reported comorbidity after hypertension in COVID-19 patients. Similarly, severe and fatal outcomes are also reported with COVID-19 patients with old age and pre-existing comorbidities such as cardiovascular diseases, diabetes mellitus (DM), chronic lung and renal disease, cancer and hypertension., A meta-analysis on 1527 COVID-19 patients also suggested that patients with cardio–cerebrovascular disease had threefold increased risk, while those with diabetes or hypertension had twofold increased risk of severe outcome or intensive care unit (ICU) admission.
Diabetes is one of the major causes of mortality and morbidity, globally. Previously, during other coronavirus pandemics, diabetes and uncontrolled glycaemia were reported as important factors affecting severity of clinical outcomes in these patients. In the same way, patients with underlying chronic illnesses are more susceptible to severity and poor prognosis due to COVID-19., In a study conducted by Bode et al. (Glytec Database) on 1122 COVID-19–confirmed patients from 88 US hospitals, the mortality rate was found fourfold higher in diabetic patients (28.8%) as compared to non-diabetic patients (6.2%) and the rate increases with age. These findings were supported by a meta-analysis of 33 studies (16,003 patients) conducted by Kumar et al. that reported a significant increase in mortality in a diabetic patient with COVID-19 with an odds ratio (OR) of 2.16 as compared to non-diabetics. Thus, DM has emerged as a significant factor involved in the fatal outcome of COVID-19 as demonstrated in [Table 1],[Table 2],[Table 3]. Accumulating evidence suggest that reciprocal relationship may exist between these two raging pandemics, thus making COVID 19 more challenging for people with diabetes as shown in [Figure 1].,
|Table 1: Severity of COVID-19 infection in patients with type 2 diabetes mellitus|
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|Table 2: Intensive care unit admission of COVID-19 infection in patients with type 2 diabetes mellitus|
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|Table 3: Survival rate of COVID-19 infection in patients with type 2 diabetes mellitus|
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|Figure 1: Diagram depicting dual interaction between two pandemics - Diabetes and COVID-19|
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| How Diabetes Mellitus Affects COVID-19?|| |
In addition to crucial role of diabetes in increasing the severity of COVID-19, it is suggested that the status of glycaemic control is also important in determining the clinical outcome. Holman et al. postulated that poorly managed glycaemia in diabetes patient leads to higher mortality rate as compared to those with well-managed glycaemia. They proposed that higher level of glycated haemoglobin (HbA1c) may play a pivotal role in COVID-19–related mortality as diabetic patients with HbA1c 10.0% or higher had increased mortality rate in COVID-19 (hazard ratio 1.61, P < 0.0001), followed by HbA1c 9%–9.9% (hazard ratio 1.36, P < 0.0001) and HbA1c 7.%–8.9% (hazard ratio 1.22, P < 0.0001) as compared to diabetics with HbA1c of 6.5%–7.0%. Therefore, patients with well-controlled diabetes have better chances of survival as compared to poorly controlled diabetes.
Decreased viral clearance due to maladaptive immune response
The association between COVID-19 severity and DM can be supported by several pathophysiological mechanisms. In DM, the innate immune system, the first line of defence, against SARS-CoV-2 is compromised. T cells are known to play a crucial role in triggering inflammatory processes and insulin resistance mediated through induction of pro-inflammatory cytokines. Hence, infiltration of adipose tissue with CD4+ cells leads to differentiation and polarisation of macrophages into pro-inflammatory macrophages M1. These macrophages release pro-inflammatory cytokines such as TNF-α, IL-6 and IL-1β, thus creating a state of chronic inflammation., The components of cell-mediated immunity such as chemotaxis, phagocytosis of neutrophils and cytokine secretion by the macrophages are altered in DM. In addition to this, natural killer cells, the effector cells of innate immunity which are involved in killing of virus-infected cells, have lower activity in type 2 DM. There is also an increase in Th17, a subset of CD4+ T cells, which secretes IL-17 and promotes chronic inflammatory processes through the release of TNF-α. It is important to note, in this regard, that regulatory T cells which are responsible for inhibiting pro-inflammatory Th17 cells are also decreased which further promotes inflammation. Muniyappa and Gubbi also postulated that deranged immune response comprising impaired macrophage activity, deranged antigen presentation and impaired neutrophil recruitment can lead to cytokine storm causing acute respiratory distress syndrome (ARDS) in COVID-19 patients with DM. Guo et al. conducted a retrospective study on 24 COVID-19 patients with diabetes and concluded that they were more susceptible to heightened cytokine storm, leading to worse clinical outcomes and bad prognosis.
It is seen that in severe cases of COVID-19, cytokine storm leads to condition of hypercoagulation and higher D-dimer levels and fibrin degradation products are poor prognostic factors for COVID-19 patients. Hyperglycaemia leads to expression of plasminogen activator inhibitor (PAI-1) which inhibits the tissue plasminogen activator. This creates a prothrombotic environment due to stimulation of vessel wall remodelling and decreased degradation of fibrin by the action of PAI-1. Furthermore, in DM, platelets are resistant to the anti-aggregatory action of insulin which predisposes them to aggregation and activation. This leads to exaggerated coagulation which can be the underlying mechanism of thromboembolic complications associated with fatal outcomes in COVID-19 patients with diabetes., A study involving 1099 COVID-19 cases conducted by Guan et al. reported higher D-dimer in non-survivors (median –2.12 μg/ml) as compared to survivors (median –0.61 μg/ml). Furthermore, Huang et al. also conducted a study on 41 COVID-19 patients and concluded that the patients requiring ICU care presented with significantly higher level of D-dimer (median = 2.4, interquartile range [IQR] = 0.6–14.4) as compared to non-ICU patients (median = 0.5, IQR = 0.3–0.8). Guo et al. observed similar findings of increased D-dimer (P < 0.01) in COVID-19 with diabetes as compared to non-diabetic patients.
ACE2 receptor-mediated altered viral entry
ACE2, the receptor for spike glycoprotein, is expressed in blood vessels (endothelial cells, vascular smooth muscle cells), heart (cardiofibroblasts and cardiomyocytes) and kidneys (glomerular endothelial cells, podocytes and proximal tubule epithelial cells), enterocytes of the intestines, upper respiratory tract (goblet and ciliated epithelial cells) and alveolar (type II) epithelial cells of the lungs. It is an integral membrane glycoprotein and terminal carboxypeptidase that acts on primarily angiotensin-II and, to a lesser extent angiotensin-I, degrading them into smaller peptides such as angiotensin (Ang 1–7) and angiotensin (1–9), respectively. Ang (1–7) inhibits the action of angiotensin-II mediated through Mas proto-oncogene receptor pathway and thus has an anti-inflammatory and antioxidant role and is involved in defensive mechanism in lungs against infections.
However, in diabetes, the activity of ACE2 is reduced due to glycosylation predisposing lungs to severe injury due to SARS-CoV2 infection., It is important to note that anti-hypertensive drugs such as ACE inhibitors/angiotensin receptor blockers are associated with higher expression of ACE2 in the lungs. Therefore, patients with DM who are undergoing chronic medication with ACE inhibitors should continue their treatment. In addition to this, it is seen that once after the virus entry, the ACE2 receptors are downregulated which increases the amount of angiotensin-II. This leads to an increase in the secretion of aldosterone which leads to hypokalemia which impairs the release of insulin and reduces peripheral glucose uptake, thus disrupting the glycaemic control in diabetic patients with COVID-19 and leading to poor prognosis. In addition, in vitro studies also suggest that increased glucose concentration in the pulmonary epithelial cells observed in uncontrolled glycaemia can boost viral replication and infection which can be attributed to various mechanisms, such as decreased neutrophil degranulation deranged complement activation and reduced phagocytosis.,,,
Impaired pulmonary function
According to Rekha Jagadapillai et al., animal studies suggest that DM is associated with increased permeability of pulmonary vasculature and dysfunctional alveolar epithelium. In addition to this, Yeh et al. reported in their study that altered pulmonary functions such as reduced forced vital capacity, total lung capacity and alveolar gas exchange are also associated with DM., Thus, it might be plausible to suggest that diabetes-induced respiratory dysfunction can predispose these individuals to more severe forms of COVID-19. In support of these findings, it was seen that in a study conducted in New York on 5700 COVID-19 patients, patients with DM who were admitted in the ICU were more likely to have received intensive mechanical ventilation as compared to the non-diabetics.
Elevated levels of furin
Fernandez et al. have suggested that high fasting plasma levels of furin were associated with higher risk of DM which can be due to the role of furin in controlling the proliferation and differentiation of β-cells of the pancreas and maturation of insulin secretory granules. Increased circulating furin can also lead to increased insulin receptors as it is involved in maturation of insulin pro-receptor. In addition to this, since furin is also involved in advancing SARS-CoV2 virus entry by facilitating the endocytosis of virus particle, there might be increased chances of COVID-19 infection in patients with underlying DM.
| How COVID-19 Affects Diabetes Mellitus?|| |
Release of hyperglycaemic hormones
COVID-19 leads to stressful condition which stimulates the release of hyperglycaemic hormones such as glucocorticoids and catecholamines causing transient hyperglycaemia uncontrolled glycaemia in such patients due to underlying acute illness. Bode et al. also conducted a retrospective study and analysed the clinical outcomes of 184 patients with diabetes and uncontrolled hyperglycaemia (defined as ≥2 blood glucose value >180 mg/dl within any 24-h period) with no underlying diabetes and concluded that patients with uncontrolled hyperglycaemia without diabetes had significantly (P < 0.001) higher percentage of mortality (41.7%) as compared to diabetic individuals (14.8%) underlying the role of stress hyperglycaemia as a poor prognostic factor of COVID-19. It is hypothesised that this hyperglycaemia along with insulin resistance produces advanced glycated end products which can trigger inflammatory processes and oxidative stress. Furthermore, it has been seen by Kohio et al. in their in vivo studies that hyperglycaemia associated with diabetes can augment respiratory virus replication. Together, all these conditions lead to higher susceptibility to infections including SARS-CoV2.
In addition to this, ACE2 which acts as a receptor for SARS-CoV2 is also found in pancreatic islets. In support of these findings, Wang et al. conducted a retrospective study on 52 COVID-19 patients and found 17% of these patients having acute pancreatitis (raised amylase and lipase) without any underlying risk factor which could be attributed to the virus-induced inflammation. Thus, COVID-19 patients with diabetes can have acute beta cell dysfunction, leading to hyperglycaemia which may be due to attributed to lack of exercise, anxiety and pancreatic cell destruction due to viral infection, leading to glucose metabolism disorders such as DM.
Endothelial dysfunction is a condition when endothelium loses its physiological properties of vasodilation, anti-aggregation and anti-fibrinolysis and can be contributed by both DM and COVID-19. SARS-CoV2 affects endothelial cells due to the presence of ACE2 receptors and can lead to endothelial dysfunction. Varga et al. suggested that post-mortem analysis showed viral inclusion bodies surrounded by inflammatory cells in the endothelial cells of the kidney. According to them, this virus-induced lymphocytic endothelialitis was found in various tissues such as lung, heart and kidney during histological examination. The endothelial inflammation along with apoptosis and proptosis can be responsible for life-threatening complications of COVID-19, especially seen in patients with other comorbidities with existing endothelial dysfunction such as diabetes. On the other hand, continuous exposure of endothelium to hyperglycaemia also leads to impairment in the release and activity of nitric oxide which is a potent vasodilator, leading to dysfunction. Thus, virus-induced endothelial dysfunction can lead to vasculitis, endothelialitis, vasoconstriction and procoagulant state, leading to organ ischemia in a diabetic individual who predisposed to endothelial dysfunction.
It has been reported that the crude fatality ratio in COVID-19 patients without any comorbid conditions is 1.4%, whereas it is much higher in COVID-19 patients with comorbid conditions such as diabetes (9.2%). This can be ascribed to low Vitamin D levels commonly associated with diabetes as Vitamin D deficiency can lead to β cell dysfunction either directly or indirectly and inhibit insulin inhibition from pancreatic β cells, resulting in progression of type 2 DM. Direct effect of Vitamin D includes modulating its effect through Vitamin D receptor (VDR) present on beta cells. It has a vital role in promotion of cytokine-mediated growth of beta cell and insulin release by regulating calbindin (calcium-binding protein), which controls depolarisation by modulating intracellular calcium. Indirectly, Vitamin D increases the expression of PPAR-delta which increases insulin sensitivity and regulates intracellular calcium which effects glucose transporter activity. In addition to this, it inhibits the expression of renin and therefore inhibits the angiotensin II–induced impaired glucose uptake. In addition to this, the implementation of nationwide lockdown in times of COVID-19 pandemic has reduced sunlight exposure drastically, leading to higher chances of Vitamin D deficiency. Since Vitamin D has antiviral and anti-inflammatory actions, Vitamin D deficiency can be associated with increased severity of COVID-19. Daneshkhah et al. also showed that Italy, Spain and France have highest fatality rate of COVID-19 because of higher deficiency of Vitamin D (<0.25 ng/L) as compared to the other countries. Another study conducted by Alipio on 212 COVID-19 suggested that increase in serum 25 OHD might be beneficial for improving the health status of COVID patients by increasing the odds of mild disease as compared to poor clinical outcome of COVID-19 (OR = 0.051, P < 0.001).
It is seen that pro-inflammatory environment created by SARS-CoV which is evident by high levels of serum cytokines in such patients can worsen the insulin resistance. Moreover, obesity has been observed as a risk factor for COVID-19 severity that requires more attention to preventive measure in suspected individuals. The proportion of patients requiring invasive mechanical ventilation increase with increasing body mass index (BMI) this proportion was highest in patients with BMI >35 (85.7%). Obesity commonly accompanies DM as a part of metabolic syndrome also decreases insulin sensitivity. Therefore, increased insulin resistance can disturb the glycaemic control in COVID-19 patients with DM and lead to poor prognosis. Several factors, e.g., male gender, older age, renal impairment, non-white ethnicity, socioeconomic deprivation and previous stroke and heart failure, were also associated with increased mortality in COVID-19 with type 2 diabetes.
| Management of Diabetes Mellitus in COVID-19|| |
Diabetes can increase the severity of infection, morbidity and mortality due to COVID-19, and therefore, glycaemic control in patients infected with COVID-19 is quite challenging. Previous studies of SARS and influenza H1N1 infections have shown that poor glycaemic control in patients increases the severity of infection, thereby increasing the risk of complications and death. The core principle of the management of individuals with COVID-19 and diabetes or at a risk of metabolic disease includes need for preventing diabetes and circumventing the risk of uncontrolled glycaemia due to underlying SARS-CoV2 infection. Diabetics should be counselled regarding self-care including strict glycaemic control (plasma glucose concentration between 72 and 144 mg/dl and HbA1c <7%) and adequate control of lipids and blood pressure. Thus, these patients should continue their anti-hypertensive treatment such as ACE inhibitors and angiotensin-II receptor blockers due to its defensive role against SARS-CoV2 virus-induced ACE2/Mas receptor-mediated severe lung injury. In addition, those on statin treatment should continue due to their anti-inflammatory action and long-term benefit to the patient. They are recommended to maintain contact with their medical practitioners through telemedicine when required to practice social distancing. Telemedicine involves the delivery of healthcare services from a distance through utilisation of telecommunication technologies, such as telephone consultations and video call consultations. Through proper monitoring of blood pressure and blood sugar levels, telemedicine would help in the management of chronic conditions such as diabetes adequately at home. COVID-19 patients at risk of metabolic disease should be adequately monitored for the development of new-onset diabetes due to deranged glycaemic control due to underlying COVID-19 disease. COVID-19 patients with diabetes should have regular glucose monitoring (plasma glucose concentration between 72 and 180 mg/dl) with the estimation of serum electrolytes, pH and blood ketone bodies. In addition to this, early intravenous insulin therapy should be instituted in cases of severe COVID-19 disease accompanied by ARDS or cytokine storm. Such patients should be screened for laboratory parameters such as high-sensitivity C-reactive protein, high ferritin levels and low platelet counts to initiate their treatment with immunosuppressive drugs such as steroids and selective cytokine blockers. Patients on insulin therapy should have glucose monitoring every 2–4 h, and the dosage of insulin should be given according to type of diabetes, comorbidities and health condition of the patient. Obese COVID-19 patients with diabetes should be given special attention as they predisposed to heightened risk of ventilation failure due to limited lung volume pronounced in the supine position.,
| Conclusion|| |
Diabetes can increase the severity of complications, morbidity and mortality due to COVID-19, and therefore, glycaemic control in COVID-19 patients with diabetes should be strictly maintained. The core principle of the management of individuals with COVID-19 with diabetes or at a risk of metabolic disease includes need for preventing diabetes and circumventing the risk of uncontrolled glycaemia due to underlying SARS-CoV2 infection. Diabetics should be counselled regarding strict glycaemic control and adequate control of lipids and blood pressure. Since COVID-19 patients are at a risk of metabolic disease, they should be adequately monitored for the development of new-onset diabetes, due to deranged glycaemic control in such patients.
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Conflicts of interest
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[Table 1], [Table 2], [Table 3]