Covid-19 and Diabetes Mellitus: A Life-Threatening Reciprocal Association
Preeti Sharma*, Afreen Arshad Choudhry, Pradeep Kumar, Tapan Mahapatra
Abstract
COVID-19 has taken the world by storm and is now posing as a massive burden on the healthcare services of the world. Another long-standing global epidemic is Diabetes mellitus and Diabetics who get infected with COVID-19 have been seen to have worse outcomes and a high non-survival rate. The global focus is to control the pandemic for which diabetes has proved to be a vulnerable group. The present review aimed to assemble the information about Diabetes mellitus and COVID-19 mainly focusing on the interrelation of pandemics of the past and Diabetes mellitus, possible pathophysiological mechanisms governing COVID-19 in diabetics, the effect of COVID-19 infection on underlying Diabetes mellitus, morbidity, and mortality in diabetic COVID-19 patients and finally the management of Diabetes mellitus in the current pandemic.it is concluded that this COVID-19 pandemic is still lurking and it is of great importance to highlight the fact that a high percentage of the population of the world is affected by various comorbidities like diabetes mellitus, hypertension, COPD, obesity, etc which makes a subset of the population more vulnerable. This vulnerable population is at increased risk for a poor outcome if affected by COVID-19. Hence, we as a society should prioritize this population at risk to avoid adding additional burden to the already overburdened health care system in the present COVID-19 scenario.
Keywords: COVID-19, SARS-Cov-2, Diabetes mellitus, Co morbidities, CVD
Introduction
COVID-19 has taken the world by storm and is now posing as a massive burden on the healthcare services of the world. The alleged epicenter of COVID-19is Wuhan, China, from where it is known to have originated and spread (Magomedova et al., 2020; Siyal et al., 2020). As of 20th January 2021, there have been 100,42,2489 COVID-19 infected cases and 2,15,3587 deaths due to COVID-19 worldwide. Recent studies show that Diabetes mellitus, hypertension, cardiovascular diseases, and Chronic obstructive pulmonary disease (COPD) are the co morbidities commonly present in COVID-19patients and are responsible for an unfavorable outcome (Guan et al., 2020; Lian et al., 2020).
Another long-standing global epidemic is Diabetes mellitus. According to International Diabetes Federation, presently there are 463 million diabetics in the world which poses an expenditure burden of USD 760 billion on health services of all parts of the world (International Diabetes Federation, 2019). Diabetics who get infected with COVID-19 have been seen to have worse outcomes and a high non-survival rate (Pal & Bhadada, 2020). The global focus is to control the pandemic for which diabetes has proved to be a vulnerable group.
Aim
The present review aims to assemble the information about Diabetes mellitus and COVID-19. It mainly focuses on the interrelation of pandemics of the past and Diabetes mellitus, possible pathophysiological mechanisms governing COVID-19 in diabetics, the effect of COVID-19 infection on underlying Diabetes mellitus, morbidity, and mortality in diabetic COVID-19 patients, and finally the management of Diabetes mellitus in the current pandemic.
Materials and Methods
The literature search was done in the Pubmed database and Google Scholar using the keywords COVID-19 and Diabetes mellitus. Information in the published articles was included in the present review. The updated data onCOVID-19 and Diabetes mellitus was taken from the official websites of the World Health Organization (WHO), International Diabetes Federation (IDF), and Centre for Disease Control and Prevention (CDC). This review is updated till the time of writing which however might change at a later date as the data is still evolving.
Results and Discussion
The interrelation of the Acute Viral Pandemics of the Past and Diabetes Mellitus
The long-term complications associated with Diabetes mellitus are associated with diminished immune responses. This increases mortality and morbidity in the case of acute infections (Akbar, 2001) Previous studies have documented that HbA1c levels greater than 9%, have been associated with critical pneumonia and acute hospitalization in case of bacterial infections. Diabetes was also associated with complications during the outbreak of Severe Acute Respiratory Syndrome (SARS Cov 1) during 2002-2003 (Yang et al., 2006; Allard et al., 2010). Also, a higher degree of risk for ICU admission was seen in Diabetics during Influenza (H1N1) infection outbreak in 2009. Similarly, during the 2012 Middle East Respiratory Syndrome coronavirus outbreak, a morbidity rate of as high as 35% was seen in Diabetics (Al-Tawfiq et al., 2014; Alraddadi et al., 2016; Badawi & Ryoo, 2016).
Possible Pathophysiological Mechanisms Governing COVID-19 in Diabetes Mellitus
Recent updates in studies have supported the preconceived idea that COVID-19 infection in Diabetics can lead to severe complications with an increased risk of admission to ICU, need for ventilator support, and death. However, the severity cannot be predicted based on the type of diabetes and that poor prognosis is seen in both; Type 1 and Type 2 diabetes (Jafar et al., 2016).
Various possible pathophysiological mechanisms can be used to support the interrelationship of Diabetes mellitus and COVID-19 severity. It has been seen that diabetic COVID-19patients have a significantly higher level of IL 6, CRP, and ferritin when compared to COVID-19 patients without Diabetes mellitus. This suggests that COVID-19 patients with Diabetes mellitus are more susceptible to an exaggerated cytokine response. This could lead to shock, acute respiratory distress, and rapid deterioration in the stability of the COVID-19 patient (Guo et al., 2020).
Also, it has been documented that the D dimer levels are higher in diabeticCOVID-19 patients. This highlights the fact the hemostatic mechanism is already in an activated state in diabetic individuals. This prothrombotic hypercoagulable state can lead to serious thromboembolic complications hence reducing the chances of recovery and survival (Hussain et al., 2020).
It is also of importance that the functioning of the innate immune system, which is the first line of defense against infections like SARS-COV-2, is compromised in uncontrolled Type 2 Diabetes mellitus.
Additionally, there is reduced expression of Angiotensin-converting enzyme 2 (ACE 2) in Diabetes mellitus. Studies have shown that ACE 2 has a protective role against the avian influenza H5N1 infection. Therefore, low expression of ACE in Diabetes mellitus explains the severe lung injury and ARDS with COVID-19 (Zou et al., 2014; Tikellis & Thomas, 2012).
ACE inhibitors and Angiotensin receptor blockers (ARBs) are used as antihypertensive drugs especially in diabetics. There is an increased expression of ACE 2 by the use of drugs based on the aforementioned mechanism. The SARS-Cov-2 virus uses ACE 2 as a receptor for entry into the host pneumocytes. Thus, upregulation of ACE facilitates the entry followed by proliferation of the coronavirus. However, once the virus enters the host cell via the ACE, the ACE 2 gets down-regulated and is now unable to protect against acute lung injury (Cure & Cure, 2020).
Another theory states that the non-structural proteins of the SARS-Cov-2attack the beta chain of hemoglobin, leading to the uncoupling of Iron atoms from the porphyrin ring. This in turn decreases theoxygen-carrying capacity of hemoglobin (Liu & Li, 2020).
Effect of COVID-19Infection on Underlying Diabetes Mellitus
It was reported by Yang et al. that patients suffering from SARS, caused due to SARS CoV (same family as SARS-Cov-2) had a higher fasting plasma glucose and worsening of glycemic control when compared to patients with non-SARS pneumonia. This could be explained by the damage of the pancreatic beta cells by the SARS CoV virus as the ACE 2 receptors are also expressed on the pancreatic islets. Also, studies showed that SARS CoV was also identified in the pancreas of patients who died due to SARS CoV (Yang et al., 2006; Yang et al., 2010).
Additionally, COVID-19 can increase insulin resistance by induction of a pro-inflammatory state. Also, obesity which is commonly present in Type 2 Diabetes mellitus can further stimulate the cytokine response, that further decreases insulin sensitivity (Wan et al., 2006; Kassir, 2020).
COVID-19has also been linked to the down regulation of ACE 2 receptors in the lungs thereby reduced the degradation of Angiotensin 2 and increased aldosterone secretion. This leads to hypokalemia that worsens the glycemic control in diabetic patients (Liamis et al., 2014; Pal & Bhadada, 2020).
COVID-19 outbreak has lead to nationwide lockdowns which has reduced outdoor activity. This leads to reduced exposure to sunlight which has added to vitamin D deficiency already prevalent in the population. As vitamin D increases insulin sensitivity, its deficiency can lead to worsening of the glycemic status in diabetic patients (Szymczak-Pajor & Śliwińska, 2019; Carter et al., 2020).
Also, the drugs used in the management of ARDS and sepsis of COVID-19 patients have an indirect effect on the glycemic status of the diabetic COVID-19 patients. Some drugs like corticosteroids, Ritonavir/ Lopinavir, Azithromycin, Interferon-beta 1 have a hyperglycemic effect whereas others like chloroquine, Tocilizumab showed an improvement in glucose profile (Table 1) (Nakamura et al., 2011; Chou et al., 2013; Epperla & McKiernan, 2015; Gautret et al., 2020; Sallard et al., 2020).
All these factors show that covid-19 in Diabetic patients leads to exacerbation of glycemic control which further compromises the existing immunity with the spawning of pro-inflammatory cytokines thereby generating a ferocious cycle (Figure 1).
Table 1. Metabolic Effects of Drugs Used in the Management of COVID-19.
|
Drugs |
Mechanism of action of drugs |
Effect on glycemic status |
Effect on Lipid profile |
|
Corticosteroids |
Anti-inflammatory |
Hyperglycemia |
Increase in TC, LDL, TG |
|
Ritonavir/ Lopinavir |
Protease inhibitors |
Hyperglycemia |
Increase in TC,TG |
|
Azithromycin |
Macrolide antibiotic |
Variable effect |
Unspecified |
|
Tocilizumab |
Monoclonal antibody against IL-6 |
Improves glucose profile |
Increase in TC, HDL, TG, no change in LDL |
|
Chloroquine |
Prevents viral entry and immunomodulator |
Improves glucose profile |
A decrease in TC, LDL, TG |
|
Interferon-beta 1 |
Adaptive immune response stimulator |
Causes autoimmune b -cell damage that leads to hyperglycemia. |
Increase in TG |
|
|
|
Figure 1. Reciprocal interaction between COVID-19 and Diabetes mellitus. |
Morbidity and Mortality in Diabetic COVID-19Patients
Recently published data shows that COVID-19 patients with diabetes have a worse outcome when compared to non-diabetic COVID patients. Also, more COVID admissions are recorded in patients with co morbidities especially diabetes mellitus.
In the study conducted in the United States, Bhatraju et al. showed that 58% of the total number of the COVID-19 subjects had diabetes mellitus (Bhatraju et al., 2020). Other studies, mainly conducted in Italy showed the presence of Diabetes mellitus in 33-36% of COVID-19 patients (Onder et al., 2020). Most of the studies were conducted in China where the percentage of COVID-19 patients with diabetes ranged from 5-20% (Table 2). Additionally, the number of admissions in ICU was more for COVID-19 with diabetes when compared to non-diabeticCOVID-19 patients. Also, most of the non-survivorCOVID-19 patients were documented to be diabetic (Table 3) (Chen et al., 2020; Fu et al., 2020; Guo et al., 2020; Huang et al., 2020; Liu et al., 2020; Wang et al., 2020; Wu et al., 2020; Yang et al., 2020; Zhang et al., 2020; Zhou et al., 2020).
Table 2. Prevalence of Diabetes Mellitus in COVID-19Patients.
|
First author of the Study |
Total no. of patients |
% of patients with Diabetes |
|
COVID-19 in China |
|
|
|
Liu et al. (2020) |
61 |
8.2 |
|
Guo et al. (2020) |
187 |
15 |
|
Wu et al. (2020) |
201 |
10.9 |
|
Yang et al. (2020) |
52 |
17 |
|
Zhang et al. (2020) |
140 |
12.1 |
|
Zhou et al. (2020) |
191 |
19 |
|
Wang et al. (2020) |
138 |
10.1 |
|
Chen et al. (2020) |
99 |
12.1 |
|
Huang et al. (2020) |
41 |
19.5 |
|
Guan et al. (2020) |
1099 |
7.4 |
|
COVID-19 in Italy |
|
|
|
Ondu et al. (2020) |
355 |
35.5 |
|
COVID-19 in the USA |
|
|
|
Bhatraju et al. (2020) |
24 |
58 |
Table 3. Prevalence of Severe versus Non-severe and Survivor versus Non-survivor diabetic COVID-19 patients.
|
First author of the Study |
Total no. of patients |
% of patients with Diabetes |
Non severe (Non ICU) care (% of total) |
Severe (ICU care) (% of total) |
Diabetic Survivors of COVID-19 (% of total) |
Diabetic Non-Survivors of COVID-19 (% of total) |
|
Liu et al. |
61 |
8.2 |
4.5% |
17.6% |
NR |
NR |
|
Guan et al. |
1099 |
7.4 |
5.7% |
16.2% |
6.1% |
26.9% |
|
Wu et al. |
201 |
10.9 |
5.1% |
19% |
12.5% |
25% |
|
Zhou et al. |
191 |
19 |
NR |
NR |
14% |
31% |
|
Yang et al. |
52 |
17 |
NR |
NR |
22% |
10% |
|
Huang et al. |
41 |
19.5 |
8% |
25% |
NR |
NR |
NR- Not reported in the study
Management of Diabetes Mellitus in the Current COVID-19Pandemic and How can Society Help.
The pandemic is still out there and there is no stopping till there is a development of herd immunity or mass vaccination. In the absence of definitive therapy, unavailability of beds in the ICUs, slow phase-in of vaccinations; it is of utmost importance that individuals with Diabetes mellitus follow necessary precautions like physical distancing, hand hygiene, and use of alcohol-based hand rubs/wipes. However, reduced outdoor exposure would lead to hindrance in their regular health check-up, physical activity, and psychological health (Winchester et al., 2016; Mukhtar & Mukhtar, 2020).
Adhering to this requirement, telemedicine has been made available at most hospitals where patients would be able to consult their registered medical practitioner telephonically or on a digital platform. Many digital platforms are broadcasting regular exercise routines that can be tailored according to personal capacity (Banerjee et al., 2020; Ghosh et al., 2020). Neighbors and friends of diabetic individuals are being encouraged by government officials to help this vulnerable population. Help from the local population would help in the reduction of the ‘supermarket shopping time’. The IDF has recommended that diabetic individuals keep an adequate stock of medication, an instrument for blood glucose monitoring, and have a healthy diet laden with protein, fibre, vitamins, minerals, and limited saturated fats (Banerjee et al., 2020).
Conclusion
TheCOVID-19 pandemic is still lurking. It is of great importance to highlight the fact that a high percentage of the population of the world is affected by various co morbidities like diabetes mellitus, hypertension, COPD, obesity, etc which makes a subset of the population more vulnerable. This vulnerable population is at increased risk for a poor outcome if affected by COVID-19 (Fang et al., 2020; Pal & Bhadada, 2020).
Hence, we as a society should give more attention to this population at risk to avoid adding additional burden to the already overburdened health care system in the present COVID-19scenario.
Acknowledgments: All the authors duly acknowledge the support of the management of Santosh deemed to be University- Ghaziabad.
Conflict of interest: None
Financial support: The study was supported by the Department of Biochemistry, Santosh Medical College- Ghaziabad.
Ethics statement: This article is a review of the articles published pertaining to Covid 19 in Diabetes mellitus patients for which due citation has been given and permission taken from Institutional Ethics Committee.
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