Understanding the Interplay between COVID-19 and Diabetes Mellitus

COVID-19 pandemic has shown greater severity in people with co-morbidities; diabetes being the leading cause of higher mortality rates in COVID-19 patients. Besides compromised immunity, there are other factors that make diabetics more prone to SARS-CoV-2 infection. To date, there is no clinically proven treatment for this disease, but fortunately there are several reports of vaccines in different stages of development. This review compiles some commonly used anti-diabetic drugs and their probable efficacy during a COVID-19 attack. This is also an attempt to understand the cause of severity of SARS-CoV-2 infection in diabetic patients. Until a proper cure or approved vaccine is available, it is best to manage the disease by improving the immune status and making use of already available drugs that show potential against the virus.


Introduction
The year 2020 started with the onset of a viral infection called the novel corona virus disease , caused by severe acute respiratory syndrome corona virus 2 (SARS-CoV-2). The first case was reported in December 2019 and the disease was declared a pandemic by March 2020. The virus has spread worldwide infecting millions of people to date [1]. Fortunately, the recovery rate is high and the death rate is low. Although only a few people become critically ill, the virus is a huge problem for people having a weak immune system. They in-rashes, and/or discolouration of fingers or toes. Interestingly the disease may or may not be symptomatic and the symptoms, if any may take up to 2 -14 days to become visible. The virus spreads in the form of droplets dispersed in the air while an infected person coughs, sneezes and even talks. This pathogen can survive on surfaces the duration varying from a few hours up to a few days depending on the environmental conditions and the type of surface [1].
Although scientists and doctors worldwide are working hard to prepare effective vaccines and drugs, unfortunately, to date there is no specific treatment available for COVID-19. The only best option is prevention and management that includes travel restrictions, patient isolation, and supportive medical care.
The present review is an attempt to understand COVID-19 and its interplay with diabetes mellitus. Since, this virus is novel, not much has been reported regarding its severity in patients having pre-existing non-communicable diseases like diabetes. For better treatment strategies, it is pertinent that we understand the reasons for the development of COVID-19 complications in immunocompromised patients. Since there are no effective treatment options for COVID-19, doctors have been prescribing drugs that are either approved for other conditions or have been tested against viral infections other than SARS-CoV-2.

SARS-CoV-2 and COVID-19
Coronaviruses are a group of large, enveloped, RNA viruses. Their genome (27 -32 kb) is packed inside a helical capsid formed by nucleocapsid proteins enclosed within another envelope. At least three structural proteins are found associated with the viral envelope. The membrane proteins and the envelope proteins are involved in the assembly of viral bodies. The spike proteins form surface protrusions giving a crown-like appearance to the virus and help in the entry of virus particles into the host cells. They also help in deciding which host to invade and are majorly responsible for the induction of host immune responses.
Understanding the structure and function of spike proteins, and their interaction with the host, will help in the management of SARS-CoV-2 infection. Several coronaviruses also encode an envelope-associated hemagglutinin-esterase protein [3]. The spike proteins of SARS-CoV-2 fit into the ACE2 receptors (angiotensin-converting enzyme 2) present on human cell surfaces initiating a structural change that causes the fusion of viral membranes with the host cell membranes. This allows the entry of viral genes into the host cell where they are replicated into multiple copies producing manifold viruses. The genome sequence has been published and tremendous research work is going on throughout the world to unravel the mechanism of infection and an effective cure for are similar, the antibodies generated against the old virus were unable to successfully bind to the spikes of the new virus suggesting that completely different antibody based treatment strategies would be required [6]. Understanding the infection mechanism by which the virus invades and damages the human host are crucial to the identification of therapeutic and diagnostic strategies so that the disease can be predicted before it becomes fatal. Several studies have been reported that attempt to explain the mechanism of SARS-CoV-2 infection. It has been suggested that the infection mechanism involves binding of the virus to the ACE2 receptors present on epithelial cells of the host lungs, kidney, intestine and blood vessels and their consequent internalization. In fact the severity of the disease has been linked to type 1 integral membrane glycoproteins. There are two forms of ACE2 receptors-glycoproteins and metalloproteases. The membrane-bound glycoproteins contain a transmembrane domain and an extracellular domain while metalloproteases are soluble and are secreted outside [7]. The significance of soluble circulating ACE2 is not clear, but studies suggest that their levels increase in chronic diseases such as diabetes, chronic kidney diseases, and hypertension [8]. The substrates for ACE2 include kinins, apelin, neurotensin, dynorphin, ghrelin, amyloid, and angiotensin. It regulates angiotensin II (Ang II) by converting Ang I into Ang-(1-9), and degrading Ang II into Ang-(1-7), a vasodilatory and anti-proliferative peptide which protects the tissues [9]. Besides ACE2, SARSCoV-2 uses the TMPRSS2 (transmembrane protease serine 2) gene for spike protein priming. Both the genes are expressed in the lungs, epithelial cells of small intestine, upper oesophagus, liver, colon, blood vessels, heart, kidneys, and the gonads. Since the receptors are widely distributed on several organs and tissues, the infection could cause multiple organ failure [9] [10] [11].
Studies suggest that the virus attacks the haemecomponent of the β chain of haemoglobin dissociating the iron to form the porphyrin and reduces the capacity of haemoglobin to carry oxygen and carbon dioxide [12]. Another more accepted mode of infection points towards the inflammatory cascades, cytokine storms, and activation of coagulation cascades on entry of the virus into the human body. These cascades lead to severe and often fatal complications, such as sepsis, disseminated intravascular coagulation (DIC), and acute cardiovascular events [13].
it can lead to blindness, kidney failure and lower-limb amputations. The disease results due to insufficient insulin secretion and/or insulin resistance. This chronic disease is one of the principal causes of morbidity and mortality throughout the world. At present 10.5% of the U.S. population is diabetic [14].
According to WHO, the rate of diabetes in Saudi Arabia is the second highest in Middle Eastern countries, and seventh in the world [15]. Approximately 463 million people, in the age group of 20 -79 years, were estimated to be living with diabetes last year in 2019 [16]. Diabetes was presented as a risk factor for mor-  [18]. It has been shown that COVID-19 deteriorates dysglycemia in diabetic patients [19].
Innate immune response, the first line of defence against SARS-CoV-2, is compromised in patients with uncontrolled diabetes, and hence the virus proliferates easily in the host without any hindrance. Moreover, there is an exaggerated cytokine response which leads to overproduction of pro-inflammatory cytokines, particularly interleukins IL-1, IL-6 and tumour necrosis factor-α. Similarly, patient with chronic obstructive pulmonary disease, have low levels of cytokine production, specifically interferon-β. This weakens host defence against coronavirus [19]. Besides, the activation of renin angiotensin system (RAS) con-  [19]. Upregulation of ACE2 seems to facilitate COVID-19 infection but interestingly the overall ACE2 expression is reduced in patients with diabetes due to the drugs that are commonly prescribed to patients. These drugs are often ACE inhibitors and angiotensin receptor blockers [21]. Hence, ACE2-stimulating drugs may be the primary cause of severity of COVID-19 disease observed in patients with metabolic co-morbidities [19].

Management and Preventive Measures
Diabetes is increasing at an alarming rate in most countries.  [23]. There are several reports where usage of drugs like lopinavir, ritonavir, interferon β-1b, RNA polymerase inhibitor remdesivir, and chloroquine have been advised although their efficacy is still doubtful and not confirmed [24]. SARS-CoV-2 has receptors that strongly bind to ACE2 and hence, as discussed earlier, RAS inhibition may play a role in the treatment of severe respiratory diseases [25] [26]. There are some antivirals that show promising effects against other viruses. Zinc nanoparticles have been shown to inhibit H1N1 but have not been tested against SARS-CoV-2 [27].
Similarly, Vitamin C, which showed a positive effect in the prevention of pneumonia, should be evaluated against COVID-19 [28]. Dexamethasone, a corticosteroid used for the treatment of many conditions like asthma, allergies etc, has been recommended for use in COVID-19 patients by WHO and many health organisations. Caution must be taken in using it against diabetic patients as this anti-inflammatory drug may increase blood glucose levels [29].
Metformin is a widely prescribed drug that lowers blood sugar levels in type 2 diabetes patients. It is also prescribed to those who have risk of developing this metabolic disorder due to obesity and other conditions. Metformin stimulates AMPK pathway. It has been reported that AMPK increases the expression of phosphorylated ACE-2 Ser 680 in HEK293T cells. Addition of a phosphate group leads to conformational changes in ACE-2 receptor and prevents its activation.
Also, it inhibits mTOR via liver kinase B1 pathway which plays an important role in MERS-CoV infection. It is hypothesised that metformin affects this pathway in SARS-CoV-2 infection, but more data is needed to confirm this [30] [31] [32]. Some reports interestingly claim that metformin has the ability to reduce inflammatory response and may help in reducing mortality rates [30] [33].
In the absence of any specific treatment or vaccine, these drugs should be used but only after careful analysis of their effect on both the virus and host. [34].
Miglitol, celgosivir and miglustat are some drugs that need to be evaluated as treatment options against COVID-19 [35]. Table 1 is a compilation of commonly used antidiabetic drugs and their effect, if any, on COVID-19. Research is also going on to use the spike proteins of SARS-CoV-2 as potential candidates for the development of vaccines. Antibodies generated against these proteins, isolated from patients after recovery are used as a treatment option. Vaccines play a major role in containing the pandemic. Their development is in progress and till then we have to depend on available drugs and various treatment strategies.

Conclusion
The health systems of several countries are hard-pressed due to the COVID-19 against COVID-19, it is convenient to repurpose already approved drugs or drugs undergoing clinical trials. The mechanism of action, and antiviral targets need to be further evaluated. Patients with co-morbidities like diabetes are definitely at higher risk and hence need special attention. Thus, it is imperative that people with diabetes mellitus take all necessary precautions and ensure good glycemic control amid the ongoing pandemic. Further studies are required that will help in the development of effective vaccines to completely eradicate these pathogens.