CHAPTER ONE

1.0 INTRODUCTION

The CoronaVirus Disease 19 (COVID-19) is a pandemic infectious disease caused by the

novel coronavirus Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2).

Coronavirus Disease-19 (COVID-19) caused by a virus of the family Coronaviridae

(commonly known as Corona Virus), documented as SARS-CoV-2. According to past

studies, several severe diseases like Severe Acute Respiratory Syndrome (SARS) and the

Middle East respiratory syndrome (MERS) affected humans by viruses belonging to the same

Coronaviridae family. Likewise, SARS-CoV-2, SARS and MERS, HKU1, NL63 and OC43

viruses also belong to the family of Coronaviridae. The first outbreak of the coronavirus

reported in Wuhan city of China where bats were consumed as a food item and are assumed

the foremost reason to justify the outbreak of this novel virus. There are various theories

associated with the outbreak of this deadly virus. Novel coronavirus caused the disease to

have an identical genome sequence to the coronavirus found in the bats which are sold in

Wuhan city market (Guo et al., 2020). The worst part about this novel virus is that it spread

rapidly throughout the world, due to its high contagious nature and as per now, no effective

treatment is available for which made it more detrimental (Johns Hopkins coronavirus

Resour. Cent. 2020).

In medicinal sciences, comorbidity is mainly defined as a condition present concurrently;

however, individuals with an additional condition or a related medical condition. In simple

term, comorbidity defines the effect of all other situations an individual patient might have

other than the primary condition of interest and can be physiological or psychological.

American epidemiologist A. R. Feinstein first introduced the term comorbidity in the 1970s

(IDF, 2020). Older age and presence of comorbidities, including diabetes, were shown to be

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associated with a more severe course and a higher fatality rate. Studies from the most affected

countries, including China, United States and Italy, seem to indicate that prevalence of

diabetes among patients affected by COVID-19 is not higher than that observed in the general

population, thus suggesting that diabetes is not a risk factor for SARS-CoV-2 infection.

However, a large body of evidence demonstrate that diabetes is a risk factor for disease

progression towards critical illness, development of acute respiratory distress syndrome, need

for mechanical ventilation or admission to intensive care unit, and ultimately death. The

mechanisms underlying the relationship between COVID-19 and diabetes remain to be

elucidated. Among the various comorbidities like hypertension, cardiovascular disease and

chronic obstructive pulmonary disease, diabetes considered as one of the critical comorbidity,

which could affect the survival of infected patients. The severity of COVID-19 disease

intensifies in patients with elevated glucose level probably via amplified pro-inflammatory

cytokine response, poor innate immunity and down regulated angiotensin-converting enzyme

2. Thus, the use of ACE inhibitors or angiotensin receptor blockers could worsen the glucose

level in patients suffering from novel coronavirus infection. It also observed that the direct β-

cell damage caused by virus, hypokalemia and cytokine and fetuin-A mediated increase in

insulin resistance could also deteriorate the diabetic condition in COVID-19 patients.

Infection with SARS-CoV2 is characterized by a wide range of clinical presentations from

asymptomatic, yet contagious forms to severe and potentially lethal illness. As other

coronaviruses, SARS-CoV2 predominantly causes respiratory manifestations, including

flulike symptoms and interstitial pneumonia, which may rapidly progress to acute respiratory

distress syndrome (ARDS) requiring admission to intensive care unit (ICU) (Wiersinga et al.,

2020). However, other organs are also affected, especially the heart, liver, and kidneys, and

some patients eventually die of multi-organ failure (Wiersinga et al., 2020). Moreover,

ageusia and anosmia are characteristic, usually reversible symptoms of COVID-19, though it

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is unclear whether these disturbances are related to damage of taste and olfactory neurons

(Wiersinga et al., 2020). Other common manifestations of COVID-19 involve the

hematopoietic, hemostatic, and immune systems and include lymphopenia and

hypercoagulability, which correlate with disease severity (Chen et al., 2019). Lymphopenia is

associated with reduction in total T cells, CD4+ and CD8+ T cell subsets, B cells, and natural

killer cells (Wang et al., 2020) and overproduction of several pro-inflammatory cytokines,

which is often massive and may cause a “cytokine storm” (Mehta et al., 2020).

Hypercoagulability is evidenced by a characteristic elevation of D-dimer and other fibrin

degradation products and by prothrombin time prolongation (Tang et al., 2020).

Abnormalities in hemostasis may result in widespread thrombosis associated with

microvascular injury in the lungs and other affected organs (Ackermann et al., 2020) and may

even end-up with life-threatening disseminated intravascular coagulation (Tang et al., 2020).

A population-based study from Iceland has shown a lower incidence of SARS-CoV-2

infection in children and females compared to adolescents or adults and males (Gudbjartsson

et al., 2020). Among symptomatic individuals hospitalized for COVID-19, older age and

presence of comorbidities, including diabetes, obesity, hypertension, chronic obstructive

respiratory disease (COPD), cardiovascular disease (CVD), chronic kidney disease (CKD),

cancer, and immunodeficiency states, were shown to be associated with a more severe course

and a higher fatality rate (Jain et al., 2020; Tian et al., 2020).

The combination of a prolonged disease like diabetes and a severe viral infection like

COVID-19 gives a tough challenge to the medical profession to save lives. Diabetes mellitus

(DM) is a chronic disease that affects the global population. Both diabetes type 1 and 2 are a

family of diseases that results in elevated sugar level in the blood. When the body unable to

produce a sufficient amount of the hormone insulin, which helps the body to get glucose into

cells for energy, the glucose builds up in the blood. The overall diabetes occurrence in 2019

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projected to be 9.3% with a probable value of 463 million people suffering from the condition

(IDF, 2020; Wang et al., 2019). Patients with diabetes considered as high-risk patients for

acquired infections. The higher the glucose, the higher the risk of infections (Alves et al.,

2012). The vast majority of patients in the United States are not reaching glucose goals (70%)

(Iglay et al., 2016). Besides, most patients with diabetes develop over time, co-morbidities

that increase such risks. Hypertension, diabetes, cardiovascular disease (CVD) and obesity

are few known or common conditions related to metabolic syndrome, and altogether or

individually, they can be inclined towards a set of causes linked to COVID-19 pathogenesis.

Coronavirus does have a potential ability to destroy islets by their angiotensin-converting

enzyme 2 (ACE2) receptor present in islets and hence promote diabetes during the infection.

According to studies, the virus predominantly infects human by allowing the cells to enter

through the ACE2 receptor (Wu et al., 2008). Due to insufficient genetic data, the existence

of coronavirus S-protein binding resistant towards ACE2 still a mystery (Cao et al., 2020).

Dysglycemia is well known to downregulate critical mediators of the innate immune response

of the host to pathogenesis. Patients associated with hyperglycaemia, diabetes and

insulinopenia deliberately disabled the host innate and humoral immune system by

weakening the synthesis of pro-inflammatory cytokines along with their downstream acute

phase reactant.

In addition, immune responses get reduced by impairing lymphocyte and macrophage

functions due to metabolic disorders which afterwards render patients more likely to be

affected by the infectious disease (Dooley and Chaisson, 2009). Though limited data is there

regarding COVID-19 patients with diabetes Wuhan shows 42.3% of 26 fatalities due to

COVID-19, where patients have diabetes (Deng and Peng, 2020). The Wuhan city of China

conducted studies where it is found that diabetes was not a significant predictor of mortality

in one study group of 140 patients with COVID-19 (Jin et al., 2020). Whereas, another group

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of 150 patients were 68 deaths cases and 82 recovered patients were reported showed that the

number of co-morbidities to be a risk factor for severe disease course (Ruan et al., 2020).

Evaluation of 11 studies associating laboratory abnormalities in COVID-19 patients did not

report diabetes or raised blood glucose level as a risk factor (Lippi and Plebani, 2020). Apart

from all these contradictory data and reports, Chinese Centre for Disease Control and

Prevention published a report where they showed all over 72,314 cases of COVID-19 and

showed increased mortality rate in people with diabetes (2.3%, overall and 7.3%, patients

with diabetes) (Z and JM, 2020). Agreeing with Current Diabetes Review, type 2 diabetes

increase the incidence of infectious diseases and related comorbidities, and type 1 also do the

same (Endocrine web, 2020).

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 CHAPTER TWO

2.0 DIABETES MELLITUS

Diabetes mellitus is a disorder that affects the body’s ability to make or use insulin. Insulin is

a hormone produced in the pancreas that helps transport glucose (blood sugar) from the

bloodstream into the cells so they can break it down and use it for fuel. People cannot live

without insulin (ADA, 2007).

Diabetes results in abnormal levels of glucose in the bloodstream. This can cause severe

short-term and longterm consequences ranging from brain damage to amputations and heart

disease (ADA, 2007).

2.1 Root causes of diabetes mellitus (DM)

The root causes of diabetes are complex. Most cases begin with one of two processes:

Metabolic: Unhealthy lifestyle factors such as overeating, physical inactivity and obesity can

impair the body’s ability to use insulin. This is called insulin resistance.

Uncontrollable risk factors including genetics, family history and age can also be involved.

Metabolic forms of diabetes include:

Type 2 diabetes: This accounts for 90 - 95% of diabetic cases, according to the U.S. National

Institutes of Health (NIH). Some of these patients have had prediabetes that went

uncontrolled. Once considered a disease of middle and old age, type 2 is also becoming more

common in youths as the incidence of childhood obesity grows.

Gestational diabetes: Hormonal changes contribute to this condition which can develop in

any previously nondiabetic woman during pregnancy, especially those who are overweight.

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 AUTOIMMUNE

The body’s immune system can mistakenly destroy the insulin-producing beta cells of the

pancreas. The causes of autoimmune diabetes are poorly understood, but genetics and family

history play a role, and viruses or other environmental factors are believed to figure in.

Autoimmune forms of diabetes include:

Type 1 diabetes: Formerly known as juvenile diabetes, this form generally develops in

children and young adults.

Latent autoimmune diabetes of adulthood: This variation of type 1 can occur later in life.

Individuals with autoimmune diabetes who overeat, are sedentary, gain weight or have

certain genes can, like people with metabolic forms of diabetes, develop insulin resistance.

This state is known as double diabetes.

Diabetes can also result from another disease, such as pancreatitis, or even from a medical

treatment, including pancreatectomy (surgical removal of the pancreas) or certain

medications. This is known as secondary diabetes. In addition, there are uncommon inherited

disorders that cause diabetes, such as maturity-onset diabetes of the young and Wolfram

syndrome. Most cases of diabetes last the rest of a person’s life. However, gestational

diabetes generally ends when the pregnancy does, and some cases of secondary diabetes are

also temporary (Cefalu et al., 2007).

2.2 Factors that contributes in DM

Diabetes involves chronic levels of abnormally high glucose (hyperglycemia). Many patients,

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especially those with type 2 diabetes, also have elevated blood pressure (hypertension),

chronic high levels of insulin (hyperinsulinemia) and unhealthy levels of cholesterol and

other blood fats (hyperlipidemia). All of these factors contribute to the long-term

complications of diabetes, which include:

Vascular disease (diabetic angiopathy), atherosclerosis, heart conditions and stroke:

These cardiovascular disorders are the leading cause of death in people with diabetes.

Kidney disease (diabetic nephropathy): Diabetes is the chief cause of end-stage renal

disease, which requires treatment with dialysis or a kidney transplant.

Eye diseases: These include diabetic retinopathy, glaucoma and cataracts. Diabetes is a

leading cause of visual impairment and blindness.

Nerve damage (diabetic neuropathy): This includes peripheral neuropathy, which often

causes pain or numbness in the limbs, and autonomic neuropathy, which can impede

digestion (gastroparesis) and contribute to sexual dysfunction and incontinence. Neuropathy

may also impair hearing and other senses.

Impaired thinking: Many studies have linked diabetes to increased risk of memory loss,

dementia, Alzheimer’s disease and other cognitive deficits. Recently some researchers have

suggested that Alzheimer’s disease might be “type 3 diabetes,” involving insulin resistance in

the brain.

Infections and wounds: Foot conditions and skin disorders, such as ulcers, make diabetes

the leading cause of nontraumatic foot and leg amputations. People with diabetes are also

prone to infections including periodontal disease, thrush, urinary tract infections and yeast

infections.

Cancer: Diabetes increases the risk of malignant tumors in the colon, pancreas, liver and

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several other organs.

Musculoskeletal disorders: Conditions ranging from gout to osteoporosis to restless legs

syndrome to myofascial pain syndrome are more common in diabetic patients than

nondiabetics.

Pregnancy complications: Diabetes increases the risk of preeclampsia, miscarriage, stillbirth

and birth defects.

Emotional difficulties: Many but not all of the studies exploring connections between

diabetes and mental illness have found increased rates of depression, anxiety and other

psychological disorders in diabetic patients. In addition to chronic hyperglycemia, diabetic

patients can experience acute episodes of hyperglycemia as well as hypoglycemia (low

glucose). Severe cases can cause seizures, brain damage and a potentially fatal diabetic coma.

Acute glucose emergencies include:

Insulin shock: This advanced stage of hypoglycemia is typically due to excessive amounts of

insulin medication or certain antidiabetic agents.

Diabetic ketoacidosis: A lack of insulin can force the body to burn fats instead of glucose for

energy. The result is a toxic byproduct called ketones, along with severe hyperglycemia.

Hyperosmolar hyperglycemic nonketotic state: This involves severe hyperglycemia and

dehydration. These dangerous glucose complications are most common in patients with

unstable diabetes, but they can develop even in individuals who do not realize they have

diabetes. About one-third of the estimated 20.8 million Americans with diabetes have not yet

been diagnosed, according to the U.S. Centers for Disease Control and Prevention (CDCP,

2005).

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 2.3 Types and differences of diabetes

There are several forms of diabetes. Scientists are still defining and categorizing some of

these variations and establishing their prevalence in the population. Types of diabetes

include:

Type 1 diabetes: An autoimmune disease in which the immune system mistakenly destroys

the insulin-making beta cells of the pancreas. It typically develops more quickly than other

forms of diabetes. It is usually diagnosed in children and adolescents, and sometimes in

young adults. To survive, patients must administer insulin medication regularly. Type 1

diabetes used to be called juvenile diabetes and insulin-dependent diabetes mellitus (IDDM).

However, those terms are not accurate because children can develop other forms of diabetes,

adults sometimes develop type 1, and other forms of diabetes can require insulin therapy.

A variation of type 1 that develops later in life, usually after age 30, is called latent

autoimmune diabetes of adulthood (LADA).

Sometimes patients with autoimmune diabetes develop insulin resistance because of weight

gain or genetic factors. This condition is known as double diabetes.

Type 2 diabetes: A disorder of metabolism, usually involving excess weight and insulin

resistance. In these patients, the pancreas makes insulin initially, but the body has trouble

using this glucose-controlling hormone. Eventually the pancreas cannot produce enough

insulin to respond to the body’s need for it. Type 2 diabetes is by far the most common form

of diabetes, accounting for 85 to 95% of cases in developed nations and an even higher

percentage in developing nations, according to the International Diabetes Federation.

This disease may take years or decades to develop. It is usually preceded by prediabetes, in

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which levels of glucose (blood sugar) are above normal but not high enough yet for a

diagnosis of diabetes. People with prediabetes can often delay or prevent the escalation to

type 2 diabetes by losing weight through improvements in exercise and diet, as the Diabetes

Prevention Program and other research projects have demonstrated. Type 2 diabetes used to

be called adult-onset diabetes and non-insulin-dependent diabetes mellitus (NIDDM). Those

terms are not accurate because children can also develop this disease, and some patients

require insulin therapy.

Gestational diabetes: A temporary metabolic disorder that any previously nondiabetic

woman can develop during pregnancy, usually the third trimester. Hormonal changes

contribute to this disease, along with excess weight and family history of diabetes. About 4%

of pregnant women develop gestational diabetes, according to the American Diabetes

Association.

Gestational diabetes can cause problems for the mother and baby, including preeclampsia,

premature deli-very, macrosomia (oversized infant), and jaundice and breathing difficulties in

the infant. This disease typically ends when the pregnancy does, but it increases the risk of

type 2 diabetes later in life for the mother and the child.

Secondary diabetes: Diabetes caused by another condition. The many potential sources of

secondary diabetes range from diseases such as pancreatitis, cystic fibrosis, Down syndrome

and hemochromatosis to medical treatments including corticosteroids, other

immunosuppressives, diuretics and pancreatectomy.

Maturity-onset diabetes of the young (MODY). An uncommon disease caused by a genetic

defect inherited from a parent. It is usually diagnosed before age 25 in people of normal

weight. MODY is sometimes classified as a form of type 2 or secondary diabetes but is often

considered a separate condition.

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There are also rare syndromes (clusters of conditions) that include diabetes, notably:

Wolfram syndrome: A genetic disorder that involves insulin-dependent diabetes, vision

problems, deafness and diabetes insipidus.

Autoimmune polyglandular syndrome (APS): Group of autoimmune endocrine diseases.

Two of the three forms of APS feature type 1 diabetes. Unstable diabetes, also known as

brittle or labile diabetes, is a term that may be used to describe any case of poorly controlled

diabetes regardless of the type. All of these conditions involve diabetes mellitus (“sugar

diabetes”). Diabetes insipidus (“water diabetes”) is an unrelated endocrine system disorder in

which the kidneys release too much water (Frank, 2004; Jawa et al., 2004).

2.4 Risk factors and causes of diabetes

The causes of diabetes are complex and only partly understood. This disease is generally

considered multifactorial, involving several predisposing conditions and risk factors. In many

cases genetics, habits and environment may all contribute to a person’s diabetes.

To complicate matters, there can be contrary risk factors for the various forms of the disease.

For example, autoimmune diabetes (type 1 and latent autoimmune diabetes of adulthood,

LADA) is more common in white people, but metabolic diabetes (type 2 and gestational

diabetes) is more common in people of other races and ethnicities. Type 1 is usually

diagnosed in children, but advancing age is a risk factor for type 2 and gestational diabetes.

Insulin resistance, prediabetes and metabolic syndrome are strong risk factors for type 2

diabetes. Other diabetic risk factors and causes include:

Genetics and family history: Certain genes are known to cause maturity-onset diabetes of

the young (MODY) and Wolfram syndrome. Genes also contribute to other forms of

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diabetes, including types 1 and 2.

Family medical history is also influential to varying degrees: For example, a person

whose parents both have type 1 diabetes has a 10 to 25% chance of developing that disease,

according to the American Diabetes Association, and someone whose parents both have type

2 diabetes has a 50% chance of developing that disease.

Weight and body type: Overweight and obesity are leading factors in type 2 diabetes and

gestational diabetes. Excess fat, especially around the abdomen (central obesity), promotes

insulin resistance and metabolic syndrome.

Most people with autoimmune diabetes (type 1 and LADA) are of normal weight, and excess

weight has not traditionally been considered to be related to these conditions. However,

recent research indicates that obesity may hasten the development of type 1 diabetes and that

the increasing rate of type 1 diabetes may be at least partly due to the rise of childhood

obesity. Furthermore, patients with autoimmune diabetes who gain weight are susceptible to

insulin resistance and double diabetes.

Sex: Though men make up less than 49% of the U.S. adult population, they account for 53%

of the adult cases of diabetes, according to the National Institutes of Health (NIH). The

prevalence of diabetes in American men and women was similar until 1999, when a growing

disparity began, according to an analysis of statistics published by the U.S. Centers for

Disease Control and Prevention (CDC). Little or no research has been conducted to explain

this trend. One factor may be the documented increase in recent years of low testosterone

levels (male hypogonadism), which scientists have linked to insulin resistance.

Level of physical activity: Lack of regular exercise is blamed for much of the twin global

epidemics of obesity and diabetes.

Diet: The effect of diet in the development of diabetes is controversial. Some studies have

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linked heavy consumption of soft drinks and other simple carbohydrates to risk of metabolic

diabetes, and foods low in the glycemic index, such as whole grains, to reduced risk. Yet the

ADA states that eating foods containing sugar does not cause the disease. The culprit, rather,

is the weight gain due to sedentary habits and excess intake of calories, according to the

ADA.

Another dispute centers around whether being fed cow’s milk early in life might be linked to

type 1 diabetes. Some researchers have noted a connection, but others have not. Further

scientific research is likely on this topic.

Other diseases: Medical conditions including high blood pressure, hyperlipidemia

(unhealthy levels of cholesterol), polycystic ovarian syndrome, asthma and sleep apnea have

been linked to type 2 diabetes. Celiac disease (gluten intolerance) and other autoimmune

diseases have been linked to type 1. The many conditions that may cause secondary diabetes

include pancreatitis, hemochromatosis, endocrine disorders including hyperthyroiddism,

Cushing’s disease and acromegaly, and genetic conditions including cystic fibrosis, Down

syndrome and some forms of muscular dystrophy, Diabetic foot and urinary tract infection

(Lipsky et al., 2004; Mokabberi and Ravakhah, 2007).

Hormones: These chemical messengers can contribute to diabetes in various ways. For

example, stress hormones such as cortisol have been linked to fluctuating glucose levels in

type 2 diabetes, and stress hormones in women during pregnancy have been linked to risk of

type 1 diabetes in the child. The release of growth and sex hormones during adolescence may

make some teens more susceptible to diabetes. A wide range of hormonal treatments

including anabolic steroids, growth hormone, estrogens, injected contraceptives, androgen

deprivation therapy for prostate cancer and corticosteroids have been linked to secondary

diabetes.

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Medical treatments: In addition to hormonal therapies, medications including diuretics, beta

blockers (another class of antihypertensives), immunosuppressives, antiretrovirals

(AIDS/HIV drugs) antipsychotics, lithium, and some ant idepressants, anticonvulsants and

chemotherapy drugs have been linked to an increased risk of secondary diabetes.

Pancreatectomy and radiation therapy may also result in secondary diabetes. Drugs including

pentamidine (used to treat pneumonia) and L–asparaginase (used to treat leukemia) have been

linked to type 1 diabetes.

Other chemicals: In addition to these pharmaceuticals, some studies have linked PCBs, other

pollutants and certain pesticides including the defoliant Agent Orange and dioxin (its active

ingredient) to insulin resistance and type 2 diabetes. Common consumer plastics and plastics

ingredients including phthalates and bisphenol A have also been linked to insulin resistance

in some cases. Exposure to agricultural pesticides during pregnancy has been tentatively

linked to gestational diabetes. A rat poison called pyriminal has been linked to type 1

diabetes.

Other environmental factors: Some researchers theorize that free radicals may contribute to

the development of type 1 and possibly other forms of diabetes. Free radicals are formed as a

result of chemical reactions in the body. Smoke, air pollution and even genetics contribute to

the formation of free radicals. When these radicals build up, they can destroy cells, including

those involved in the production of insulin. Cold weather is another possible environmental

factor in type 1 diabetes. This disease occurs more commonly in cold climates and develops

more frequently in the winter than the summer.

Viruses: Some people are diagnosed with type 1 diabetes after a viral infection. Viruses

thought to be related to type 1 diabetes include mumps, rubella and coxsackie virus (related

to the virus family that causes polio and hepatitis).

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Smoking: Cigarette smoking is a risk factor for type 2 diabetes and possibly other forms of

diabetes.

Alcohol: Excessive use of alcohol is a risk factor for diabetes. For example, it can cause

pancreatitis. However, some research has found that light drinking may decrease the risk of

becoming diabetic. Most of these risk factors can be described as either uncontrollable, such

as genetics and age, or controllable, such as exercise and diet. Some, such as obesity, may

involve genetics and lifestyle choices. People cannot alter their uncontrollable risk factors,

but they can lower their risk of developing diabetes by reducing controllable risk factors

through improved health habits.

2.5 Signs and symptoms of diabetes

Diabetes often goes undetected because symptoms can be attributed to many other causes and

some patients experience no symptoms or fail to heed warning signs.

Possible indicators of diabetes include:

- Excessive thirst (polydipsia)

- Excessive urination (polyuria) and dehydration

- Excessive hunger or appetite (polyphagia)

- Unexplained weight loss

- Blurred vision, nearsightedness or other vision problems

- Frequent infections, including skin infections, thrush, gingivitis, urinary tract infections and

yeast infections

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- Slow healing of sores

- Skin problems, such as itchiness or acanthosis nigricans

- Fatigue, lethargy or drowsiness

- Shakiness or trembling

- Mood swings or irritability

- Dizziness or fainting

- Numbness, tingling or pain in the feet, legs or hands

Type 1 diabetes can develop rapidly and often occurs after an illness, but symptoms may be

mistaken for the flu or other common conditions. Type 2 diabetes can take many years to

develop and sometimes becomes apparent only after long-term complications occur, such as

sexual dysfunction or leg pain that is due to diabetic neuropathy or claudication (caused by

peripheral artery disease). Some people, especially young people with type 1 diabetes, go

undiagnosed until they are brought to a hospital with an emergency condition called diabetic

ketoacidosis. Indicators of diabetic ketoacidosis include sweet fruity-smelling or wine-

smelling breath, confusion and heavy labored breathing (Kussmaul breathing). Sometimes

patients are diagnosed with diabetes only after suffering other serious complications

including insulin shock, hyperosmolar hyperglycemic nonketotic syndrome or diabetic coma.

To help prevent such complications, people are advised to undergo periodic screening for

diabetes with glucose tests, especially if they have risk factors.

2.6 Diagnosis methods for diabetes

Physicians use glucose tests to diagnose diabetes. These blood tests measure the level of

17
glucose (blood sugar) in a person’s bloodstream. Often when people have a physical

examination they are screened for diabetes with a fasting plasma glucose test (FPG). An FPG

is usually performed in the morning because this makes it easier for the patient to fast for the

required eight hours. Glucose is measured in milligrams per deciliter (mg/dl) of blood. FPG

results below 100 mg/dl are normal. Glucose between 100 and 125 mg/dl is considered

prediabetes. Glucose above 125 mg/dl indicates diabetes. To confirm diagnosis, another

glucose test should be performed on another day, according to the National Institute of

Diabetes and Digestive and Kidney Disorders. If glucose testing determines that a patient has

diabetes, additional tests may be offered to establish the type. For example, a C-peptide test

can distinguish autoimmune from metabolic diabetes. People with type 2 diabetes have C-

peptide, which is a byproduct of insulin production, but people with type 1 diabetes and latent

autoimmune diabetes of adulthood do not nor have a very low level. Autoantibody testing can

reveal misguided antibodies present in autoimmune but not metabolic diabetes. Genetic tests

can help diagnose conditions such as maturity-onset diabetes of the young and Wolfram

syndrome.

Other tests, such as thyroid blood tests, may be ordered to find the cause of secondary

diabetes.

During pregnancy, usually during the 24th to the 28th week, women may be screened for

gestational diabetes with a glucose challenge test, which evaluates the body’s ability to

metabolize sugar. Blood is drawn an hour after the patient drinks a solution containing 50 g

of glucose. If results are abnormal, an additional, more complicated blood test called an oral

glucose tolerance test (OGTT) is used to confirm diabetes (Peters et al., 1996).

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 CHAPTER THREE

3.0 CORONA VIRUS (COVID-19)

Coronaviruses belong to the Coronaviridae family in the Nidovirales order. Corona represents

crown-like spikes on the outer surface of the virus; thus, it was named as a coronavirus.

Coronaviruses are minute in size (65–125 nm in diameter) and contain a single-stranded

RNA as a nucleic material, size ranging from 26 to 32kbs in length . The subgroups of

coronaviruses family are alpha (a), beta (b), gamma (c) and delta (d) coronavirus.

The severe acute respiratory syndrome coronavirus (SARS-CoV), H5N1 influenza A, H1N1

2009 and Middle East respiratory syndrome coronavirus (MERS-CoV) cause acute lung

injury (ALI) and acute respiratory distress syndrome (ARDS) which leads to pulmonary

failure and result in fatality. These viruses were thought to infect only animals until the world

witnessed a severe acute respiratory syndrome (SARS) outbreak caused by SARS-CoV, 2002

in Guangdong, China (Zhong et al., 2003). Only a decade later, another pathogenic

coronavirus, known as Middle East respiratory syndrome coronavirus (MERS-CoV) caused

an endemic in Middle Eastern countries (Wang et al., 2013).

Recently at the end of 2019, Wuhan an emerging business hub of China experienced an

outbreak of a novel coronavirus that killed more than eighteen hundred and infected over

seventy thousand individuals within the first fifty days of the epidemic. This virus was

reported to be a member of the b group of coronaviruses. The novel virus was named as

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Wuhan coronavirus or 2019 novel coronavirus (2019-nCov) by the Chinese researchers. The

International Committee on Taxonomy of Viruses (ICTV) named the virus as SARS-CoV-2

and the disease as COVID-19 (Cui et al., 2019; Lai et al., 2020; WHO, 2020). In the history,

SRAS-CoV (2003) infected 8098 individuals with mortality rate of 9%, across 26 contries in

the world, on the other hand, novel corona virus (2019) infected 120,000 induviduals with

mortality rate of 2.9%, across 109 countries, till date of this writing. It shows that the

transmission rate of SARS-CoV-2 is higher than SRAS-CoV and the reason could be genetic

recombination event at S protein in the RBD region of SARS-CoV-2 may have enhanced its

transmission ability.

3.1 Key features and entry mechanism of human coronaviruses

All coronaviruses contain specific genes in ORF1 downstream regions that encode proteins

for viral replication, nucleocapsid and spikes formation (Van Boheemen et al., 2012). The

glycoprotein spikes on the outer surface of coronaviruses are responsible for the attachment

and entry of the virus to host cells. The receptor-binding domain (RBD) is loosely attached

among virus, therefore, the virus may infect multiple hosts (Raj et al., 2013; Pearlman and

Netland, 2007). Other coronaviruses mostly recognize aminopeptidases or carbohydrates as a

key receptor for entry to human cells while SARS-CoV and MERS-CoV recognize

exopeptidases (Wang et al., 2013). The entry mechanism of a coronavirus depends upon

cellular proteases which include, human airway trypsin-like protease (HAT), cathepsins and

transmembrane protease serine 2 (TMPRSS2) that split the spike protein and establish further

penetration changes (Glowacka et al., 2011; Bertram et al., 2011). MERS-coronavirus

employs dipeptidyl peptidase 4 (DPP4), while HCoV-NL63 and SARS-coronavirus require

angiotensin-converting enzyme 2 (ACE2) as a key receptor (Wang et al., 2013; Raj et al.,

2013).

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SARS-CoV-2 possesses the typical coronavirus structure with spike protein and also

expressed other polyproteins, nucleoproteins, and membrane proteins, such as RNA

polymerase, 3- chymotrypsin-like protease, papain-like protease, helicase, glycoprotein, and

accessory proteins (Wu et al., 2020; Zhou et al., 2020). The spike protein of SARS-CoV-2

contains a 3-D structure in the RBD region to maintain the van der Waals forces (Xu et al.,

2020). The 394 glutamine residue in the RBD region of SARS-CoV-2 is recognized by the

critical lysine 31 residue on the human ACE2 receptor (Wan et al., 2020).

3.2 Genomic variations in SARS-CoV-2

The genome of the SARS-CoV-2 has been reported over 80% identical to the previous human

coronavirus (SARS-like bat CoV) (Wu et al., 2020). The Structural proteins are encoded by

the four structural genes, including spike (S), envelope (E), membrane (M) and nucleocapsid

(N) genes. The orf1ab is the largest gene in SARS-CoV-2 which encodes the pp1ab protein

and 15 nsps. The orf1a gene encodes for pp1a protein which also contains 10 nsps [Wu et al.,

2020; Lu et al., 2020; Chen et al., 2020].

According to the evolutionary tree, SARS-CoV-2 lies close to the group of SARS-

coronaviruses (Hui et al., 2020; Li et al., 2020). Recent studies have indicated notable

variations in SARS-CoV and SARS-CoV-2 such as the absence of 8a protein and fluctuation

in the number of amino acids in 8b and 3c protein in SARS-CoV-2 (Wu et al., 2020). It is

also reported that Spike glycoprotein of the Wuhan coronavirus is modified via homologous

recombination. The spike glycoprotein of SARS-CoV-2 is the mixture of bat SARS-CoV and

a not known Beta-CoV (Li et al., 2020). In a fluorescent study, it was confirmed that the

SARS-CoV-2 also uses the same ACE2 (angiotensin-converting enzyme 2) cell receptor and

mechanism for the entry to host cell which is previously used by the SARS-CoV (Gralinski

and Menachery, 2020; Xu et al., 2020). The single N501T mutation in SARS-CoV-2’s Spike

21
protein may have significantly enhanced its binding affinity for ACE2 (Wan et al., 2020).

Potential therapeutic strategies against COVID-19 Initially, interferons-a nebulization, broad-

spectrum antibiotics, and anti-viral drugs were used to reduce the viral load (Ng et al., 2020;

Wang et al., 2019; Wang et al., 2020), however, only remdesivir has shown promising impact

against the virus (Agostini et al., 2018). Remdesivir only and in combination with

chloroquine or interferon beta significantly blocked the SARSCoV-2 replication and patients

were declared as clinically recovered (Sheahan et al., 2020; Holshue et al., 2020; Wang et al.,

2020). Various other anti-virals are currently being evaluated against infection. Nafamostat,

Nitazoxanide, Ribavirin, Penciclovir, Favipiravir, Ritonavir, AAK1, Baricitinib, and Arbidol

exhibited moderate results when tested against infection in patients and in-vitro clinical

isolates (Sheahan et al., 2020; Richardson et al., 2020; Holshue et al., 2020; Wang et al.,

2020). Several other combinations, such as combining the antiviral or antibiotics with

traditional Chinese medicines were also evaluated against SARSCoV- 2 induced infection in

humans and mice (Sheahan et al., 2020). Recently in Shanghai, doctors isolated the blood

plasma from clinically recovered patients of COVID-19 and injected it in the infected

patients who showed positive results with rapid recovery (Derebail and Falk, 2020). In a

recent study, it was identified that monoclonal antibody (CR3022) binds - with the spike

RBD of SARS-CoV-2. This is likely due to the antibody’s epitope not overlapping with the

divergent ACE2 receptor-binding motif. CR3022 has the potential to be developed as a

therapeutic candidate, alone or in combination with other neutralizing antibodies for the

prevention and treatment of - COVID-19 infection (Tian et al., 2020).

3.3 Vaccines for SARS-CoV-2

There is no available vaccine against COVID-19, while previous vaccines or strategies used

22
to develop a vaccine against SARS-CoV can be effective. Recombinant protein from the

Urbani (AY278741) strain of SARS-CoV was administered to mice and hamsters, resulted in

the production of neutralizing antibodies and protection against SARS-CoV (Bisht et al.,

2005; Kam et al., 2007). The DNA fragment, inactivated whole virus or live-vectored strain

of SARS-CoV (AY278741), significantly reduced the viral infection in various animal

models [58–63]. Different other strains of SARS-CoV were also used to produce inactivated

or live-vectored vaccines which efficiently reduced the viral load in animal models. However,

there are few vaccines in the pipeline against SARS-CoV-2. The mRNA based vaccine

prepared by the US National Institute of Allergy and Infectious Diseases against SARS-CoV-

2 is under phase 1 trial [72]. INO-4800- DNA based vaccine will be soon available for human

testing [73]. Chinese Centre for Disease Control and Prevention (CDC) working on the

development of an inactivated virus vaccine [74,75]. Soon mRNA based vaccine’s sample

(prepared by Stermirna Therapeutics) will be available [76]. GeoVax-BravoVax is working to

develop a Modified Vaccina Ankara (MVA) based vaccine [77].While Clover

Biopharmaceuticals is developing a recombinant 2019-nCoV S protein subunit-trimer based

vaccine [78].

Although research teams all over the world are working to investigate the key features,

pathogenesis and treatment options, it is deemed necessary to focus on competitive

therapeutic options and cross-resistance of other vaccines. For instance, there is a possibility

that vaccines for other diseases such as rubella or measles can create cross-resistance for

SARS-CoV-2. This statement of cross-resistance is based on the observations that children in

china were found less vulnerable to infection as compared to the elder population, while

children are being largely vaccinated for measles in China.

23
 CHAPTER FOUR

4.0 IMPACT OF DIABETES MELLITUS AS A CO-MORBIDITY IN COVID-19

PANDEMIC

4.1 Diabetes investigation in COVID-19 patients

COVID-19 management teams around the world must be conscious about the nuances of

endocrine screening and diagnosis for patients with diabetes. People infected with

coronavirus must be screened for diabetes and other illnesses. At present, there is lack of

proper guidelines to screen diabetes patients suffering from COVID-19, standard American

Diabetes Association criteria for the diagnosis of diabetes should use for the screening

process (Care, 2020). Two abnormal glycaemic test reports usually required to approve a

diagnosis of diabetes in infected persons. In symptomatic cases, a solo abnormal glucose

value might be sufficient to diagnose diabetes. Health care personals must be aware of the

possibility of stress hyperglycaemia and differentiate it from pre-existing diabetes.

In the case of type 1 diabetes, the immune cells of the body begin to destroy β-cells, which

are solely liable for the production of insulin hormone in the pancreas. Data from various

studies as well as coronavirus infected patients indicates that the novel virus destroys insulin-

producing β-cells, which is further resulted as hyperglycemia (Mallapaty, 2020). Different

viruses, including one that causes SARS, were related to autoimmune conditions, including

24
such as type 1 diabetes (Yang et al., 2010). There are multiple organs involved behind the

regulation of blood sugar in the body and also consists of different proteins like ACE2, and

coronavirus further uses it to infect the cells (Hamming et al., 2004). Blood sugar and ketones

are seen in higher levels in COVID-19 infected patients. If the body is unable to produce an

adequate level of insulin to breakdown the blood sugar, it utilizes ketone as another source of

fuel, which further leads to diabetic ketoacidosis (Li et al., 2020; Chee et al., 2020)

In the pancreas, β-cells produce blood sugar-lowering hormone insulin, and α-cells make the

glucagon hormone that increases blood sugar. SARS-CoV-2 may infect α- and β-cells; as a

result, few of them gets destroyed. The virus can also induce some protein production

(chemokines and cytokines), which can trigger an immune response that can also kill the

specific cells and alter insulin secretion (Yang et al., 2020). In obese people, insulin

resistance (IR) may be a crucial aspect of the incidence of COVID-19. ACE2 is the potential

link between IR and COVID-19 since the virus enters the host body via ACE2. ACE2 helps

in the maintenance of RAAS and abnormality of the same leads to IR and cardiovascular

dysfunction. Degradation of angiotensin 2 results to the reduction of IR by decreasing

oxidative stress, improving insulin signaling and enhanced insulin transport. It is important to

normalize the blood glucose and insulin level, thereby reducing the expression of ACE2 and

eventually COVD-19 severity (Finucane and Davenport, 2020). It is assumed that insulin

production and SARS-CoV-2 are interconnected to each other. Low levels of insulin

contribute to hyperglycemia, and patients with COVID-19 exacerbates the situation.

However, IR and interaction with COVID-19 are not yet fully understood. Clinical and

biochemical insulin resistance markers should, therefore, be evaluated for their prognostic

usefulness. In addition, where there is a correlation between insulin sensitivity and the

incidence of COVID-19 is found, and attention should be given to the evaluation of medical

25
measures to improve insulin sensitivity. Therefore, additional care and treatment are also

required for patients with low insulin levels.

4.1.1 Genetic polymorphism of ACE

Spike proteins of coronavirus usually bind to the ACE receptors in the lungs. It is a peptidase

enzyme and expressed in other tissues too to regulate the renin-angiotensin-aldosterone

system (RAAS). This enzyme is the main component that converts Ang-I to Ang-II. Binding

of the virus to the receptor helps the virus to invade to the host body as well as it causes

depletion of ACE2 and degradation of lung tissues due to damaging effects of AngII (Devaux

et al., 2020). Genetic polymorphism to ACE is recently observed in human populations.

ACE1 enzyme shows polymorphism by insertion/deletion (I/D) in intron 16; it is associated

with a change in levels of ACE in different tissues, including lungs. Even though they have

genetic variation, there is no marked difference in their structural conformation. ACE

polymorphism causes the blood pressure to change due to its effect on RAAS. Deletion leads

to reduced levels of ACE2 in circulation. This I/D polymorphism is different in different

geographical regions; e.g. in China, the northern region shows the genetic difference from the

southern region (Hussein et al., 2020).

Genetic mutation to this ACE2 affects its interaction with the spike proteins. Based on this

polymorphism, the incidence rate in different geographic areas around the globe is different.

COVID-19 vulnerability cannot be clarified exclusively by severity or even by ACE2

polymorphism. ACE2 polymorphism and Ang II lead levels were observed in severe

COVID-19 patients. Multi-organ failure is another risk factor related to COVID-19. ACE2

polymorphism is associated with a change in blood pressure due to its influence on RAAS

(Turner et al., 2004). ACE2 mutation is first identified in Chinese people, with three forms of

polymorphism. In Canadian teenagers, another three types of genetic polymorphism are

26
observed. Mutations of both ACE1 and ACE2 are recorded among Brazilians. Such

mutations have clinical effects, primarily cardiac complications, diabetes and complications

of the cerebrovascular system. Cardiac complications among COVID-19 patients was found

to be one of the comorbidities. ACE2 expression is less frequent in patients with SARS-CoV.

Genetic polymorphism may explain why COVID-19 has the highest incidence rate in Europe

than in Africa (Delanghe et al., 2020; Hatami et al., 2020; Alifano et al., 2020; Ciaglia et al.,

2020).

4.2 Impact Of Dm as a co-morbidity in Covid 19 Pandemic

4.2.1 Glycemic control

Whether poor glycemic control is a risk factor for disease progression in COVID-19 patients

is still a matter of debate. In fact, a retrospective, multicenter survey from the Hubei Province

in China showed that patients with well-controlled blood glucose levels had lower rates of

death (1.1% vs 11.0%; hazard ratio, HR, adjusted for age and gender and hospital sites, 0.10

[95% CI, 0.03–0.32], p < 0.001), ARDS (7.1% vs 21.4%; 0.32 [0.20–0.51], p < 0.001), and

other complications, compared with individuals with poorly controlled blood glucose levels

(Zhu et al., 2020). Likewise, a whole population study from UK showed that risk of death,

adjusted for region of residence and duration of diagnosed diabetes, increased significantly

for a hemoglobin (Hb) A1c ≥ 86 and ≥ 59 (and < 48) mmol/mol in individuals with type 1 and

2 diabetes, respectively (Holman et al., 2020). Conversely, the CORONA study, a

prospective, multicenter survey from France, showed that long-term glycemic control was not

associated with a composite outcome including mechanical ventilation and/or death, either in

the univariable or in the multivariable analysis (Cariou et al., 2020).

However, in this scenario, it should be considered also the possible diabetogenic effect of

SARS-CoV2 due to its direct action on key metabolic organs, including the β-cell, and

27
resulting in new-onset hyperglycemia or sudden deterioration of pre-existing diabetes,

beyond the well-recognized stress response associated with severe illness (Rubino et al.,

200). Three recent reports showed that fasting blood glucose at admission, irrespective of

previous diagnosis of diabetes, was an independent predictor of critical illness (Liu et al.,

2020), death (Wang et al., 2020), or poor outcome (Zhang et al., 2020) in patients

hospitalized with COVID-19.

The practical recommendations for the management of diabetes in patients with COVID-19

outline the importance of achieving optimal glycemic control and point out potential

metabolically interfering effects of metformin, sodium-glucose-co-transporter 2 inhibitors,

and glucagon-like peptide-1 receptor agonists related to dehydration (Bornstein et al., 2020).

In addition, medications commonly used in diabetic patients, including anti-hyperglycemic,

lipid-lowering, and anti-hypertensive drugs, have been implicated in COVID-19 onset and

progression by virtue of their pleiotropic effects, especially on inflammation.

4.2.2 Facilitation of virus entry into the cell

It has been suggested that diabetes may detrimentally impact the course of the disease

through its effects on receptors that mediate virus entry into the cell. Coronavirus receptor

proteins include the angiotensin-converting enzyme 2 (ACE2) and DPP4, which are both

involved in the regulation of several physiological processes, including glucose metabolism,

and are modulated by hyperglycemia and pharmacological treatments commonly used in

diabetic individuals (Ducker et al., 2020). Moreover, both receptors exist as a transmembrane

and a soluble form, with the latter potentially serving as decoy receptor, which binds and

sequesters circulating virus particles (Ducker et al., 2020). As DPP4 is a receptor for MERS-

CoV (Song et al., 2020), but not for SARS-Cov-2 (Letko et al., 2020), ACE2 has gained

most of the attention. A large body of evidence has indicated that treatment with RAS

28
blockers, which increase ACE2 expression, is not associated with either COVID-19 diagnosis

or poorer disease outcomes (Mancia et al., 2020; Reynolds et al., 2020; Fosbøl et al., 2020),

thus arguing against the hypothesis that the exacerbating effect of diabetes (as well as of

hypertension, CVD, and CKD) on COVID-19 is mediated through ACE2 upregulation

associated with pharmacological RAS blockade. Therefore, discontinuation of these agents is

not recommended in COVID-19 patients in order to maintain their anti-hypertensive and

cardioprotective effects (Bavish et al., 2020). Indeed, it has been postulated that binding of

SARS-Cov-2 to ACE2, by reducing the expression and/or the activity of this receptor,

enhances the vasoconstrictor and pro-inflammatory/pro-oxidant activity of angiotensin II,

thus increasing the risk for acute lung injury (ALI), and that RAS blockade may help mitigate

these deleterious effects of angiotensin II (Zhang et al., 2020). However, though this concept

is consistent with the finding that ACE2 protects from ALI (Imai et al., 2005) and with a few

studies and a meta-analysis reporting a benefit with RAS blockers (Zhang et al., 2020; Gao et

al., 2020; Pirola et al., 2020 ), current guidelines do not recommend initiating treatment with

these agents in COVID-19 patients unless clinically indicated (Bavishi et al., 2020).

In addition to RAS activation, diabetes and related comorbidities are also associated with

elevated levels of plasmin (ogen), a protease that cleaves the S protein of SARS-CoV2, thus

favoring virus binding to ACE2 and entry into the cell; moreover, fibrin breakdown by

plasmin leads to increased levels of D-dimer and other fibrin degradation products, which are

characteristic features of severe illness (Ji et al., 2020).

4.2.3 Impaired immune and inflammatory response

Diabetes may also favor the onset and progression of SARS-CoV2 infection by impairing the

adaptive immune response to the virus, while enhancing the innate immune system

29
inflammatory reaction. Diabetes has long been recognized as a risk factor for morbidity and

mortality from various types of infections, including those caused by respiratory viruses

(Gupta et al., 2020). In addition, diabetes is also known to be accompanied by a chronic pro-

inflammatory and pro-coagulant state, albeit of low grade, which characterizes also the

associated comorbidities/complications (Hotamisligil et al., 2020). Increased susceptibility to

infections has been related to several immune defects, including blunted anti-viral interferon-

γ response, delayed activation of CD4+ cells with shift toward Th17 responses, and

diminished regulatory T cells, which all contribute to hyperinflammation (Muniyappa et al.,

2020). In patients with COVID-19, immune, inflammatory and coagulation abnormalities

were found to be significantly more pronounced in diabetic than in non-diabetic individuals

(Yan et al., 2020), independently of other comorbidities (Guo et al., 2020), and to correlate

with glycemic control (Wang et al., 2020). As these abnormalities were shown to predict

disease severity and adverse outcomes, it was suggested that they may be responsible for the

exacerbating effect of diabetes (and related comorbidities) (Gupta et al., 2020).

4.3 Management of diabetes in SARS-CoV-2 infected patients

Endocrinopathy required long-lasting management and without proper guidance; patients

should not alter the therapy or stop the medications. In the case of COVID-19 disease

affected patients; the daily routine must change to decrease the chances of spreading as well

as the severity of the disease (Laffe, 2000). Persons affected with the virus must inform the

healthcare persons about their diabetic profile when they admitted to hospital for their better

treatment management; especially people dealing with type 1 diabetes and those who depend

on adrenal corticosteroids/mineralocorticoids for survival. If patients are not in a condition to

take the oral tablets or are unable for subcutaneous insulin, they must give them

30
intravenously. The management of diabetes itself a unique challenge, particularly for those

who are on non-insulin depended diabetes mellitus (NIDDM) or type 2 diabetes. In cases

with uncontrolled hyperglycaemia, it would be pragmatic to intensify insulin dosing,

relatively than other oral drugs (Umpierrez and Pasquel, 2017). Present data give an idea that

hydroxychloroquine (HCQ) is the drug of choice for the patient affected with Coronavirus

due to its antiviral properties (Prajapa et al., 2020). Still, there are not enough pieces of

evidence present to support the uses of hydroxychloroquine as an ideal drug for the

management of diabetes complicated by COVID-19 infection. Healthcare professions must

alert the potential endocrine and adverse metabolic effects of the drugs, which are in use.

Like corticosteroids, able to cause dysglycaemia, however long-term antiretroviral therapy

may be associated with metabolic syndrome (Yi and Kang, 2017). Apart from the lack of

specific therapies and knowledge about potential therapeutic targets, it is challenging to treat

a disease along with other comorbidities. The drug repurposing for SARS-CoV-2 also found

to be an exciting option to combat with this novel virus infection for diabetic patients

(Pandey, 2020).

4.4 Treatment of diabetes during SARS-CoV-2 infection

Poor glycaemic control always results in a severe risk factor for different infections and

adverse outcomes. Escalation of any infection (can be bacterial pneumonia) depends on the

average glucose level of a human being. Treating with glucocorticoids to hyperglycaemic

patients affected with COVID-19 come up with tremendous challenges to the medical

professional. The problem associate with this novel virus infection results in loss of

glycaemic, control due to unstable food intake and intercurrent diseases like fever and others.

To keep the glucose level optimum, frequent glucose monitoring in addition to continuous

change in antidiabetic medications required.

31
Patients having type 1 diabetes generally treated with basal-bolus or insulin pump therapy

and the doses of insulin should be frequent and be monitored to avoid a situation like

hypoglycaemia as well as severe hyperglycaemia and ketoacidosis mainly in patients with

reduced food intake. Patients having a diabetic profile should follow some basic prevention

instruction to dodge the novel coronavirus infection. This quickly spreading virus infection

can stop since this is a communicable disease; several recommendations help to diminish the

spread of the deadly virus.

4.5 General prevention advice to control coronavirus infection.

Patients are having a profile of type 2 diabetes, Sodium-glucose co-transporter-2 (SGLT2)

inhibitors along with metformin, should be stopped to control moderate to severe illness.

Chances of dehydration and diabetic ketoacidosis during infection is there, so additional

precaution requires to be taken by the patients to avoid such incidences. Inhibitors like

Dipeptidyl peptidase-4 (DPP4) linagliptin can be useful in the cases of impaired kidney

function without risk of hypoglycaemia. Drugs class, like sulphonylureas, consider as one of

the reasons for inducing hypoglycaemia in patients having a low-calorie intake, so before

taking this class of drug, proper guidance should be followed. Uses of drugs like long-acting

glucagon-like peptide-1 (GLP-1) receptor agonist should not be discontinued without the

proper consultation of a physician. Patients having a profile of Type 2 Diabetes Mellitus,

insulin treatment is better and vital to be started. Treatment of patients in the case of

intercurrent disease a time-involved process, which is a serious issue (Bornstein et al., 2020).

A drug like pioglitazone a thiazolidinedione should be avoided; it may trigger the severity of

the disease.

32
 4.6 List of drugs therapies recommended for COVID-19 patients suffering

from diabetes.

There is no current treatment available for this novel virus infection. Still, a small trial

testified from France using a combination of hydroxychloroquine and azithromycin, showing

decent outcomes in patients suffering from respiratory symptoms (Gautret et al., 2020). The

reported study endpoint based on a negative test, which means the absence of the virus after

receiving treatment, and not on the health status of the participating persons. Furthermore, a

clinical trial with remdesivir versus placebo for the treatment of COVID-19

(ClinicalTrials.gov identifier NCT: NCT04280705) presently under process in the National

Institute of Allergy and Infectious Diseases (Adaptive COVID-19 treatment trial, 2020). This

trial is still in progress and needs time; due to the short duration of the intervention, findings

must turn out to be accessible in a reasonable time.

Angiotensin-converting-enzyme 2 (ACE2), a membrane glycoprotein, mainly expressed in

epithelial cells of the lungs, intestine, kidney and blood vessels. ACE2 plays a vital role in the

breakdown of angiotensin-II (Ang-II) and to some extent, angiotensin-I (Ang-I) to peptides,

angiotensin(1 – 7) and angiotensin(1 – 9), separately (Tikelis and Thomas, 2012).

ACE2/Angiotensin (1–7) have significant anti-inflammatory, anti-oxidant role in the

protection of lung against acute respiratory distress syndrome as well as in the case of H5N1

infection. The role of ACE2 in the relation between COVID-19 and DM is often found

attractive (Zou et al., 2014). The expression level of ACE2 found reduced in case of DM

probably because of glycosylation. Due to this reason, the chances of severe lung injuries

closely followed by acute respiratory distress syndrome (ARDs) with COVID-19 increases

(Tikelis and Thomas, 2012). Some reports even also state that overexpression of ACE2

unfavourable in the case of COVID-19. SARS-CoV-2 considered ACE2 as their receptor to

enter into the host pneumocytes (Wrapp et al., 2019). ACE inhibitors and Angiotensin II

33
receptor blocker (ARBs) are widely used in the treatment of DM. ACE2 expression found

remarkably increased in DM suffering patients, which is an adaptive response to counter the

increased levels of Ang-II and Ang-I. So the use of ACE2 stimulating drugs found

detrimental in SARS-CoV-2 infected cases. At present, pioglitazone and liraglutide shown

upregulation of ACE2 in animal studies (Fang et al., 2020; Romaní-Pérez et al., 2015).

However, none of these drugs was used in the treatment. Due to ACE2 expression,

thiazolidinediones class of drugs cannot be used in patients suffering from COVID-19 along

with diabetes (Fang et al., 2020).

Some reports recommend that several incidences of COVID-19 infection in patients primarily

connected with the low cytosolic pH. The regulation of cell pH often a complex mechanism

involving Serum lactate dehydrogenase (LDH), a cytosolic enzyme and its rising level in

serum cause the cell to break down. Due to this novel virus infection, serum LDH level

dramatically increased in patients. In the case of anaerobic conditions, lactate formation

increases from pyruvate. Due to increased lactate level in the extracellular area, the symporter

carries the lactate and H+ ion into the cell, resulting in acidic intracellular pH followed by

Na+/H+ exchange activation. Even though H+ ion threw out of the cell, Na+ and Ca2+ enter

into the cell. When the level of Na+ and Ca2+ increase within the cell, the cells start swelling

and further leading to cell death. An SGLT2 inhibitor (Dapagliflozin) reported to have a

lactate reducing profile is useful in this scenario. Reduction in lactate level is found beneficial

for pH maintenance. In another mechanism, dapagliflozin also inhibits the Na+ and Ca2+

flow. It is worthy of using dapagliflozin in patients having a pre-diabetic profile to prevent

the severe development of COVID-19 infection as well as a combination therapy for diabetes

treatment (Cure and Cumhur Cure et al., 2020).

Dipeptidyl peptidase-4 (DPP-4) was revealed as a receptor for MERS-CoV while SARS-

CoV-2 appears to use preferentially angiotensin-converting enzyme 2 to enter the cell (Letko

34
et al., 2020). Yet, since DPP-4 inhibitors are popular glucose-lowering medications

worldwide, it will be of interest to explore whether they might protect against SARS-CoV-2

infection (Fadini et al., 2020; Gentile et al., 2020). And so far now, no such specified drug or

vaccine has been approved for COVID-19 (Li et al., 2020). To get control over the pandemic,

large clinical trials of drugs (like tocilizumab, chloroquine phosphate, remdesivir, ribavirin,

lopinavir/ritonavir, arbidol, interferon etc.) are under progress to assess both the therapeutic

activity and safety as well (WHO 2020). Despite being an immunomodulant and anti-malarial

drug, chloroquine (CQ) and its hydroxy-analogue (Hydroxychloroquine) do have broad-

spectrum antiviral activity. Thus, it comes under the limelight of having potential

pharmacological activity for the patient of COVID-19 with diabetes though no such clinically

proven reports are submitted in the support. However, there are pieces of evidence for being a

highly effective drug in controlling SARS-CoV-2 in vitro. The most reliable and considerable

reason for taking it under consideration is that it interrupts the glycosylation of SARS-CoV's

cellular receptors by increasing endosomal pH and hence effectively blocks the viral infection

(Wang et al., 2020). As per the report of a Chinese Clinical trial of more than 100 patients

depicts that CQ showed a superior effect in controlling the disease along with promoting a

negative virus conversion, inhibiting pneumonia exacerbation and radiological improvement

without any severe adverse effects (Gao et al., 2020).

And on the other hand, countable studies have been reported which states that HCQ improves

treatment-refractory diabetic patients and glycaemic control in decompensated (Rekedal et

al., 2010; Gerstein et al., 2002). In India, CQ already being approved for the treatment of

Type-2 DM along with as a therapy for those patients who cannot achieve glycaemic targets

even after administrating two other glucose-lowering drugs (Kumar et al., 2018). HCQ

lowers glycosylated haemoglobin (HbA1c) in diabetes patients without the rheumatic disease,

35
the mechanism of HCQ over glycaemia remains still unknown (Rekedal et al., 2010).

Somewhere down the line, an improved pancreatic β-cell function has been reported by the

increase in C-peptide response by the impact of CQ (Gerstein et al., 2002). According to a

few submitted reports of animal studies, it has been found that HCQ effectively increased

insulin accumulation and reduced intracellular insulin degradation. Apart from all the data

and reports on glucose metabolism, considerable caution should be taken before the use of

HCQ/CQ to diabetic patients and COVID-19 patients as well and if required dose adjustment

can be made to prevent hypoglycaemic events. Dexamethasone, an uncommon medication,

has been found potential in Covid-19 treatment (Clin. Trials Arena, 2020; Mahase, 2020).

ChAdOx1 nCoV-19 vaccine displayed an appropriate safety profile, although homologous

boosting increased responses to the antibody. Such findings, along with the activation of

humoral and cellular immune responses, support this candidate vaccine's wide-ranging

evaluation in an ongoing phase 3 trial (Folegetti et al., 2020).

4.7 List of drugs used for COVID-19 patients and their effect on glucose.

In silico molecular modelling and docking studies has been widely used in identifying newer

drugs or repurposing of existing drugs for the treatment of COVID-19. In several of such in

silico docking studies lopinavir, remdesivir and ritonavir reported interacting with more than

one protein targets of COVID-19. Notably, anti-HIV drug lopinavir, as compared with others

closely followed by ritonavir, showed very interesting in silico binding with COVID-19 main

protease (Mpro) but showed poor bioavailability in in vivo studies. Most of the HIV protease

inhibitors are tested for their action against novel coronavirus infection solely or in a

combination form along with some other drugs. Remarkably, these drugs are successful in in

silico, in vitro and animal models but unfortunately failed to deliver the maximum efficacy in

36
clinical studies (Cao et al., 2020; Choy et al., 2020; Smith et al., 2020). Remdesivir, an

analogue of adenosine, is a remdesivir-triphosphate prodrug shows its action by inhibiting

RNA-dependent RNA polymerase (Elfiky, 2020). In in silico molecular docking simulation

studies, remdesivir also demonstrate promising results (Shah et al., 2020; Kumar et al.,

2020). Other than this, drugs like ribavirin, chloroquine, hydroxychloroquine, camostat

mesylate, darunavir, cobicistat, favipiravir, umifenovir, interferon-β1 and Oseltamivir, which

are used to treat SARS-CoV-2 in patients with pre-existing diabetic profile, shows good to

excellent in silico binding efficacy with the protein structure of COVID-19 Mpro (Kumar et

al., 2020). In a study reported by Shah et al. (Shah et al., 2020), the protease inhibitor

lopinavir interacted with the protein structure of COVID-19 Mpro (PDB: 5R81) and displays

H-bond binding interactions with amino acid Glu166, His41 (Shah et al., 2020).

Nevertheless, it is failed to prove its worth in clinical trials. In the same study, remdesivir

showed H-bond interaction with Glu166 and Asn142 of COVID-19 Mpro. It is assumed that

the 5-cyano-3,4-dihydroxytetrahydrofuran ring scaffold present in remdesivir is responsible

for decent clinical activity against the deadly SARS-CoV-2. In another in silico study, Kumar

et al. (Kumar et al., 2020) demonstrate a combination of lopinavir-ritonavir displays various

binding interactions with different amino acids of viral protein (SARS-CoV-2 Mpro PDB ID:

6Y2F) and promising antiviral action against SARS-CoV-2. Similarly, baloxivir-marboxil

also exhibited interesting in silico interactions with the same protein structure.

4.8 Unexplored therapies and future prospective

In the absence of any particular drug therapy, various antiviral drugs are used to treat the

novel virus infection. Drugs like lopinavir, ritonavir followed by RNA polymerase inhibitors,

interferon-1β and hydroxychloroquine are widely used. Some reports suggest that the binding

site of the novel coronavirus receptor having a strong affinity with the ACE2. Therefore, it is

37
assumed that the renin-angiotensin system (RAS) inhibitors could have an essential role in

the treatment. In the other side, zinc nanoparticles and vitamin C like options not yet tested

with currently used drugs, so it is interesting to check their effectiveness in combination with

other drugs. There is still no specific vaccine available to treat this novel virus, and the

process of development of a vaccine is ongoing, which is assumed to be a significant way to

overcome this pandemic. Leprosy medication sepsivac showed promise in the COVID-19

trial, and its efficacy is further being evaluated. Some Rasayana botanicals defined in

Ayurveda like Withania somnifera (Ashwagandha), Tinospora cordifolia (Guduchi),

Asparagus racemosus (Shatavari), Phyllanthus embelica (Amalaki), and Glycyrrhiza glabra

(Yashtimadhu) are potential immunomodulators, may also consider as an add-on treatment

for COVID-19 patients. Repurposing of existing drugs could be considered as an excellent

option in identifying novel therapies for COVID-19 treatment. The severity of this contagion

also warrants the design and development of new chemical entities (NCEs).

38
 CHAPTER FIVE

5.0 CONCLUSION

Diabetes is one of the standards and significant risk factor connected with mortality triggered

by COVID-19. Diabetes closely characterised by impaired immunity that assumed to lead an

augmented susceptibility to COVID-19 contagion, particularly in those with an elevated level

of blood glucose. Cardiovascular disease, collective comorbidity towards endocrine disease

comprising diabetes, is a significant donor to COVID-19 morbidity (Alves et al., 2012; Chen

et al., 2020).

Death rate appears to be about threefold greater in the case of people having diabetes

matched with the overall mortality of COVID-19 in China (Yang et al., 2020), (Wu et al.,

2020). Remarkably, diabetes used to be a more significant risk factor for severe disease and

mortality in the earlier SARS, MERS coronavirus infections along with severe influenza A

H1N1 pandemic in 2009 (Yang et al., 2006; Schoen et al., 2019; Wang et al., 2011). Patients

with type 2 diabetes tend to be obese, and obesity is another risk factor for severe infection

39
(Huttunen and Syrjänen, 2013). It was clarified from the period of influenza A H1N1

epidemic in 2009 that the disease was more severe and had a lengthier duration of

approximately two-fold more patients with obesity who were then treated in intensive care

units compared with a related population (Honce and Schultz-Cherry, 2019). Specifically, a

high-risk factor always associated with metabolically active abdominal obesity. A chronic

low-grade abdominal obesity resulted due to abnormal secretion of adipokines and cytokines

(TNF-α, interferon) may lead to induce in impaired immune response (Almond et al., 2013).

People are suffering from severe abdominal obesity as well having complications like

mechanical respiratory problems, with the reduction in the ventilation of the basal lung

caused increase in the risk of pneumonia in addition to resulting declined oxygen saturation

of the blood. Obesity suffering people are also showing an increased incidence of asthma

risk, and those patients with obesity and asthma have shown diverse symptoms, extra

frequent and severe exacerbations and also affected decreased response to several asthma

medications (Dixon and Peters, 2018).

Earlier SARS virus has been reported to bind target cells through angiotensin-converting

enzyme 2 (ACE2), which mainly expressed by the epithelial cells of the lung, kidneys,

intestines and blood vessels. The upregulated expression in people usually treated with

angiotensin-converting enzyme (ACE) inhibitors and angiotensin II type I receptor blockers

(ARBs), which are also a drug of choice to treat hypertension when a patient is suffering

from a metabolic disorder like diabetes. Medicines like ibuprofen and thiazolidinediones,

precisely pioglitazone linked to increased ACE2 expression (Wan et al., 2020; Zhang et al

2014). Augmented ACE2 expression, on the contrary, found to be useful and linked to

reduced inflammation in the lungs, which a probable area of therapy in people living with

inflammatory lung disease. In addition, individuals with different ACE2 polymorphisms

would more complicate the picture. Still, this leftover an area of active research and the

40
picture is likely to be more transparent shortly.

In general, patients who have diabetes, often have weakened immune response, both

concerning cytokine profile as well as changes in immune-responses together with T-cell and

macrophage activation (Ferlita et al., 2019). Weaker glycaemic control harms several aspects

of the immune response by a viral infection and in addition to the risk of potential bacterial

secondary infection in the lungs (Critchley et al., 2018). According to reports, it is shown that

a novel virus-infected patient having pre-existing diabetes history shows a reduction in

metabolic control all over the world.

Not only diabetes, its associated diseases such as diabetes ketoacidosis, nephropathy and

ischaemic heart disease can also cause the susceptibility to COVID-19 disease severity. This

kind of complication results not only in an increased number of infected patients but also

causes an inadequate immune response. In several cases, patients required care, such as acute

dialysis. Few reports indicate that COVID-19 could be the reason behind acute cardiac injury

through heart failure, leading towards deterioration in circulation. Without a doubt,

individuals with diabetes are always in high-risk for severe disease (Li et al., 2020).

41
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