Introduction
The COVID-19 pandemic is taking a great toll globally. To control the situation effectively, measures to lower the death rate have to be taken. Doctors have already stated that people with comorbidities like diabetes are at a higher risk of getting severe symptoms of COVID-19 infection.
Increase in Risk
The fluid and electrolyte balance of the body is maintained with the help of the renin-angiotensin system. When a person complains of low blood pressure, the renin (present in the kidney) forms angiotensin I by breaking down the enzyme angiotensinogen. Angiotensin-converting enzyme(ACE) converts angiotensin I into angiotensin II to activate it.
This Angiotensin-converting enzyme (usually present on the lungs, kidney, and heart) binds to the Angiotensin-converting enzyme receptors and squeezes the blood vessels, thus raising the blood pressure of the body. Then the Angiotensin-converting enzyme-2 (ACE-2) breaks down the angiotensin II into molecules that neutralize its harmful effects.
SARS-CoV-2 has a high affinity for ACE-2 receptors present on the surface of healthy cells. Thus it attaches itself to the ACE-2 and attacks the lungs, kidney, and heart.
The levels of ACE-2 increase in a diabetic person (a condition with high blood glucose levels, hyperglycemia) allowing the virus to attack the organs of the diabetic person more disastrously. Acute hyperglycemia upregulates ACE-2 expression on cells which might facilitate viral cell entry. Chronic hyperglycemia downregulates ACE-2 expression making the cells vulnerable to the inflammatory and damaging effects of the virus.
Link Between COVID-19 and Diabetes
COVID-19 is an acute respiratory infection caused by a coronavirus named Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and is spread through air droplets or close contact with an infected person. Often older people(above 65 years of age) & people with pre-existing diabetic conditions are affected.
The risk of a fatal outcome from COVID-19 is up to 50% higher in patients with diabetes. When diabetic patients develop a viral infection it can increase inflammation and the treatment is hard because of fluctuations in blood glucose levels and the presence of diabetic complications. This is because of the compromised immune systems making it difficult to fight with the virus leading to a longer recovery period.
Linked Complications & Risk Factors
Complications like Acute respiratory distress syndrome (ARDS) & multi-organ failure are prevalent in prediabetic Covid-19 patients. It involves the lower respiratory tract which can offset pneumonia, rapidly progressing to ARDS associated with multi-organ failure.
Acute respiratory distress syndrome (ARDS) is a severe lung condition causing fluid accumulation in the alveoli, progressive fibrosis which comprises the gas exchange. The type 1 & 2 pneumocytes lining the alveoli become dysfunctional leading to a decrease in surfactant levels & the ability of lungs to expand causing Sepsis (a serious infection which causes the immune system to attack the body) and Severe pneumonia (Pus collection in air sacs).
COVID-19 prediabetic patients have direct viral invasion which causes functional immune deficiency and directly reduces immune cell function. This leads to diminished bactericidal clearance, increased infectious complications, and protracted sepsis mortality. Thus they may develop pneumonia leading to sepsis.
SARS-CoV-2 infects the upper respiratory tract & circulating immune cells (CD3, CD4, and CD8 T cells) inducing lymphocyte apoptosis with elevated inflammatory biomarkers such as C-reactive protein, serum ferritin, and IL-6. The T cells inhibit the overactivation of innate immunity resulting in lymphocytopenia, which suppresses the innate immune system and enhances the cytokine secretion resulting in a cytokine storm causing a multi-organ failure.
Body mass index (BMI) in obesity of 30 or above increases the risk. Abdominal obesity is associated with a higher risk involving abnormal secretions of adipokines and cytokines like TNF-alpha and interferon which may induce an impaired immune response. Obese people also experience mechanical respiratory problems, with reduced ventilation of the basal lung sections increasing the risk of pneumonia.
If a person with diabetes has a fever from COVID-19, they lose additional fluids. This can lead to dehydration, which may require intravenous fluids.
Diabetes damages arteries with fatty material deposition on their inner walls (atherosclerosis) which can cause Hypertension. Arterial hypertension is also highly prevalent in Covid19 patients due to the use of ACE inhibitors since SARS-CoV-2 binds to ACE2 to enter target cells. ACE inhibitors and angiotensin receptor blockers increase the expression of ACE2 which facilitates target organ infection and promote the progression of the disease.
Management of Diabetes in Patients with COVID-19
In COVID-19 the endothelial dysfunction associated with hypoxia causes intravascular disseminated coagulation. It involves the formation of abnormal clumps of thickened blood clots inside the blood vessels, leading to massive bleeding in other places causing inflammation & infection. Diabetes is associated with a pro-thrombotic state, which plays a key role in blood clotting with an imbalance between clotting factors and fibrinolysis. Pre-Diabetic patients with COVID-19 have a longer prothrombin time and higher concentrations of D-dimer(a small protein fragment in the blood after a blood clot). Other risk factors such as obesity, older age, and being admitted to the hospital could increase the pro-coagulative state and the risk of thrombotic complications.
Diabetes causes disturbance of glucose homeostasis and worsening of hyperglycemia(a characteristic of Diabetic Ketoacidosis). In diabetic patients with Covid-19, there is a direct effect of SARS-CoV-2 binding to ACE receptors expressed in pancreatic tissue and β-cells harming the β-cell function. Therefore there is an acute loss of insulin secretory capacity, stress condition, and a cytokine storm resulting in Diabetic Ketoacidosis (DKA).
Figure 1 : Synopsis of reciprocal effects of diabetes and COVID-19
Poor glycemic control is a risk factor for serious infections but is useful in some conditions like bacterial pneumonia. To maintain optimal glycaemic control it requires frequent blood glucose monitoring and continuous change in anti-diabetic treatment after the measured glucose levels.
Pre-Diabetic patients with COVID-19 infection should have regular blood glucose monitoring and adequate glycemic control which might reduce the risk of this severe infection. Special considerations to avoid certain antihyperglycemic agents should be noted. In Type 2 diabetes, Metformin (initial drug of choice) possesses a risk of dehydration & lactic acidosis hence should be avoided in patients who have greater potential to progress to severe COVID-19. Dipeptidyl peptidase (DPP)-4 inhibitors are well tolerated & can be used as an alternative to Metformin. Sodium-glucose cotransporter-2 inhibitors have risks of dehydration & Diabetic Ketoacidosis which is one of the complications hence avoided. Similarly, Glucagon-like peptide 1 receptor (GLP-1) agonists have a risk of dehydration so patients on these medications should be closely monitored. If any anti-hyperglycemic drugs are discontinued alternate treatment is usually Insulin and it should be continued if it is already ongoing in a patient.
In type1 diabetes frequent blood glucose monitoring every 3-4hrs & adjustments of insulin dose based on blood glucose values is needed. Urine ketones along with blood glucose should be monitored if fever with hyperglycemia occurs. Systematic screening for pre-diabetes in patients with proven COVID-19 infection is advisable.
Conclusion
There is a bidirectional relationship between Covid-19 and diabetes. On one hand, diabetes is associated with an increased risk of severe Covid-19 while on the other hand new-onset diabetes and severe metabolic complications of preexisting diabetes, including diabetic ketoacidosis and hyperosmolar for which exceptionally high doses of insulin are warranted, have been observed in patients with Covid-19.
It is important to recognize the importance of diabetes as a vital comorbidity in patients with COVID-19. Any prediabetic patient who develops COVID-19 symptoms should contact their healthcare provider as soon as possible. Although people with diabetes are at a risk of more serious complications from COVID-19, it is possible to reduce the risk by maintaining ideal blood sugar levels and following infection prevention measures.
References
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Pratiksha Baliga, Youth Medical Journal 2020
Youth Medical Journal 