The Interesting Link Between Diabetes and COVID-19

Article by: Elad Goren

Covid-19 is a rapidly spreading infectious disease caused by a newly discovered coronavirus.

Scientific evidence shows that older individuals as well as people with preexisting and underlying metabolic disorders caused by diabetes mellitus, hypertension and hyperlipidemia are a significant higher risk of morbidity and mortality.

There is a startling reciprocal relationship between diabetes and Covid-19.
People with diabetes are at an increased risk of having a Covid-19 infection.

Further metabolic complications of preexisting diabetes, such as: hypertension, ketoacidosis, persistent oxidative stress, hyperosmolarity and hyperglycemia are induced by Covid-19 infection and people without preexisting diabetes can develop diabetes when infected with Covid (1,2)  These complications and manifestations of diabetes present immense clinical challenges in managing the disease and also suggest complex pathophysiology of Covid-19 related diabetes.

Theories about why there is a linkage of Covid: A contradictory and confusing connection with ACE-2.  Is ACE-2 Good or Bad??

The interactions of  SARS-CoV-2 and ACE-2 are schematically represented above. (3)

Background on angiotensin, ACE and ACE2.

The renin angiotensin system consists of renin secreted by the kidney in times of low blood pressure.  This catalyzes the conversion of angiotensinogen to angiotensin 1 which is converted by angiotensin-1 converting enzyme (ACE) to angiotensin 2, a substance that can increase blood pressure. ACE-2 (not ACE) converts Angiotensin 1 and Angiotensin-2 to Angiotensin 1-7, which acts on the Mas receptor . The activation 1-7-Mas in turn induces a protective mechanism able to decrease inflammatory and fibrosis, a helpful response in the lung- A Good action of ACE2!

People with diabetes who are being treated with hypertension  (high blood pressure), may have elevated ACE-2 in lung and beta cells (insulin producing cells in the pancreas). This elevated ACE2  could potentiate the binding of the Covid-19 virus to these cells and in  turn increase the rate of lung infection and islet cell damage which could cause new onset diabetes (9).-  Not Good Action of ACE2.

In the respiratory system, activation of ACE leads to the recruitment of white blood cells to cause inflammation and fibrosis (3,4)-NOT Good Action of ACE!  

Once ACE related pathway is activated (with downregulation of the ACE-2 pathway) which is seen in people with diabetes who are not on blood pressure treatment, can result in multi organ complications that can be seen in metabolic disease such as  cardiac fibrosis, diabetic nephropathy, hyperactivity of adrenal gland, decrease insulin release and increase insulin resistance- Not Good.

To add question to all these theories, people who were treated with ACE and Angiotensin 1 blockers for hypertension before Covid infection have been shown to have poorest results and prognosis in Covid-19.(5,6,7), yet treatment of Covid patients with ACE and Angiotensin 1 blockers may not have a deleterious effect.

There is no up to date clinical data to support one or the other direction, which is why ‘the American Heart Association and the American College of Cardiology have both issued statements to suggest that there no evidence of harm or benefit with the use to ACE- inhibitors or Angiotensin 1 receptor blockers and that patients should continue to take their medications as usual’. (8)

The Diabetogenic Effect of Coronavirus:

It seems there is a greater incidence of high fasting blood glucose levels as well as acute onset diabetes among patients with SARS coronavirus 1 pneumonia than among those with non-SARS pneumonia (11).  It is speculated that this new viral cause of ketosis-prone diabetes may be related to coronavirus that binds to ACE-2 receptors on beta cells (insulin producing) of the pancreas (10).

CoviDIAB :Plan to answer Covid induced new onset diabetes

How frequent is the phenomenon of new onset diabetes due to Covid-19?

Is it a classic type 1 or type 2 diabetes, or is it a new type of diabetes we have not yet to discover?

Do these patients remain at higher risk after the infection is cured?

Does Covid-19 change the pathophysiology of an existing diabetes?

Answering all of these questions is of vital importance so that we can inform the immediate clinical care and it remains a top priority in the battle against Covid-19.

In an effort to find answers to some of these questions, a group of top international diabetes researchers participating in the ‘CoviDIAB’ project have established a global registry of patients with Covid-19 related diabetes (covidiab.e-dendrite.com)
 

The main goal of the registry is to describe and understand a new phenotype of Covid associated acute onset diabetes, diabetes mellitus that is defined by : hyperglycemia, confirmed Covid-19, negative history of diabetes, and a history of normal glycated hemoglobin levels.  The registry is planned to expand in the future so it can include people with preexisting diabetes who present with Covid and severe acute metabolic disturbance too.

This registry will also be used to investigate the epidemiologic features and pathogenesis of Covid-19 related diabetes, so clues regarding appropriate care for people during and after the course of Covid-19 can be gained.

Reference:
 

1.  Li J, Wang X, Chen J, Zuo X, Zhang H, Deng A. COVID-19 infection may cause ketosis and ketoacidosis. Diabetes Obes Metab 2020 April 20 (Epub ahead of print).

2. Special Expert Group for Control of the Epidemic of Novel Coronavirus Pneumonia of the Chinese Preventive Medicine Association[An update on the epidemiological characteristics of novel coronavirus pneumonia COVID-19] Zhonghua Liu Xing Bing Xue Za Zhi 202041139–144

3.  Korean Society of Infectious Diseases, Korean Society of Pediatric Infectious Diseases, Korean Society of Epidemiology, Korean Society for Antimicrobial Therapy, Korean Society for Healthcare-associated Infection Control and Prevention, Korea Centers for Disease Control and Prevention. Report on the Epidemiological Features of Coronavirus Disease 2019 (COVID-19) Outbreak in the Republic of Korea

4. Guan W J, Ni Z Y, Hu Yet al.For the China Medical Treatment Expert Group for COVID-19. Clinical Characteristics of Coronavirus Disease 2019 in China N Engl J Med 202010.1056/NEJMoa2002032[Epub ahead of print

5. Wu C, Chen X, Cai Yet al.Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China JAMA Intern M Ed 202010.1001/jamainternmed.2020.0994[Epub ahead of print]

6. Dalan R, Bornstein SR, El-Armouche A, et al. The ACE-2 in COVID-19: Foe or Friend?. Horm Metab Res. 2020;52(5):257-263. doi:10.1055/a-1155-0501

7. Bozkurt B, Kovacs R, Harrington B. HFSA/ACC/AHA statement addresses concerns re: using RAAS antagonists in COVID-19. Published and accessed on: March 17. 2020

8. Hamming I, Timens W, Bulthuis ML, Lely AT, Navis G, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus: a first step in understanding SARS pathogenesis. J Pathol 2004;203:631-637.

9. Hamming I, Timens W, Bulthuis ML, Lely AT, Navis G, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus: a first step in understanding SARS pathogenesis. J Pathol 2004;203:631-637.

10. Yang J-K, Lin S-S, Ji X-J, Guo L-M. Binding of SARS coronavirus to its receptor damages islets and causes acute diabetes. Acta Diabetol 2010;47:193-199.

11. Hamming I, Timens W, Bulthuis ML, Lely AT, Navis G, van Goor H. Tissue distribution of ACE2 protein, the functional receptor