Obesity and diabetes appear to worsen the symptoms of COVID-19. The question is why? Researchers have found that adipocyte-like cells may be the potential culprit. The surrounding tissue becomes a viral reservoir, but the solution may be right in front of our noses.
Some people do not even notice being infected with SARS-CoV-2. Others start with a fever, cough, fluid in the lungs, severe inflammation and may progress to needing a ventilator.
Researchers have found that old age is a risk factor for developing severe symptoms in COVID-19. Chronic diseases such as asthma, cancer and heart disease can also increase the risk of ending up in the intensive care unit. And then the trajectory of COVID-19 is statistically more severe and long term for people with diabetes or obesity than for those outside the high-risk groups.
“Our Center specializes in the physiology of fat cells: the role they play in the body and what exactly happens when we become obese, which is often closely associated with type 2 diabetes and with greater susceptibility to viruses and serious outcomes. Our background prompted us to examine the underlying reasons for this,” explains Philipp Scherer, Professor and Director of the Touchstone Diabetes Center at the University of Texas Southwestern Medical Center in Dallas.
Explaining the interaction between fat cells and SARS-CoV-2
The fact that fat cells (adipocytes) can play several roles has become more and more clear for researchers in recent years. Fat cells can grow, shrink or die but also have the ability to transform themselves.
One of these types of adipocyte-like cells is called a lipofibroblast and is present in the lungs. In an article published in Obesity, Philipp Scherer and Ilya L. Kruglikov argue that lipofibroblasts are essential in explaining why SARS-CoV-2 makes some people more ill than others.
Lipofibroblasts are usually benign. But when SARS-CoV-2 enters the adipocytes, they are activated and may turn into malicious myofibroblasts.
“The assumption confirmed in other studies is that myofibroblasts cause fibrosis. And we see more and more data that support fibrosis playing a significant role in COVID-19. Myofibroblasts clog up the interface of the lungs, worsen oxygen exchange and therefore make breathing more difficult,” says Philipp Scherer.
But not only the myofibroblasts cause harm. The virus needs a pathway. That role is played by angiotensin‐converting enzyme 2 (ACE2), a protein present on the outer membrane of adipocytes. Research suggests that ACE2 is present to varying degrees in all of us but has higher density and activity in the adipose tissue of people with diabetes or obesity. This may explain why these people experience COVID-19 more severely.
Various parasites act the same way. They love fat cells, break into them and can live there for a very long time. They get all the food they want and are protected from the immune system. The virus has a front door, which is ACE2. The fat cell becomes a kind of viral reservoir where the virus can thrive and proliferate.
Diabetes medicine may alleviate symptoms
Researchers globally are racing to find medicine to at least slow down SARS-CoV-2 and preferably prevent it from proliferating. Some have more success than others.
Experiments have been performed with blood plasma from people who have had COVID-19; with camostat mesylate, a medicine produced in Japan for treating heartburn or pancreatitis; with adrenocorticotropic hormone; with remdesivir; and with hydroxychloroquine. Most recently, the anti-inflammatory drug dexamethasone has shown promising results.
“As diabetes researchers, we are entering the world of infectious disease research from left field,” says Philipp Scherer.
This is a tough area to get into, because there are already a handful of treatments out there. But none of them have really shown a dramatic effect yet. The antivirals have reduced the average hospital stay by a couple of days but have not affected the mortality rate significantly.
In their article on adipocytes and COVID-19 symptoms, Scherer & Kruglikov suggest yet another remedy: various types of thiazolidinediones (TZDs), which are already used in treating people with type 2 diabetes. These are anti-inflammatory agents that can potentially prevent the lipofibroblasts in the lungs from developing into myofibroblasts and may even reverse that process. These antidiabetic medicines may in theory alleviate the fibrosis in the lungs, repair the damaged adipose tissue and thereby alleviate the symptoms of COVID-19.
They also have the potential to block the pathway of infection with SARS-CoV-2 by suppressing ACE2 and thus preventing the virus from entering the adipocytes.
Philipp Scherer says that one advantage of TZDs is that they are already well known clinically.
“This is not a miracle cure, but it might buy time for the body’s own immune cells to take charge the situation. If you can inhibit the viral load, you also give the immune system the opportunity to catch up and take over. Eventually, the body will have to do most of the work.”
Trials with TZDs on the way
Philipp Scherer’s expectations are based on studies in mice and on what is known about the related SARS coronavirus (SARS-CoV), which hit Asia especially hard in the early 2000s.
Since the current coronavirus, SARS-CoV-2, is similar to SARS-CoV in its structure and behaviour, Scherer argues that the findings about SARS-CoV are likely to be transferrable to today’s tormentor.
“There is already much useful evidence from other fields. For example, the transition from lipofibroblasts to myofibroblasts has been demonstrated for several chronic diseases. All we did is connect the dots. This is hypothesis-driven work based on a big data platform that now has to be tested in this specific context,” explains Philipp Scherer.
Philipp Scherer and his colleagues are therefore currently preparing trials to test the TZDs in practice for people with COVID-19.
For the people with COVID-19 who also have diabetes, TZDs may have several benefits. They are anti-inflammatory, reduce fibrosis and improve insulin sensitivity. Thus, they can both alleviate and prevent.
“It has been and still is the wild west in proposing and testing what might be effective or not against COVID-19. The first rule must be not to cause more harm than good.”
The only side-effect of TZDs is that they may cause some people to gain a little weight. However, since life and death are at stake, Philipp Scherer proposes trying this treatment.
We have a sound theoretical and scientific basis for proposing TZDs. But the most important criterion will be whether they make a clinical difference.
“The role of adipocytes and adipocyte-like cells in the severity of COVID-19 infections” has been published in Obesity. In 2017, Philipp Scherer received the EASD–Novo Nordisk Foundation Diabetes Prize for Excellence for his extensive contributions to diabetes research.