Underlying mechanisms linking obesity and diabetes with severe COVID-19

Breaking new ground 27. dec 2020 4 min Professor Philipp Scherer Written by Kristian Sjøgren

People with obesity and Type 2 diabetes have a substantially increased risk of a severe outcome of COVID-19. Researchers have found a biological link and a possible treatment.

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The COVID-19 pandemic is raging around the world, and no one is spared.

People with obesity or Type 2 diabetes are hit the hardest. For them, COVID-19 can quickly develop into a death sentence.

The idea that Type 2 diabetes and obesity predispose to general poor health is the reason for the high risk of severe COVID-19 is generally plausible, but there are even more important underlying biological mechanisms.

Now researchers are proposing why people with obesity or Type 2 diabetes are especially likely to occupy hospital beds around the world during the COVID-19 pandemic.

“Evidence demonstrates that people with obesity or Type 2 diabetes who develop COVID-19 have an increased risk of a severe trajectory. However, their general poor health clearly explains only part of this. In this study, we found some possible biological mechanisms that may explain what happens when COVID-19 becomes severe or fatal for these people. Our model might be used to form the basis for how to diagnose the risk of a severe trajectory,” says Philipp Scherer, Professor, Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, United States.

The research has been published in eLife.

Bacterial cell membranes cause inflammation

The background for the new study is a review of the literature in this field. The study aimed to find the characteristics of obesity and Type 2 diabetes that may explain the link to severe COVID-19.

Based on the literature, the researchers found two possible mechanisms.

One is differences in intestinal permeability. We all have bacteria in our gut, and they should preferably stay there. Bacteria should especially not enter the bloodstream through the gut wall because blood poisoning and other serious conditions can ensue if this happens.

Bacterial degradation products, including especially lipopolysaccharides, which are one of the main components in the cell membranes of bacteria, should be prevented from passing through the gut wall and into the bloodstream.

However, lipopolysaccharides still occasionally cross the intestinal wall into the blood. This happens to all of us, but people with obesity or Type 2 diabetes have a slightly more permeable gut wall than healthy people, so lipopolysaccharides can more easily enter the body.

“People with obesity or Type 2 diabetes have higher levels of lipopolysaccharides in the blood than people of normal weight and people without Type 2 diabetes,” says Philipp Scherer.

COVID-19 causes an overburdened immune response to go crazy

Elevated levels of lipopolysaccharides in the blood are a real problem. They are a sign of inflammation, which means that the body and the immune system are operating on overdrive because they perceive threats everywhere.

According to Philipp Scherer, if a person then gets COVID-19, this can put further pressure on the immune response, which reacts by going completely crazy.

When the immune system goes crazy, this triggers a cytokine storm, which is basically a disproportional increase in proinflammatory cytokines that is much higher than the result of a single exposure to either viral or bacterial agents. This can become life-threatening, and according to Philipp Scherer, this is what happens to many people with obesity or Type 2 diabetes when they develop COVID-19.

The overreaction of the immune system kills people – not COVID-19.

“This corresponds to anaphylactic shock. People’s immune system goes nuts. The immune system must respond to threats, but in this case, it is already under pressure and then overreacts when it encounters SARS-CoV-2,” says Philipp Scherer.

Inflammation from COVID-19 causes scarring of the lungs

The second part of the explanation for why people with obesity and Type 2 diabetes have a greater risk of severe COVID-19 is fat cells or their equivalents in the lung, the lipofibroblasts. They can grow, become smaller, die or go back to an earlier stage of development, from which they can differentiate into other types of cells.

That is very useful, such as in breast tissue when a woman needs to lactate, when fat cells undergo these reversible changes.

When inflammation pressures these precursor cells, they may transform themselves into myofibroblasts, a type of connective tissue cell.

Myofibroblasts form scar tissue, and this is especially bad for the lungs. So if the body is burdened by inflammation from obesity or Type 2 diabetes and then encounters COVID-19, the myofibroblasts may form thick scar tissue in the lungs. In especially severe cases, this can reduce the ability to breathe normally.

“This kills people because they cannot oxygenate their blood,” says Philipp Scherer.

Antidiabetic drugs may counter the effects of COVID-19

This is where Philipp Scherer and his colleague, Ilja Kruglikov, have an interesting suggestion. Anti-inflammatory and antifibrotic drugs might be used to counter the negative outcomes of COVID-19.

These drugs are called peroxisome proliferator-activated receptor (PPAR)-gamma agonists and are used to lower the levels of triglycerides and blood glucose among some people with prediabetes.

“They have been marketed for 20 years but are especially interesting for COVID-19 because they target its worst aspects,” explains Philipp Scherer.

Philipp Scherer and his colleagues are planning to start a clinical study to examine their hypothesis and determine whether PPAR-gamma agonists can alleviate the symptoms of COVID-19.

“They are safe to use, and we will give PPAR-gamma agonists to trial participants with obesity and with Type 2 diabetes to determine whether these can keep them out of the hospital if they get COVID-19,” explains Philipp Scherer.

PPAR-gamma agonists make penetrating cells more difficult for SARS-CoV-2

Philipp Scherer explains that PPAR-gamma agonists work by downregulating the angiotensin-converting enzyme 2 (ACE2) receptors on the surface of both fat cells and myofibroblasts.

The ACE2 receptors are expressed broadly on the fat cells and especially the myofibroblasts in the lungs.

The ACE2 receptor is also the functional receptor that SARS-CoV-2 exploits to enter host cells.

Finally, PPAR-gamma agonists also affect the permeability of the intestinal wall.

“This is good news all around because PPAR-gamma agonists have positive effects on all the aspects that make COVID-19 dangerous. Many of these effects have also been demonstrated in cell culture, so our hypothesis is based on solid evidence. We believe that these types of drugs can make a real difference for people with COVID-19,” says Philipp Scherer.

The main focus in our laboratory is the identification and physiological characterization of adipocyte-specific gene products and the elucidation of p...

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