UM Study Reveals Why Diabetics May Develop Severe COVID-19

By Stone Andrews Last updated Sep 28, 2021

ANN ARBOR – New research from the University of Michigan recently revealed why people with type 2 diabetes are at high risk of developing severe cases of COVID-19.

Researchers identified an enzyme called SETDB2 – the same enzyme that can make inflammatory wounds difficult to heal in diabetics – as the likely culprit behind serious COVID infections.

After researcher W. James Melvin observed runaway inflammation in COVID patients in the intensive care unit, he decided to see if there was a possible link between the enzyme and the cases they were seeing.

Working in Katherine Gallagher’s laboratory in the Michigan Medicine Departments of Surgery and Microbiology and Immunology, they started a mouse model of COVID in diabetes-infected mice, in which they observed a decrease in SETDB2 in immune cells affected by the inflammatory response.

The immune cells, called macrophages, responded similarly in people with diabetes and severe COVID cases. In humans, the researchers observed the same reaction in monocyte macrophages using blood samples.

“We believe we have a reason these patients develop a cytokine storm,” Melvin said in a statement.

In both the human and mouse models, Gallagher and Melvin said that inflammation increased as SETDB2 decreased. Their research also showed a way that SETDB2 in macrophages known as JAK1 / STAT3 regulates during active COVID infection.

Their results point to a potential therapeutic avenue that could have benefits in reversing the pattern exhibited by COVID patients with diabetes.

The lab previously found that interferon, an important cytokine for viral immunity, was able to increase SETDB2 when it was responsive to wound healing. As part of the new study, researchers found that blood serum from intensive care patients with diabetes and severe COVID infections were more likely to have reduced interferon beta levels compared to non-diabetic patients.

“Interferon has been studied as a potential therapy throughout the pandemic, with efforts going back and forth between trying to raise or lower interferon levels,” Gallagher said in a statement. “I have a feeling that its effectiveness as a therapy will be both patient and time specific.”

The study team was able to lower inflammatory cytokines and increase SETDB2 in diabetic COVID-infected mice by administering interferon beta.

“We’re trying to figure out what controls SETDB2, which is sort of the primary regulator of many of those inflammatory cytokines that you hear are elevated in COVID-19, like IL-1B, TNFalpha and IL-6,” Gallagher said in a statement .

“If you look upstream of what SETDB2 controls, interferon is at the top, with JaK1 and STAT3 in the middle. Interferon increases both, which increases SETDB2 in a kind of cascade. “

The importance of identifying the signaling pathway is that it gives researchers alternative methods to target the enzyme, Gallagher said.

“Our research shows that if we can target patients with diabetes with interferon, especially early on in their infection, it can actually make a huge difference,” Melvin said in a statement.

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