SARS-CoV-2 may make people more vulnerable to developing diabetes

May 26, 2021
Is diabetes a cause of severe COVID-19, or does the SARS-CoV-2 virus have an effect on the pancreas itself? (AP Photo/Jorge Saenz)

Is diabetes a cause of severe COVID-19, or does the SARS-CoV-2 virus have an effect on the pancreas itself? (AP Photo/Jorge Saenz)

The virus responsible for the deadly COVID-19 pandemic induces cell death in the pancreatic beta cells that produce insulin but does not target the rest of the pancreas, according to a new study on the connection between COVID-19 and diabetes.

The study, published May 18 in Cell Metabolism, supports existing evidence that the incidence and severity of COVID-19 is higher in patients with diabetes. However, unlike in previous studies, the researchers of this study have discovered that this connection could go both ways: Not only does diabetes make a person more vulnerable to severe COVID-19, but SARS-CoV-2, the virus that causes COVID-19, could also make people more susceptible to developing diabetes by damaging the cells of the pancreas and inhibiting insulin production.

"The question is, is [diabetes] a preexisting cause of severe COVID? Or does the virus actually have something to do with having an effect on the pancreas itself?" said senior author Peter Jackson, a professor of microbiology and immunology at Stanford University. "Is it cause or consequence?"

As reported by the Centers for Disease Control and Prevention, there have been 32,947,548 cases of COVID-19 in the United States as of May 25, resulting in 587,342 deaths. Patients with diabetes and COVID-19 are at greater risk of sepsis, a life-threatening condition in which the body's immune response attacks its own tissues. This has led to greater COVID-19 mortality in patients with diabetes.

The first study on COVID-19 and diabetes, conducted in May 2020, reported that 10% of COVID-19 patients with diabetes die within seven days of being hospitalized. And while new developments such as better COVID-19 testing, contact tracing and vaccines may reduce mortality, this is not the only issue to be addressed in studying SARS-CoV-2.

"For those patients who do not [die], what would this mean in the long run?" Jackson asked. "That's one of those things we really don't understand."

To help answer this question of long-term effects, Jackson and his team are investigating the biological mechanisms at play in SARS-CoV-2 infections. Building on their previous work on COVID-19 and airway cells, the researchers turned to the cells of the pancreas. While this may appear to be somewhat of a left turn, there is a connection between these two cell types: Both are covered in tiny hairlike structures called cilia. 

A prior interest in cilia, coupled with access to pancreatic tissue samples through the Stanford Diabetic Research Center, allowed the team to shift its focus to determining how SARS-CoV-2 affects the pancreas.

"We started working with more pathologists and getting tissue samples and realized that, staining the patient's samples for antigens to COVID-19 spike protein, that the virus was indeed pretty selectively present in beta cells," Jackson said.

In other words, when SARS-CoV-2 enters the pancreas, it does not attack all cells with equal vigor. Instead, it focuses more on the beta cells, which are responsible for the production of insulin. And the results of this attack are multifaceted.

"We found that the virus did several things," Jackson said. "It infected the beta cells selectively, it caused beta cell killing, and it also suppressed the ability of glucose to stimulate insulin secretion."

The researchers also wanted to know why SARS-CoV-2 would attack these cells so selectively. It turns out the answer lies in the receptors that the virus uses to attach to cells. While the main receptor for the virus is ACE2, which is found in a wide variety of human cells, there are also co-receptors that help the virus enter cells more efficiently.

"Imagine that you're trying to catch the viral particle like a ball," Jackson said. "ACE2 is critical. It's like your strong hand. But it's always great to have a second hand to position the ball when it comes in."

This second hand, in the case of SARS-CoV-2, is a variety of co-receptors that team up with ACE2 to allow the virus to infect healthy cells. In the pancreatic tissue samples, the researchers found elevated levels of the co-receptor neuropilin-1, which is also found in the cells of the nose. This co-receptor helps explain the long-term loss of smell reported by many COVID-19 patients, even those who experience only a mild case.

To confirm their hypothesis that this receptor was allowing the virus to infect beta cells in the pancreas, the researchers inhibited the receptor to see whether this would reverse the selectivity.

That is precisely what happened.

"We could actually rescue beta cell infection, beta cell killing and glucose-stimulated insulin secretion — all three," Jackson explained.

The findings suggest that there could be damage to the pancreas in patients who contract SARS-CoV-2, even if they are not already diabetic. While the researchers warn that these are only preliminary findings, and that more research will be needed to determine how this mechanism affects the health of living patients, the team also maintains that scientists and the public should not become complacent in the face of the pandemic, despite several successful vaccines.

"We're not quite done as scientists," Jackson said. "If the lesson from all this is getting Moderna and Pfizer to make a great vaccine, sure; that's a wonderful thing they did. But we're not done. And we should be ready for the next thing."

The study, "SARS-CoV-2 infects human pancreatic β-cells and elicits β-cell impairment," published May 18 in Cell Metabolism, was authored by Chien-Ting Wu, Ivan T. Lee, Ran Cheng, Tsuguhisa Nakayama, Sizun Jiang, Janos Demeter, Romina J. Bevacqua, Charles A. Chang, Robert L. Whitener, Bokai Zhu, Han Chen, Yury Goltsev, Jayakar V. Nayak, Garry P. Nolan, Raul Andino and Peter K. Jackson, Stanford University; Peter V. Lidsky and Yinghong Xiao, University of California, San Francisco; and Anna K. Stalder, Matthias S. Matter and Alexandar Tzankov, University of Basel. 

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