During the spring of 2020, doctors in New York City, the epicenter of the then American pandemic, noticed that a significant number of people hospitalized with COVID-19 had too much sugar in their blood, a condition called hyperglycemia, which is a signature feature of diabetes.
“[My colleagues and I] found it very challenging to control blood sugar levels in some COVID-19 patients, even those without diabetes, ”says stem cell biologist Shuibing Chen at Weill Cornell Medicine. More surprising, Chen says, was that some patients who did not have diabetes before the infection developed incipient diabetes after recovering from COVID-19.
COVID-19 virus, SARS-CoV-2, is best known to wreak havoc on the lungs and cause acute respiratory distress. But how and why a COVID-1
A global 2020 analysis led by population survey Thirunavukkarasu Sathish at McMaster University in Canada found that nearly 15 percent of severe COVID-19 patients also developed diabetes. But, he admits, “this number is likely to be higher among people at high risk, such as prediabetes.” Research led by endocrinologist Paolo Fiorina at Harvard Medical School and published in 2021 reported that of 551 patients admitted due to COVID-19 in Italy, almost half became hyperglycemic.
Peter Jackson, a biochemist at Stanford University School of Medicine, estimates “as many as 30 percent of patients with severe COVID-19 may develop diabetes.”
Imprisoned by the surprising link between COVID-19 and diabetes, both Chen and Jackson launched independent studies to uncover how SARS-CoV-2 can trigger hyperglycemia. Both groups published their findings in the May issue of Cell metabolism.
“Their findings provide critical insight into the underlying mechanisms by which COVID-19 may lead to the development of onset diabetes in infected patients,” said Rita Kalyani, associate professor of medicine at the Johns Hopkins Division of Endocrinology, Diabetes and Metabolism, who was not involved in any of the studies.
The pancreas is another target for the COVID-19 virus
SARS-CoV-2 affects humans in very different ways. Many people experience only minor symptoms, but others develop severe, life-threatening illness. As the pandemic unfolded, it became clear that this virus could spread beyond the lungs and damage other critical organs, including the liver, heart and kidneys. It also became clear that diabetes and obesity were common risk factors for severe COVID-19.
In a previous study, Chen’s group cultured different types of tissues in the laboratory and tested those that were vulnerable to the COVID-19 virus. “Very surprisingly, we found that beta cells in the pancreas are very permissible for SARS-CoV-2 infection,” says Chen. The pancreas, which lies behind the stomach, is a complex organ composed of several types of cells that help with digestion. It also contains beta cells that produce insulin, the hormone that escorts sugar molecules from the blood to the body’s cells, where it is used for energy.
But just because a virus can infect cells grown in a bowl in the laboratory does not mean it attacks the body in the same way. To ensure that laboratory observations were a true reflection of what happens in living humans, both the Chen and Jackson teams obtained autopsy samples from patients who succumbed to COVID-19. Both groups detected SARS-CoV-2 in pancreatic beta cells from these deceased patients.
But how exactly does a respiratory virus move from the lungs to the pancreas? After patients experience pneumonia, the infection in the lower lung can cause tissue damage that allows the virus to leak from the pulmonary alveoli and into the blood vessels, Jackson explains. “When in circulation, the virus can enter other highly vascularized tissues such as the pancreas, brain and kidneys.” Others have speculated that the virus can enter the bloodstream by leaking out of the gut, which can occur in patients who lack healthy gut bacteria. (Microbes in your gut can be new recruits in the fight against viruses)
How the virus shuts down insulin production
Both research teams noted that beta cells infected with SARS-CoV-2 stop producing insulin. In Jackson’s study, the infected beta cells died via apoptosis, a genetically programmed autodestruction sequence initiated by damaged cells.
Chen’s group found that infected beta cells underwent a process called transdifferentiation, which means that they are converted to another type of cell; one that no longer produces insulin. It is possible that some infected beta cells undergo transdifferentiation while others self-destruct.
In both cases, the end result is the same: when COVID-19 virus attacks beta cells in the pancreas, insulin production decreases.
This can lead to type 1 diabetes, which is usually due to genetic risk factors that stimulate an autoimmune reaction that attacks and destroys beta cells. Type 1 diabetes is seen earlier in life and requires patients to inject insulin every day as their body no longer produces the hormone. Type 1 diabetes also involves an environmental trigger, such as an infection, to trigger the autoimmune reaction.
In contrast, the much more common type 2 diabetes occurs when the body becomes resistant to the insulin it produces. Type 2 diabetes can be managed with changes in diet and exercise, although sometimes medication is needed that improves insulin sensitivity. In total, 34.2 million Americans have diabetes, according to a 2020 report issued by the Centers for Disease Control.
The fate of the infected beta cells is important to investigate further, as there may be a way to prevent their destruction in patients with severe COVID-19. Chen’s team examined a large panel of chemicals in hopes of finding one that could prevent the transdifferentiation process.
The study identified a compound called trans-ISRIB that helped beta cells maintain their identity and their ability to produce insulin when infected with SARS-CoV-2. Trans-ISRIB, which stands for Integrated Stress Response InhiBitor, is a compound discovered in 2013 that is capable of preventing a cell’s normal response to stress. Such compounds are being investigated as potential therapeutic agents to prevent widespread apoptosis and injury.
Chen warns: “Trans-ISRIB is not an FDA-approved drug, so it cannot be used in patients yet. However, our studies support the idea that a new drug could be developed to prevent COVID-19 from causing diabetes. Jackson’s group found that a cellular protein receptor called neuropilin-1 was critical for SARS-CoV-2 to invade beta cells; blocking this receptor prevents them from becoming infected.
There is also great interest among the broader research community to develop drugs that prevent cells from destroying themselves by apoptosis. Experimental compounds called caspase inhibitors that prevent cell suicide are being investigated by others as potential therapies for the improvement or prevention of severe COVID-19. Unfortunately, caspase inhibitors have not proven to be a complete success at the clinic despite great promise and interest. Nevertheless, “they may be able to work for short-term exposure to limit virus damage,” Jackson said.
Chen adds that SARS-CoV-2 is not the only virus that threatens the pancreas. Coxsackievirus B, rotavirus, mumps virus and cytomegalovirus have been shown to infect and damage beta cells. Whether they are a direct cause of type 1 diabetes has been controversial. More research is needed to determine if it is possible to neutralize viral attacks on the pancreas, either by blocking infection or preventing the virus from reaching the organ in the first place.
Kalyani stresses that these studies “further underscore the importance of being vaccinated against COVID-19. People who contract COVID-19, especially those with prediabetes or other risk factors for diabetes, should inform their healthcare providers if they develop symptoms of hyperglycemia, such as frequent urination, excessive thirst, blurred vision or unexplained weight loss. “
These new findings underscore that there is much to learn about COVID-19 and its aftermath. It seems that for some unfortunate people it is only the beginning of defeating the virus. Additional complications can occur depending on which systems in the body have been damaged in the wake of the viral infection.