During the spring of 2020, physicians in New York City, the U.S. epicenter of the pandemic at the time, noticed a considerable number of people hospitalized with COVID-19 had too much sugar in their blood, a condition called hyperglycemia that is a signature feature of diabetes.
“[My colleagues and I] found it very challenging to control the blood glucose level of some COVID-19 patients, even those without a history of diabetes,” says stem cell biologist Shuibing Chen at Weill Cornell Medicine. More surprising, says Chen, was that some patients who did not have diabetes prior to the infection, developed new-onset diabetes after recovering from COVID-19.
The COVID-19 virus, SARS-CoV-2, is best known for wreaking havoc in the lungs and causing acute respiratory distress. But how and why a COVID-19 patient would suddenly develop a chronic disease like diabetes is a mystery, as is the number of people who must then deal with this complication.
A global 2020 analysis led by population health researcher Thirunavukkarasu Sathish at McMaster University in Canada found that nearly 15 percent of severe COVID-19 patients also developed diabetes. But, he admits, “this figure is likely to be higher among high-risk individuals, prediabetes for example.”Research led by endocrinologist Paolo Fiorina at Harvard Medical School and published in 2021 reported that of 551 patients hospitalized for COVID-19 in Italy, nearly half became hyperglycemic.
Peter Jackson, a biochemist at the Stanford University School of Medicine, estimates “as many as 30 percent of patients with severe COVID-19 may develop diabetes.”
Intrigued by the startling connection between COVID-19 and diabetes, Chen and Jackson both launched independent investigations to uncover how SARS-CoV-2 might trigger hyperglycemia. Both groups published their results in the May issue of Cell Metabolism.
“Their findings provide critical insights into the underlying mechanisms by which COVID-19 can lead to the development of new-onset diabetes in infected patients,” says Rita Kalyani, an associate professor of medicine at Johns Hopkins Division of Endocrinology, Diabetes, and Metabolism, who was not involved with either study.
The pancreas is another target of the COVID-19 virus
SARS-CoV-2 affects people in very different ways. Many people experience only minor symptoms, but others develop severe, life-threatening disease. As the pandemic unfolded it became apparent 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 an earlier study, Chen’s group grew various types of tissues in the lab and tested which ones were vulnerable to the COVID-19 virus. “Very surprisingly, we found that beta cells of the pancreas are highly permissive to SARS-CoV-2 infection,” says Chen. The pancreas, which lies behind the stomach, is a complex organ composed of numerous types of cells that assist with digestion. It also contains beta cells that make insulin, the hormone that escorts sugar molecules from the blood into the body’s cells where it is used for energy.
But just because a virus can infect cells grown in a dish in the lab doesn’t mean it attacks the body in the same way. To ensure the laboratory observations were a true reflection of what happens in living humans, both the Chen and Jackson teams acquired 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 of the lower lung may cause tissue damage that allows the virus to leak from lung alveoli and into the blood vessels, explains Jackson. “Once in circulation, the virus can enter other highly vascularized tissues like the pancreas, brain, and kidney.” Others have speculated that the virus could get into the bloodstream by leaking out of the gut, which may occur in patients lacking healthy intestinal bacteria. (Microbes in your gut may 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 making insulin. In Jackson’s study, the infected beta cells died via apoptosis, a genetically-programmed autodestruct sequence initiated by injured cells.
Chen’s group found that infected beta cells underwent a process called transdifferentiation, which means they converted into another type of cell; one that no longer manufactures 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 the COVID-19 virus attacks the pancreatic beta cells, insulin production decreases.
This can lead to type 1 diabetes, which is usually caused by genetic risk factors that spur an autoimmune reaction that attacks and destroys beta cells. Type 1 diabetes is more commonly seen early in life and requires patients to inject insulin every day since their body no longer makes the hormone. Type 1 diabetes also involves an environmental trigger, such as an infection, to initiate the autoimmune reaction.
In contrast, the far more common type 2 diabetes occurs when the body becomes resistant to the insulin it makes. Type 2 diabetes can be managed with changes in diet and exercise, although sometimes medications that enhance insulin sensitivity are needed. Collectively, 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 study further as there may be a way to prevent their destruction in patients with severe COVID-19. Chen’s team surveyed a large panel of chemicals in hopes of finding one that could prevent the transdifferentiation process.
The survey 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 able to prevent a cell’s normal response to stress. Such compounds are being explored as potential therapeutics to prevent widespread apoptosis and damage.
Chen cautions, “Trans-ISRIB is not an FDA-approved drug, so it cannot be used in patients yet. But 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 keeps them from being infected.
There is also great interest among the broader research community to develop drugs that stop cells from destroying themselves by apoptosis. Experimental compounds called caspase inhibitors, which prevent cell suicide, are being studied by others as potential therapies to ameliorate or prevent severe COVID-19. Unfortunately, caspase inhibitors have not proved a complete success in the clinic despite great promise and interest. Nonetheless, “they might work for short term exposure to limit viral damage,” Jackson says.
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 the 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 getting vaccinated for COVID-19. Individuals who contract COVID-19, particularly those with prediabetes or other risk factors for diabetes, should let their health care providers know if they develop symptoms of hyperglycemia such as frequent urination, excessive thirst, blurry vision, or unexplained weight loss."
These new findings emphasize that there is much to learn about COVID-19 and its aftereffects. It seems clear that for some unlucky people, defeating the virus is only the beginning. Additional complications may arise depending on which systems in the body have been damaged in the wake of the viral infection.