During the spring of 2020, doctors in New York City, the then epicenter of the pandemic in the United States, noticed a significant number of people hospitalized with COVID-19 who had very high blood sugar, something called hyperglycemia and a trait hallmark of diabetes.
«[A mis colegas y a mí] We were having a hard time controlling blood glucose in some COVID-19 patients, even those with no history of diabetes,” says Shuibing Chen, a stem cell biologist at Weill Cornell Medicine. Most surprising, according to Chen, was that some patients who did not have diabetes before infection developed newly diagnosed diabetes after recovering from COVID-19.
The virus that causes COVID-19, SARS-CoV-2, is best known for wreaking havoc on 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 deal with this complication.
Intrigued by the surprising link between COVID-19 and diabetes, Chen and Jackson launched independent research to discover how SARS-CoV-2 could trigger hyperglycemia. Both groups published their results in the May issue of Cell Metabolism.
“Their findings provide fundamental information about the underlying mechanisms by which COVID-19 can lead to the development of newly diagnosed diabetes in infected patients,” said Rita Kalyani, assistant professor of medicine in the Division of Endocrinology, Diabetes and Metabolism at Johns Hopkins University, which was not involved in any of the studies.
The pancreas, another target of the COVID-19 virus
SARS-CoV-2 affects each person very differently. Many people suffer only mild symptoms, but others develop serious, life-threatening illness. As the pandemic unfolded, it became clear that this virus could spread beyond the lungs and damage other important organs, such as 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 grew several types of tissues in the lab and tested which were vulnerable to the virus that causes COVID-19. “To our surprise, we found that pancreatic beta cells were very permissive to SARS-CoV-2 infection,” says Chen. The pancreas, located under the stomach, is a complex organ consisting of numerous types of cells that contribute to digestion. It also contains beta cells that make insulin, the hormone that accompanies glucose 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 lab dish doesn’t mean it attacks the human body in the same way. To ensure that the laboratory observations were a true reflection of what happens in living humans, both Chen’s and Jackson’s teams acquired autopsy samples from patients who had 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? When patients suffer from pneumonia, the infection in the lung can cause tissue damage that allows the virus to leak from the alveoli into the blood vessels, Jackson explains. “Once in circulation, the virus can penetrate other highly vascularized tissues such as the pancreas, brain and kidneys.” Others have speculated that the virus could enter the bloodstream by leaking through the intestines, which could occur in patients without healthy intestinal bacteria.
How the virus prevents insulin production
Both research teams observed that beta cells infected by SARS-CoV-2 stopped making insulin. In Jackson’s study, infected beta cells died by apoptosis, a genetically programmed self-destruct sequence initiated by wounded cells.
Chen’s group discovered that infected beta cells underwent a process called transdifferentiation, meaning they became another type of cell; one that no longer makes 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 cause type 1 diabetes, which is usually due to genetic risk factors that trigger an autoimmune reaction that attacks and destroys beta cells. Type 1 diabetes is most commonly seen at a young age and requires patients to inject insulin daily as their body no longer makes this hormone. Type 1 diabetes also involves an environmental trigger, such as an infection, to initiate the autoimmune reaction.
In contrast, type 2 diabetes, much more common, occurs when the body becomes resistant to the insulin it produces. Type 2 diabetes can be managed with changes in diet and exercise, although medication that increases insulin sensitivity is sometimes needed.
It is important to continue studying the fate of infected beta cells, as there may be a way to prevent their destruction in patients with severe COVID-19. Chen’s team analyzed a large set of chemicals in the hope of finding one that would prevent the transdifferentiation process.
Possible treatments
Chen warns that “trans-ISRIB is not an FDA-approved drug.” [Administración de Alimentos y Medicamentos de Estados Unidos], 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 discovered a cellular protein receptor called neuropilin-1 was critical for SARS-CoV-2 to invade beta cells; Blocking this receptor prevents it from infecting them.
There is also great interest in the research community to develop drugs that prevent cells from being destroyed by apoptosis. Experimental compounds called caspase inhibitors, which prevent cell suicide, are being studied as possible therapies to improve or prevent severe COVID-19. Unfortunately, caspase inhibitors have not been completely successful in the clinic despite their great promise and interest. However, “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. «Coxsackie B virus, 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 somewhat controversial.” Further research is needed to determine whether it is possible to neutralize viral attacks on the pancreas, either by blocking the infection or by preventing the virus from reaching the organ.
Kalyani insists that these studies “underscore the importance of getting vaccinated against COVID-19. “People who contract COVID-19, especially those with prediabetes or other diabetes risk factors, should let healthcare professionals know if they develop symptoms of hyperglycemia, such as frequent urination, excessive thirst, blurred vision, or unexplained weight loss.” .
These new findings highlight that much remains to be learned about COVID-19 and its aftermath. It is clear that, for some unfortunate people, overcoming the virus will only be the beginning. Additional complications could arise depending on which body systems have been damaged following the viral infection.