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Not long after COVID-19 struck Milan, Italy, in early 2020 with devastating effects, Paolo Fiorina, an endocrinologist at the Università degli Studi di Milano, was heading into his workplace at Sacco Hospital when a pathologist there contacted him about patients she had examined who had recently died of the disease. All of the deceased—not just those with diabetes—had had high blood sugar levels, known as hyperglycemia. Fiorina says his first thought was that there must have been a mistake. “Diabetic patients are more prone to die of COVID-19 as compared to the nondiabetic ones, so I thought this could be the cause,” he explains, but that wouldn’t explain why the metabolically healthy individuals had also been hyperglycemic when they died.
Fiorina went through the records of the deceased patients and checked out the medical records for some other people admitted to the hospital with COVID-19, and soon realized that an unexpectedly large number of both had abnormally high blood sugar levels. Some of them had medical records available from before their COVID-19 admissions, and these generally showed no sign of diabetes or prediabetes, conditions associated with dysregulated blood sugar. “So we started to think about a potential link between COVID-19 and dysglycemia or glycometabolic abnormalities,” Fiorina says.
That led to publication of a study in May 2021 that reported on a cohort of 551 people admitted to Fiorina’s hospital with COVID-19; nearly half had higher than normal blood sugar levels. Even among the 27 percent of patients who had normal blood sugar levels, further monitoring revealed some of these showed changes in their blood sugar control over time after recovering from COVID-19.
Fiorina and his colleagues are just one group among many around the world who have linked COVID-19 and diabetes. Numerous studies now suggest that in addition to diabetes being tied to worse outcomes from COVID-19, SARS-CoV-2 infection may be triggering new-onset diabetes, even in people with no preexisting risk factors. The findings raise the possibility that the pandemic could lead to a dangerous and costly increase in the frequency of a chronic disease that was already shooting up in prevalence globally prior to the current pandemic.
Tracing new cases of diabetes stemming from the pandemic
Ziyad Al-Aly, chief of research and development at VA Saint Louis Health Care System in Missouri, was first alerted to a possible link between COVID-19 and diabetes by patient reports. Even in the first few months of the pandemic, people who had recovered from COVID-19 were coming back to the clinic describing the symptoms that are now labelled as long COVID, such as brain fog, fatigue, and muscle pain. But some also exhibited symptoms of metabolic disorders, including heart disease and diabetes. Al-Aly and colleagues decided to investigate further. To do so effectively, they needed a control group exposed to the same pandemic conditions—for example, lockdowns, stress, and lack of exercise—but who hadn’t gotten COVID-19.
The group’s research, published last month and involving more than 180,000 people who contracted COVID-19 and 4.1 million controls, revealed that COVID-19 is associated with a 40 percent higher risk of new-onset diabetes in the year following infection. That translates to more than one additional new case of diabetes per 100 cases of COVID-19.
“If you start to contextualize what one percent to two percent of people with COVID-19 might mean on a global level, that translates into millions and millions and millions of people with diabetes,” over and above what were already high rates of the disease, Al-Aly says. And that has major health, societal, and economic implications. “Diabetes is a very costly disease to treat, and has really serious downstream ramifications,” he says, pointing to an increased risk of strokes, heart disease, and eye disease. “I think it’s going to be a serious problem for all of us to contend with.”
How COVID-19 may increase diabetes risk
Before COVID-19, diabetes was the ninth leading cause of death worldwide, and in 2017, a little more than 6 percent of the global population had type 2 diabetes—a disorder in which the body becomes less responsive to the insulin that directs the storage of excess blood sugar in cells as a future energy source. In contrast to type 1 diabetes, an autoimmune condition that destroys insulin-producing beta cells in the pancreas, type 2 diabetes is linked to lifestyle factors such as poor diet and lack of physical activity.
Rates of type 2 diabetes around the world had been rising even before SARS-CoV-2 came along, but studies such as Al-Aly’s suggest that COVID-19 may add to the trend.
One possible explanation for the apparent connection between the two diseases is that people with diabetes risk factors such as obesity and heart disease, or who were already been on a path to developing diabetes in a state known as pre-diabetes, might be more likely to get very sick with COVID-19, more likely to end up in hospital, and more likely to die. For example, Fiorina says he and his colleagues’ 2021 study found that around one in two people with the highest blood sugar levels died from COVID-19, while those with the lowest blood sugar levels almost all survived. That could explain why the rate of high blood sugar and diabetes among Fiorina and Al-Aly’s patients was greater than expected.
If you start to contextualize what one percent to two percent of people with COVID-19 might mean on a global level, that translates into millions and millions and millions of people with diabetes.
—Ziyad Al-Aly, VA Saint Louis Health Care System
But Al-Aly and colleagues found that even among people with very few or no risk factors for diabetes, COVID-19 was associated with a higher risk of developing diabetes in the year after their infection.
It could be that the high rate of diabetes was found simply because, with so many more people being hospitalized or coming into the healthcare system during the pandemic, routine monitoring of blood sugar levels as part of their care was picking up cases of diabetes and pre-diabetes that might otherwise have gone undetected for a while longer. But Al-Aly’s study corrected for this “ascertainment bias”—for example, by accounting for healthcare use among the COVID-19 and control cohorts—and still showed a much higher rate of diabetes among recovered COVID-19 patients.
One clue about what’s happening physiologically comes from people who already have diabetes before they get COVID-19, according to Paul Zimmet, a diabetes researcher at Monash University in Melbourne, Australia. Studies have shown that “people who are very sick with COVID-19 who have got diabetes and are on insulin, they get a dramatic increase in the amount of insulin they need, because their body cells become resistant to insulin,” Zimmet says.
Domenico Accili, director of the Columbia University Diabetes and Endocrinology Research Center in New York, says he was shocked by the number of COVID-19 patients developing diabetic ketoacidosis, a state of dangerously high blood sugar levels, despite having no evidence of diabetes or abnormal blood sugar before they came into the hospital.
This by itself might be expected in people hospitalized with a severe infection, Accili says, because the high level of inflammation that occurs in this situation reduces the ability of tissues to respond to insulin and store blood sugar. “It’s well known that especially elderly patients with . . . pneumonia, sometimes develop stress-induced hyperglycemia,” he says. That might contribute to the later development of diabetes in people who had no obvious risk factors for the disease, in much the same way that people who get gestational diabetes during pregnancy have a higher risk for developing type 2 diabetes later in life.
The mechanism of such stress-induced hyperglycemia isn’t entirely clear, but inflammation might be to blame. A common feature of COVID-19, and particularly severe COVID-19, is a runaway immune response that leads to high levels of inflammation characterized by the production of signaling molecules called cytokines. Fiorina says he and colleagues found in their study that patients hospitalized with severe COVID-19 have extremely high levels of an inflammatory cytokine called IL-6. Insulin-producing beta cells in the pancreas have lots of receptors for IL-6, which could be how the inflammation is damaging those cells and affecting the production of insulin, he says. They have also shown in a recent study that exposing pancreatic beta cells to serum taken from COVID-19 patients triggers the beta cells to self-destruct.
Further evidence to support this idea that SARS-CoV-2 has a destructive effect on these insulin-producing cells comes from the observation by Fiorina and colleagues that among patients who had high levels of IL-6 and high blood glucose, those who were treated with tocilizumab that targets the IL-6 receptor showed greater reductions in their blood sugar levels than those who didn’t receive the drug.
Separately from the inflammation it causes, SARS-CoV-2 could trigger blood sugar dysregulation by virtue of the way the virus interacts with cells, says Al-Aly. The spike protein on its surface connects to the ACE2 receptor on the surface of the host cell. This receptor is found throughout the body, but—importantly—also on the surface of beta cells. “That spike protein interaction with the ACE2 receptor on the surface of the pancreatic beta cells might in some way impair insulin secretion and all downstream sequences that might lead to the phenotype of diabetes,” Al-Aly posits.
Charlotte Steenblock, who studies cellular stress responses at the University Clinic Carl Gustav Carus in Dresden, Germany, and colleagues showed last year that the SARS-CoV-2 virus had spread throughout the pancreas, including in beta cells, in patients who had died from COVID-19. The researchers also found evidence suggesting that the insulin-producing cells had undergone preprogrammed cell death in response to the infection. While they only had incomplete clinical information on the patients, the data suggested that those with higher blood sugar levels had greater levels of virus in their pancreases and more ACE2 receptors on pancreatic cells.
But Steenblock notes that this wasn’t a consistent pattern. Some patients with high blood sugar who died had low levels of ACE2 receptors, she says, while in others the reverse was true. She recalls an obese patient who succumbed very quickly to the infection; “she had a really high expression of ACE2, but you could also see a lot of virus everywhere in her body.” The findings suggest, Steenblock says, that the concentration of ACE2 receptors is linked to the risk and severity of hyperglycemia in some patients with severe and fatal COVID-19, but it’s not the only piece of the COVID-19 and diabetes puzzle.
The pandemic has not only highlighted the influence that SARS-CoV-2 infection has on the risk of diabetes, it’s also shown the importance of effectively treating existing diabetes. “Well-controlled diabetics don’t come into the COVID-19 ward,” says Accili, and high blood sugar levels translate into worse outcomes from COVID-19. “It’s either the hyperglycemia, or the stress associated with it, or the fact that if they’re poorly controlled they have more complications so their end organ function is already compromised.”
Fiorina argues that doctors need to be looking for high blood sugar and diabetes in people with COVID-19 because if it’s there, a variety of medications can be used to lower blood sugar. (Fiorina is also the founder and chief scientific officer of the autoimmune-focused biotech company Enthera, which is investigating therapeutics for Type 1 diabetes, among other conditions.)
Zimmet says he is most worried about the long-term implications of this potential new wave of diabetes diagnoses in the wake of COVID-19 infection. “The diabetes situation is really very, very serious,” he says. It’s just one facet of the bigger issue of long COVID, and what Zimmet describes as “Chapter 2” of the pandemic story. “We’re a long, long way away, still, from being ready to deal with the long-term effects of COVID-19.”