Early in the pandemic, scientists found that many people with diabetes who got COVID-19 had severe outcomes. Three years later, researchers continue to study the effects of COVID-19 on people with diabetes, the phenomenon of new-onset diabetes after COVID-19, and the possible mechanisms underlying the COVID-19–diabetes relationship. Jane Reusch, MD‚ co-chair of the Metabolic Disorders Task Force for NIH’s Researching COVID to Enhance Recovery (RECOVER) Initiative, explains how research may affect diabetes diagnosis, treatment, and long-term complications.

Q: How does having COVID-19 affect people with diabetes?

A: We learned from early reports out of China that people who had diabetes prior to a COVID-19 infection were more likely than people without diabetes to have a poor outcome. For example, people with diabetes who were hospitalized for COVID-19 were more likely to require oxygen or ventilator support, to be admitted to the ICU, or even to die prematurely from a COVID-19 infection. For people with other comorbidities, such as heart disease, high blood pressure, or obesity, the risk of serious COVID-19 complications was higher still.

We don’t know as much about how these patients fare after they leave the hospital and their COVID-19 infection resolves. What is their clinical trajectory? What is their natural history? Are they more likely to have lingering symptoms of COVID-19, such as blood clots or shortness of breath? We’re not sure yet.

Like diabetes, COVID-19 affects the microvasculature, or small blood vessels. There is evidence of disrupted glucose and metabolic control after COVID-19 infection in people with diabetes. We are concerned that people with diabetes and a severe COVID-19 infection could do worse in the long run, and we will keep an eye on that.

Q: What is long COVID? Are people with diabetes more likely to develop this condition?

A: We are in a rapid, exciting, confusing evolution of defining long COVID. It’s probably not just one thing. Basically, long COVID is defined as new, ongoing, or returning symptoms 4 weeks or more after an initial infection with SARS-CoV-2, the virus that causes COVID-19. The syndrome presents with a spectrum of diseases and with clusters of related symptoms such as fatigue, shortness of breath, heart palpitations, brain fog, and anxiety. It can affect nearly every organ and system in the body.

Prevalence estimates vary. According to the CDC, about 15% of adults in the United States have had post-COVID symptoms lasting 3 months or longer. The exact causes are unknown.

Some studies suggest that people with diabetes may be more likely than those without it to develop a post-COVID condition. The likelihood is even higher in women and in people who were hospitalized with severe COVID-19.

We’ve also observed that in people with long COVID, certain symptoms—including fatigue and respiratory problems—seem to be more common in those with diabetes. Conversely, neurological symptoms are not as common.

Interestingly, results of a clinical trial showed that taking metformin decreased the likelihood of developing long COVID in adults with overweight or obesity.

Q: What should health care professionals know about treating patients with diabetes who have or have had COVID-19?

A: As a clinician taking care of patients with diabetes who have had COVID-19, I ask them much more diligently about symptoms they might not usually tell me about—for example, exercise intolerance and brain fog. For dizziness or shortness of breath, previously I might have interpreted those symptoms as an indicator of heart disease progression. Now I might align those symptoms with a post-COVID syndrome or at least consider them in a differential diagnosis.

Since COVID-19 can really hit the cardiovascular and microvascular systems, the number one thing I want my patients to do is try to keep up their physical activity. I also want them to manage sleep and nutrition as much as they can. These fundamentals of diabetes care become even more important after a COVID-19 infection. They may also turn out to be important in preventing post-COVID conditions.

If patients have exercise intolerance—a common symptom of long COVID—we need to help them increase their ability to exercise. As with any patient who’s just come off a ventilator, we want to help them gradually increase their physical activity. Ask patients, “How much can you move? Let’s have you move that much and then add a little bit.” Set a low bar, with a gradual increase so they develop strength and endurance. Don’t rush. It doesn’t need to happen all at once.

With the rapid evolution of medications to treat acute COVID-19, health care professionals need to consider drug interactions. For patients with active COVID-19, Paxlovid has shown no clinically relevant drug interactions with the diabetes medications metformin, insulin, empagliflozin, and pioglitazone. Dosage may need to be adjusted for saxagliptin. Health care professionals are advised to monitor for adverse effects with glyburide.

The NIH has COVID-19 treatment guidelines. The CDC has guidance for clinical care of COVID-19 and evaluating and treating post-COVID conditions. In addition, the American Academy of Physical Medicine and Rehabilitation has long COVID guidance statements and other resources for health care professionals.

Q: What underlying mechanisms explain the relationship between diabetes and COVID-19?

A: There are several possible reasons why an individual could develop decreased insulin secretion or increased insulin resistance with an acute SARS-CoV-2 infection.

First, studies have shown that the SARS-CoV-2 virus may infect pancreatic beta cells and change their function. The pancreatic beta cells produce insulin. If beta cells are infected, they may secrete insulin less effectively or die. It’s a bit of a theory at this point, but it is possible to find SARS-CoV-2 in a beta cell.

Another possible mechanism is inflammation, leading to both decreased insulin secretion and increased resistance to circulating insulin. During a severe COVID-19 infection, the immune system produces high levels of cytokines, which are small proteins secreted by immune cells in response to infection and related inflammation. Pro-inflammatory cytokines can cause beta cells to malfunction or die. Much of the hyperglycemia observed in hospitalized patients with a COVID-19 infection may be due to beta cells not working well in the context of elevated cytokines. In addition to their impact on insulin secretion, cytokines make the body less responsive to circulating insulin, which contributes to a failure to move glucose from the bloodstream into cells that need it. As such, cytokines affect both insulin secretion and insulin action.

SARS-CoV-2 infects endothelial cells, which are part of blood vessels and capillaries in every organ in the body. ACE2 receptors—a main way that SARS-CoV-2 enters into cells—are often found in the endothelium. Diabetes or any level of hyperglycemia also harms the endothelium.

For example, classic complications of diabetes, such as eye and kidney disease, are known as microvascular complications (endothelial cells line the microvasculature). The collision of endothelial cells infected with SARS-CoV-2 and the widespread dysfunction of endothelial cells caused by diabetes might contribute to the poor outcomes observed in early studies of hospitalized patients. We do not yet know if this will have an impact on long-term diabetes complications, which are both microvascular and macrovascular (cardiovascular disease).

Theoretically, at least, the intersection of COVID-19 and diabetes may have both acute and chronic long-term consequences. The longer-term consequences may be vascular complications of diabetes.

Q: What do we know about new-onset diabetes after having COVID-19?

A: We have seen about a 60% increase in risk for new-onset diabetes in people who had COVID-19, usually type 2, compared with people who never had COVID-19. A study of over 181,000 U.S. veterans showed that those who had COVID-19 had a 40% higher risk of new diabetes, compared with controls, after 1 year. And one meta-analysis showed a 66% higher risk of new-onset diabetes in people who had COVID-19, compared with those who didn’t.

But other cohort studies suggest there’s not a big increase in post-COVID diabetes, and that it is only observed in hospitalized patients. Clearly, this topic warrants further study. It’s possible that early in the pandemic, people weren’t getting regular medical care and had diabetes that wasn’t diagnosed until later. That raises the question of whether COVID-19 really caused their diabetes. Still, based on a consistent increase in incident diabetes in many cohorts across the globe, we should anticipate that global diabetes incidence will be higher after the pandemic.

There is an unanswered question of how long incident diabetes after COVID-19 lasts. I have had patients who developed diabetes, and then it went away. A UK study found that new cases of diabetes were much higher in people who’d had COVID-19 than in people who hadn’t in the first 4 weeks after an infection. But by 13 to 52 weeks, there was no difference in diabetes incidence between the two groups.

At this point, we don’t know if new-onset diabetes after COVID-19 is persistent or if it behaves differently than diabetes unrelated to COVID-19. If it is persistent, the implications for the global epidemic of diabetes could be horrific. NIDDK is funding a longitudinal, observational study of adults and children to characterize the onset, clinical course, and pathophysiology of new-onset diabetes after COVID-19.

Q: What are the risk factors for developing post-COVID diabetes?

A: In the veterans study, the more severe the COVID-19, the greater the risk and burden of diabetes. But even people who’d had mild COVID-19 infections were more likely to develop diabetes than those who’d never had COVID-19.

Beyond that, the classic diabetes risk factors—obesity and overweight, family history, physical inactivity, and so on—are important.

In general, COVID-19 vaccination appears to be a protective factor that lowers the risk of developing incident diabetes after COVID-19 for all people.

Q: Is diagnosing and treating patients with incident diabetes after COVID-19 any different than for other patients with diabetes?

A: At this point, no. Theoretically, people with incident diabetes after COVID-19 may have decreased beta cell function, but clinically, I don’t have any reason to see them as deteriorating more than others.

The more important point is to make sure we’re screening people for diabetes appropriately. It’s a good idea to screen patients who’ve had COVID-19, especially a severe infection. However, health care professionals must consider other possible causes of new-onset diabetes, including unmasking of pre-existing diabetes or SARS-CoV-2 reinfection.

In terms of treatment, we don’t know enough yet about whether incident diabetes after COVID-19 behaves differently than other diabetes.

Q: What else should health care professionals know about COVID-19 and diabetes?

A: A severe COVID-19 infection could conceivably set the stage for more aggressive diabetes complications to progress. We need to develop cohorts within the health care system so we can see if the risk of complications is accelerated in patients with diabetes.

In addition, people with glucose levels in their target range at the time of a severe COVID infection do much better than people whose levels are outside their target range. As always, health care professionals need to provide comprehensive care for people with diabetes. We need to help patients with diabetes manage their blood pressure, weight, cholesterol, and blood glucose levels. We want to be mindful that the next variant could really hit people hard.

Editor’s Note: NIH is recruiting children, adolescents, and adults, including pregnant people, for studies of people with long COVID, called Researching COVID to Enhance Recovery, or RECOVER.

What signs and symptoms have you seen in your patients who had COVID-19? Tell us below in the comments.