New diabetes cases linked to COVID-19

Mihail Zilbermint is used to treating diabetes - he heads a special team that cares forpatients with the metabolic disorder at Suburban Hospital in Bethesda, Md. But as the hospital admitted increasing numbers of patients with COVID-19, his caseload ballooned.

"Before, we used to manage maybe 18 patients per day," he said. Now his team cares for as many as 30 daily.

Many of those patients had no prior history of diabetes. Some who developed elevated blood sugar while they had COVID-19, the illness caused by the novel coronavirus, returned to normal by the time they left the hospital. Others went home with a diagnosis of full-blown diabetes. "We've definitely seen an uptick in patients who are newly diagnosed," Zilbermint said.

Although COVID-19 often attacks the lungs, it is increasingly associated with a range of problems including blood clots, neurological disorders, and kidney and heart damage. Researchers say new-onset diabetes may soon be added to those complications- both Type 1, in which people cannot make the insulin needed to regulate their blood sugar, and Type 2, in which they make too little insulin or become resistant to their insulin, causing their blood sugar levels to rise. But scientists do not know whether COVID-19 might hasten already developing problems or actually cause them - or both.

As early as January 2020, doctors in Wuhan, China, noticed elevated blood sugar in patients with COVID-19. Physicians in Italy, another early hot spot, wondered whether diabetes diagnoses might follow, given the long-observed association between viral infections and the onset of diabetes. That association was seen in past outbreaks of other coronavirus illnesses such as influenza and SARS.

A year after the pandemic began, the precise nature and scope of the COVID-19-diabetes link remain a mystery.Many of those who develop diabetes during or after COVID-19 have risk factors, such as obesity or a family history of the disease.Elevated blood glucose levels also are common among those taking dexamethasone, a steroid that is a front-line treatment for COVID-19. But cases also have occurred in patients with no knownrisk factors or prior health concerns.And some cases develop months after the body has cleared the virus.

John Kunkel, a 47-year-old banking executive in Evening Shade, Ark., was one of the surprise cases. He was hospitalized with COVID-19 in early July. During a follow-up visit with his doctor, he learned he had dangerously high blood glucose levels and was readmitted. Kunkel has since received a diagnosis of Type 2 diabetes.

"I had no preexisting health issues," he said. "I was blown away. Why?"

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Kunkel has had five emergency room visits and three hospital stays since getting COVID-19. He recently lost his job because he was unable to return to work, given his continuing health problems. "Will you get your life back?" he asked. "Nobody knows."

Asmany as 14.4% of people hospitalized with severe COVID-19 developed diabetes, according to a global analysis published Nov. 27 in the journal Diabetes, Obesity and Metabolism. The international group of researchers sifted through reports of uncontrolled hyperglycemia, or high blood sugar, in more than 3,700 COVID-19 patients across eight studies. While those diagnoses might be the result of a long-observed response to severe illness, or to treatment with steroids, the authors wrote, a direct effect from COVID-19 "should also be considered."

Concerns that COVID-19 might be directly implicated also were supported, they said, by the exceptionally high doses of insulin that diabetes patients with severe COVID-19 often require and the dangerous complications they develop.

Researchers do not understand exactly how COVID-19 might trigger Type 1 or Type 2 diabetes, or whether the cases are temporary or permanent. But they are racing to find answers to these and other questions, including whether the novel coronavirus may have spawned an entirely new type of diabetes that might play out differently from the traditional forms of thedisease.

Francesco Rubino, a diabetes surgery professor at King's College London, is convinced there is an underlying connection between the diseases.

Over the summer, he and a group of other diabetes experts launched a global registry of patients with COVID-19-related diabetes. After they spread the word with an editorial in the New England Journal of Medicine, more than 350 institutions from across the world responded, he said.

The database is accumulating patients - over 150 so far - although it will take months for researchers to sift through the data to draw any conclusions. "We really need to dig deeper," Rubino said. "But it sounds like we do have a real problem with COVID-19 and diabetes."

Some of the cases reported to his database do not fit the usual profile of Type 1 diabetes,inwhich the pancreas produces little or no insulin, or Type 2, in which people become insulin resistant, he said. Usually, a patient with one type of diabetes will experience specific complications; for instance, those with Type 1 may burn through their fat stores, or those with Type 2 may experience a syndrome that can involve severe dehydration and coma as the body pumps excess blood sugar into the urine. In some patients with COVID-19, though, complications cross types.

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"There's a good chance that the mechanism of the diabetes isn't typical," Rubino said. "There could be a hybrid form. It's concerning."

Rubino is especially worried about reports of diabetes diagnoses after mild or asymptomatic coronavirus infections. As the number of novel coronavirus infections continues to rise, he said, "you could see a significant new volume of diabetes diagnoses."

Diabetes already is increasing at an alarming rate in the United States. An estimated 34.2 million people, or 10.5 percent of the population, have the disorder, according to federal health data. And approximately 1 in 3 Americans, or 88 million people, have prediabetes, which indicates they are on a path to Type 2.If left uncontrolled, the disease can damage many parts of the body and is associated with serious complications including heart disease, stroke, blindness, kidney failure and nerve damage.

But whether those with diabetes that is newly diagnosed after COVID-19 will have a lifelong problem is unclear. After the 2003 SARS pandemic, Chinese researchers tracked 39 patients with no history of diabetes who had developed acute diabetes within days of hospitalization with SARS. For all but six, blood sugar level had fallen by the time they were discharged, and only two still had diabetes after two years. The researchers also found evidence that the SARS virus might attack insulin-producing beta cells in the pancreas.

Beta cells play starring roles in both types of diabetes: The bodies of those with Type 1 attack and destroy the cells altogether, halting insulin production. Type 2 diabetics become resistant to the insulin they produce, so the beta cells make more and more, and eventually are worn out.

"If scientists could figure out how or if viral infection can damage beta cells, or what role viruses play in the development of the disease, it would be a real turning point," said Katie Colbert Coate, a diabetes researcher and research instructor in medicine at Vanderbilt University Medical Center.

Though people with diabetes are no more susceptible to contracting COVID-19 than those without, they are at much higher risk of severe complications or death once they do. In the early days of the pandemic, just over a third of thosewho died of COVID-19 in British hospitals had preexisting cases of diabetes.Doctors in Wuhan also noticed that those with newly diagnosed diabetes were more likely to need intensive care than those who had diabetes before they contracted COVID-19.

New diagnoses of diabetes in people with no classic risk factors also are scattered throughout case reports: A 37-year-old, previously healthy Chinese man who went to the hospital with a severe, and in some cases fatal, diabetes complication; a 19-year-old German who developed Type 1 diabetes five to seven weeks after a novel coronavirus infection but who lacked the antibodies commonly associated with the autoimmune disease.

Doctors at Children's Hospital Los Angeles, meanwhile, noticed an increase in the number of Type 2 diagnoses in children, as well as a severe complication of diabetes. After some of them showed evidence of past coronavirus infections, Senta Georgia, an investigator in the hospital's Saban Research Institute, began looking deeper. Her research, which repurposes tissue from primates used in vaccine tests, is undergoing peer review.

"Only with the scientific public square can we put all of this data out there, evaluate its strengths and weaknesses . . . until we really get the information we need," Georgia said.

Such reports also have increased the sense of urgency for researchers like Coate, who dropped other work and began looking for keys to understanding the mechanism of the disease by examining how COVID-19 might damage beta cells or other structures in the pancreas. She and others are asking whether certain COVID-19 symptoms predict whether a patient is vulnerable to diabetes and, most important, whether the disease's onset is an effect of the immune response or a result of the virus directly attacking insulin-producing cells.

ACE2 receptor cells, the novel coronavirus's entryway into the body, could provide one answer. When the spike proteins that surround the virus latch onto a host cell with an ACE2 receptor, they open up a cellular doorway that allows the virus to hijack the cell.

Strong evidence of ACE2 receptors on beta cells could confirm the long-standing suspicion that viruses trigger diabetes. But the research findings are inconclusive: Since the pancreas breaks down quickly after death, obtaining good samples from autopsied humans is difficult. And each study has its own limitations.

Last year, Cornell University researchers grew human pancreas cells and managed to infect them with SARS-CoV-2, as the novel coronavirus is technically known. They found ACE2 receptors on the cells, but the cells had been cultivated in a laboratory, not a human body.

Coate and her colleagues at Vanderbilt University were able to confirm the presence of ACE2 receptors in the physical structures of the pancreas, but their study focused on patients without COVID-19 and found no evidence of the receptors on the insulin-producing beta cells. An Italian study did find the receptors in beta cells, but the donors did not have COVID-19, either. Until receptors in pancreatic beta cells in tissue from COVID-19 patients can be consistently confirmed by other researchers, the hunt for the mechanism underlying the diabetes-COVID-19 connection continues. So does research on ways COVID-19 might harm other parts of the endocrine system, which also might play a role in the disease mechanism.

For newly diagnosed patients such as nurse practitioner Tanisha Flowers, the answers can't come soon enough.

Infected in April while working in a COVID-19 ward in a Richmond, Va., hospital, the 40-year-old was diagnosed with diabetes in October. She now takes daily medications, watches her diet and is all too aware that she may be diabetic for life.

“I’m not myself anymore,” Flowers said. “No one knows what the lasting outcomes are.”