Researchers are exploring the complex, push-pull relationship between COVID-19 and diabetes. Is the virus truly the cause of a new type of diabetes or is it merely hastening an inevitable development in susceptible patients?
From the earliest days of the COVID-19 pandemic, its effects on glycemic control have been among its challenges. Patients with diabetes are at high risk for severe disease, and the glycemic control of many patients would go haywire. Even patients with no known history of diabetes would suddenly require large doses of insulin.
Clinicians treating these patients began wondering, does COVID-19 actually cause diabetes —and perhaps even new kind?
As the chief of the Division of Endocrinology at Columbia University’s New York Presbyterian Hospital, Domenico Accili, MD, witnessed the earliest surge in this country. He says that from the “very first week” he was struck not only by the number of patients with symptoms of diabetes, but more unusually, by the number of patients with diabetic ketoacidosis, even in patients without type 1 diabetes.
- With hyperglycemia one of the biggest challenges in severely ill COVID-19 patients, an ongoing debate is examining whether the virus could be causing a new form of diabetes — or merely providing a final push in susceptible patients.
- Research on whether pancreatic beta cells offer an entry point for the virus — and hence a direct threat to insulin production — has led to conflicting results.
- A global registry of COVID-19–related diabetes has been established to study the extent, pathogenesis, and outcome of this emerging problem.
“When I saw this, my first reaction was, maybe this virus is attacking the beta cells of the pancreas,” Accili says. With more experience, he has since tempered that reaction, and considered the many ways a virus can affect glycemic control. With the millions of COVID-19 infections around the world, there is no clear evidence of a concomitant uptick in diabetes, he says.
COVID-19 Diabetes Registry
But other experts continue to be concerned. In a letter to the editor in the August 20, 2020, New England Journal of Medicine, an international group of researchers led by Francesco Rubino, MD, announced the establishment of a global registry of COVID-19–related diabetes. The registry “is specifically designed to establish the extent and characteristics of new-onset, COVID-19–related diabetes, and to investigate its pathogenesis, management and outcomes,” according to its website.
By mid-February, 164 cases had been added to the registry, with the effort just beginning to get off the ground, according to Robert H. Eckel, MD, professor of medicine emeritus in the divisions of endocrinology, metabolism, and diabetes and cardiology at the University of Colorado Anschutz Medical Campus in Aurora, one of the signatories of the letter to the New England Journal.
Betting on Beta Cells
There are several mechanisms by which COVID-19 could be disrupting glucose metabolism, and thereby causing — or causing symptoms similar to — diabetes.
“If this were causing diabetes, now that there are tens of millions of patients all over the world, we would have seen an increase in the incidence of diabetes which we have not seen. A small number of patients develop diabetes when they develop COVID-19. But they were on the verge of developing it, and the disease pushed them over the edge. This is known to happen with many infectious diseases.” – Domenico Accili, MD, chief, Division of Endocrinology, Columbia University’s New York Presbyterian Hospital, New York, N.Y.
The beta cells in the pancreatic islets have been an obvious focus, given their role in insulin secretion. The SARS-CoV-2 virus binds to angiotensin-converting enzyme 2 (ACE2) receptors as an entryway to cells, and it has been posited that the presence of these receptors on pancreatic islet cells could offer entrée to the virus, and hence cause damage. The New England Journal letter says: “There are several precedents for a viral cause of ketosis-prone diabetes, including other coronaviruses that bind to ACE2 receptors. Greater incidences of fasting glycemia and acute-onset diabetes have been reported among patients with SARS coronavirus 1 pneumonia than among those with non-SARS pneumonia.”
Several researchers have looked for these and related receptors in beta cells, and some have reported finding them and others have not. Eckel had recently attended the virtual meeting of the Network for Pancreatic Organ Donors and reported: “Some researchers claim the ACE2 protein is relevant and functional and could be a cause of new-onset diabetes, and others feel that the technology is not adequate to say for sure that this protein is expressed in the beta cells or islets.”
“Any viral infection or bacterial infection can make glucose control worse by causing an inflammatory state,” Accili says. “And an inflammatory state is associated with cytokines and lipid breakdown, things that can cause insulin resistance. There is also the release of hormones that are antagonistic to insulin, like glucocorticoids, catecholamines, glucagon, and growth hormone. The inflammatory state can also affect the beta cell and can cause what I would call a temporary blindness of the beta cell so that insulin is not released. However, this is not a permanent loss of the beta cell. It is functional damage that gets resolved if the inflammation is resolved.”
Eckel agrees that “a lot of new onset diabetes in hospitalized patients relates to the stress of the illness, so that could be what we are looking at.”
The treatment can also contribute to hyperglycemia. National Institutes of Health guidelines recommend that severely ill COVID-19 patients who are receiving supplemental oxygen be treated with dexamethasone or a similar steroid. These drugs tamp down inflammation, but also raise glucose levels.
A Push over the Edge?
Although there have been reports of otherwise healthy people with no history of poor glucose control developing diabetes, Accili says that when he studied the hemoglobin A1c levels of his patients who developed diabetes, the vast majority already had poor glucose control. Many had undiagnosed diabetes or prediabetes. Because diabetes is a risk factor for severe COVID-19, that finding rather flips the perception of cause and effect in this discussion.
“Any viral infection or bacterial infection can make glucose control worse by causing an inflammatory state. And an inflammatory state is associated with cytokines and lipid breakdown, things that can cause insulin resistance.” – Domenico Accili, MD, chief, Division of Endocrinology, Columbia University’s New York Presbyterian Hospital, New York, N.Y.
“If this were causing diabetes, now that there are tens of millions of patients all over the world, we would have seen an increase in the incidence of diabetes which we have not seen,” Accili says. “A small number of patients develop diabetes when they develop COVID-19. But they were on the verge of developing it, and the disease pushed them over the edge. This is known to happen with many infectious diseases.”
Accili does not dismiss the possibility that SARS-CoV-2 can cause diabetes but does not see the evidence for it at this point.
Eckel acknowledges that at this point there are still more questions than answers but hopes that the registry will provide some of the answers. As recognition of the heterogeneous nature of diabetes grows — with more varieties than type 1 and type 2 — the registry will provide a forum to analyze real-world data to see how COVID-19 fits into this picture.
Seaborg is a freelance writer based in Charlottesville, Va. In the March issue, he wrote about how COVID-19 has impacted the use of continuous glucose monitoring in a hospital setting.
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