The Endocrine Society

The Endocrine Society

Issue: May 2021
Source:

Atkinson M, et al. The endocrine system in the COVID pandemic. Presented at: ENDO annual meeting; March 20-23, 2021 (virtual meeting).

Disclosures: Atkinson reports no relevant financial disclosures. Rubino reports he has received research grants, advisory and consultant fees from Ethicon, GI Dynamics, Keyron, Medtronic, the National Institute for Health Research and Novo Nordisk.
March 20, 2021
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Evidence ‘conflicting’ on COVID-19 as cause of new-onset diabetes

Issue: May 2021
Source:

Atkinson M, et al. The endocrine system in the COVID pandemic. Presented at: ENDO annual meeting; March 20-23, 2021 (virtual meeting).

Disclosures: Atkinson reports no relevant financial disclosures. Rubino reports he has received research grants, advisory and consultant fees from Ethicon, GI Dynamics, Keyron, Medtronic, the National Institute for Health Research and Novo Nordisk.
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Case reports and news articles have reported on the possibility of a form of new-onset diabetes that is related to COVID-19 infection; however, epidemiologic data suggest there is much to be learned before firm conclusions are made.

Mark Atkinson

“When these articles ask the question, can COVID-19 induce diabetes, these studies [referenced] are case reports and they describe a form of diabetes that occurs within a reasonable time period of COVID-19 infection,” Mark Atkinson, PhD, the Jeffrey Keene Family Professor at the University of Florida and director of the University of Florida Diabetes Institute, said during a pre-meeting presentation at the ENDO annual meeting. “What is confusing about these cases is sometimes they look like ‘classic’ type 1 or type 2 diabetes, but on other occasions, the presentations do not fit those two types exactly. The question has become, is this a new form of diabetes? Is it really due to a loss of insulin or hepatic glucose production, or both? Then, there have been reports that COVID-19 infection induces hyperglycemia in many individuals.”

Diabetes Words 2019
Source: Adobe Stock

Epidemiologic literature examining whether SARS-CoV-2 is associated with an increased incidence of diabetes is conflicting, Atkinson said. A multicenter regional study conducted in the United Kingdom and published in Diabetes Care in August showed that, compared with a typical, pre-pandemic year, researchers estimated an 80% increase in new type 1 diabetes cases during the pandemic, with apparent clusters observed in two units.

However, a much larger study conducted in Germany, also published in Diabetes Care, demonstrated that type 1 diabetes incidence in 2020 followed the increasing trend observed between 2011 and 2019, without upward or downward deviation, indicating no short-term influence of the COVID-19 pandemic.

Francesco Rubino

“The message is there is clearly a bidirectional relationship between diabetes and COVID-19, but it remains to be seen whether COVID-19 can actually cause new diabetes, and that is what we set out to investigate with a registry,” Francesco Rubino, MD, professor and chair of metabolic and bariatric surgery at King’s College London and honorary consultant at King’s College Hospital, told Healio. “Certainly, there is no question that there is an interplay between the two diseases. Whether COVID-19 triggers diabetes in people who are predisposed or causes new diabetes entirely is something under investigation.”

What may link diabetes, COVID-19

From early on in the pandemic, researchers have focused on the mechanism of entry of the virus into cells — angiotensin-converting enzyme 2, or ACE2, which has been established as the COVID-19 receptor.

Some research suggests ACE2 may be expressed in beta cells and the kidneys, explaining an uptick in new-onset diabetes cases with rising COVID-19 infection rates, Atkinson said.

There, too, data are conflicting, he said.

“A New England Journal of Medicine article says SARS-CoV-2 may impact diabetes because this [ACE2] receptor is expressed in beta cells and the kidneys. The challenge here is the paper most often cited for this was published over 10 years ago in a low-impact journal where it was one case and lacking in details,” Atkinson said. “This article looking at coronavirus and expression in beta cells had very few citations, but in the last year, it exploded; so this notion of ACE2 expression in beta cells has become almost dogma, but it is controversial.”

Small studies assessing the expression of ACE2 in induced pluripotent stem cells transitioned into beta-cell surrogates, as well as research using isolated islet cells and pancreatic sections, have demonstrated ACE2 expression, Atkinson said.

“You might believe at that point that, yes, there is a certainty around this,” Atkinson said. “But in reality, my own group published in Cell Metabolism in December a study where we looked extensively in all ages across normal pancreases and could not find the expression of ACE2 in beta cells. We could see it on an mRNA level, but it was restricted to pancreatic ducts. ACE2 expression is in the pancreas, but not in the endocrine cells.”

Rubino said other possibilities should be examined.

“People sometimes focus on whether the virus can bind to the beta cell in the pancreas. The evidence there can be confusing,” Rubino said in an interview. “Some studies do show that; some don’t. But if we are only focusing on the beta cells, our focus is too narrow. We should look at other possibilities — defects in the pancreas at large, not just beta cells, and defects and damage to other organs that could cause dysfunction in the endocrine cells, such as the gut, liver, fatty tissue. We are learning by the day that this virus can cause microthrombosis and damage organs. Inflammation can cause systemic dysfunction. At the moment, we are not clear about which biological pathways are relevant, but certainly there is a clinical interplay.”

Learning from case reports

With many factors still unknown, Rubino and a group of leading diabetes researchers established a global registry for COVID-19-related diabetes cases. The registry, a joint initiative with King’s College London and Monash University, is designed to establish the extent and characteristics of new-onset, COVID-19-related diabetes and investigate its pathogenesis, management and outcomes. The registry also collects data about presentations with severe metabolic disturbance in preexisting diabetes, such as diabetic ketoacidosis.

“We launched this project with the hypothesis that there could be a relationship between COVID-19 and diabetes, at the same time as we announced the creation of a global registry, with leading experts from around the world to gather as much information as possible, from as many clinicians as possible,” Rubino said. “We anticipate that many ‘new-onset diabetes’ cases that we find might actually be preexisting diabetes. Or perhaps a minority will truly be new-onset, but by calling on the entire world to contribute, we hope to gather a large sample size of cases to truly understand the relationship between diabetes and COVID-19.”

To adjudicate whether a diabetes case is truly new diabetes, secondary hyperglycemia due to acute illness or preexisting disease, the researchers, working with leading experts, will use a set of criteria that includes HbA1c history, administration of drugs such as dexamethasone, and other possible triggers for hyperglycemia.

“What is the evolution? Is the hyperglycemia resolving with the resolution of the peak of COVID-19, or is it persisting?” Rubino said. “We hope to understand more.”

To submit a case to the registry, clinicians must apply and sign a data-sharing agreement, along with their institution. So far, more than 400 people have applied to share data and 30 clinicians have completed the process, sharing information on more than 300 cases.

“We hope this will increase exponentially in the coming weeks,” Rubino said. “We hope to apply what we learn to other viruses as well. We may learn more about diabetes at large. These people are vulnerable, not just to COVID-19, but to another pandemic. This should be a call to all of us.”

Reference:

COVIDIAB registry. Available at: https://covidiab.e-dendrite.com. Accessed March 19, 2021.