‘We have more to learn’: Data inconclusive on COVID-19 driving form of type 1 diabetes
Click Here to Manage Email Alerts
Reports of patients developing new-onset type 1 diabetes in the setting of COVID-19 infection have researchers questioning whether the virus is entering and subsequently destroying beta cells in pancreatic islets, according to a speaker.
The question of whether clinicians are seeing new-onset type 1 diabetes in the setting of COVID-19 is in part inspired by observations of new-onset ketoacidosis and a rapid deterioration of glucose control in some adolescents and adults infected with the novel coronavirus, Daniel J. Drucker, MD, senior scientist at the Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital and professor of medicine at the University of Toronto, said during an online presentation at the virtual European Association for the Study of Diabetes annual meeting. Some researchers have suggested that people infected with COVID-19 develop a form of insulin-deficient diabetes because the virus might be entering beta cells via angiotensin-converting enzyme 2 (ACE2), which has been established as the SARS-CoV-2 (COVID-19) receptor, and the downstream transmembrane protease serine 2 (TMPRSS2), an enzyme encoded by the TMPRSS2 gene, which is required for cellular infectivity.
“As endocrinologists, we do see new-onset type 1 diabetes or new-onset ketoacidosis worldwide — thousands of patients per month,” Drucker said. “It is hard to interpret this data from an epidemiology perspective. We know that viruses might trigger type 1 diabetes, COVID-19 type 1 diabetes registries have been formed, and hopefully we will get an answer to this question.”
COVID-19, ACE2 and beta cells
Currently, there is controversy regarding how much ACE2 may be expressed in normal pancreatic islets, or in the islets of people with COVID-19, that may contribute to development of insulin deficiency and symptoms of new-onset diabetes, Drucker said.
“It is now widely accepted that COVID-19 infects endothelial cells throughout the body since the majority of endothelial cells express ACE2,” Drucker said. “One indirect explanation for how SARS-CoV-2 may affect endocrine organs may be the simple fact that all organs have endothelial cells. This virus homes in on ACE2 expressed in endothelial cells and might cause local organ damage through destruction and inflammation mediated through endothelial cell infection.”
The emerging literature on beta cells and ACE2 expression can be confusing, Drucker said; in studies, the answer often depends on what model and reagents are used to ask the question. One recent study looking at stem cell-derived beta cells showed they do express ACE2 and are infected by the SARS-CoV-2 virus, he said.
“But we all know that these cells are not normal, differentiated beta cells,” Drucker said. “So, what about using validated reagents and experiments to interrogate ACE2 expression in normal islets?”
Mouse islets do show some ACE2 expression in a few studies, whereas human islets appear to have much less, if any, beta-cell ACE2 expression, Drucker said.
Complicating the picture, conflicting studies report that the presence or absence of ACE2 expression in human islets beta cells, with a lesser degree or absent ACE2 expression in glucagon-producing cells, and that inflammation and cytokines can upregulate ACE2 expression.
“However, if one looks at a range of preprints... looking at human islets in pancreata from normal donors and from people with type 2 diabetes across the lifespan, several groups do not see ACE2 expression in beta cells or alpha cells. In fact, they also don’t see the necessary cofactor TMPRSS2 in alpha cells or beta cells.”
Additionally, in analyses of ACE2 expression in pancreatic sections from three individuals with COVID-19 infection, there was no evidence for infection within the islet cells, rather in one subject, the virus was detected in pancreatic ducts and perhaps in some blood vessels, Drucker said.
“Obviously, these are early days, and the numbers are limited,” Drucker said. “These types of studies need more corroboration to reshape our concepts of whether beta cells express ACE2. I think that is far from clear with the available data.”
More data needed
Drucker, who called the available evidence controversial, said current data in preprint form from at least two independent expert groups provide “compelling evidence” that the beta cell does not express the receptors for SARS-CoV-2.
“It is really the endothelial cells and the ducts in the pancreas, and not the endocrine cells or the beta cells, that express the receptor,” Drucker said during a press conference discussing the findings. “We have a lot more to learn about this.”
Collapse
Drucker D. COVID-19 and type 2 diabetes: Do shared pathways have therapeutic implications. Presented at: EASD Annual Meeting; Sept. 21-25, 2020 (virtual meeting).
Read more about
Click Here to Manage Email Alerts