How the ACE2 protein is critical in damage
The detailed mechanism of how SARS-CoV-2 attacks the insulin-producing cells of the pancreas by targeting the angiotensin-converting enzyme 2 (ACE2) protein on the surface of these cells is discussed of a special presentation at this year’s annual meeting of the European Association for the Study of Diabetes, given by Prof. Francesco Dotta, Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy.
“The SARS-CoV-2 virus attacks specific host tissues due to the presence of viral receptors on the surface of target cells. As such, the binding of the virus to the ACE2 protein is the key determinant of its entry, spread and transmissibility, ”explains Professor Dotta.
“Multiple studies have shown that older people and people with chronic conditions like heart and lung disease and / or diabetes are at the highest risk for complications from SARS-CoV-2 infections. Additionally, impaired blood sugar control is associated with an increased risk of severe COVID-19, suggesting a link between COVID-19 infection and diabetes. Several reports indicate a wide, although variable, distribution of the ACE2 protein among different tissues.
Professor Dotta’s team and others studied the expression pattern of ACE2 in pancreatic tissue samples from non-diabetic multi-organ donors to better understand the molecular link between COVID-19 and diabetes. In particular, their collaborative group analyzed pancreatic tissue samples in the context of the INNODIA consortium, a large diabetes research project funded by the EU, JDRF and the Helmsely Foundation under the European initiative IMI2.
In the “normal” pancreas, ACE2 is highly expressed in microvascularization (small blood vessels) and in ductal cells (cells lining the connection between the pancreas and the common bile duct). “It is important to note that ACE2 was expressed in human pancreatic islets, where it is preferentially expressed in insulin-producing beta cells. We also demonstrated that ACE2 levels were increased under pro-inflammatory conditions, thus confirming the link between inflammation and ACE2 also in pancreatic islet beta cells.
In order to correctly identify the mechanism involved in the upregulation of ACE2 induced by inflammation, ACE2 levels were measured in human pancreatic islets pretreated with two drugs that block inflammation in beta cells, namely Baricitinib or Nimbus (inhibitors of Jak1 / 2 and TYK2), then exposed to pro-inflammatory conditions. Professor Dotta said: “We have shown that these drugs prevent the inflammation-induced increase in ACE2 in human pancreatic islets, demonstrating that the SARS-CoV-2 ACE2 receptor is regulated by specific molecular pathways. and that its increased expression can be prevented. “
“In our collaborative work with the University of Pisa, the University of Louvain and the University of Brussels, we have studied the mechanisms of entry of the SARS-CoV-2 virus into insulin-producing beta cells and we found that these cells express the SARS-CoV-2 ACE2 receptor, ”concludes Professor Dotta. These data have been independently confirmed by other authors.
It should be noted that additional published data has confirmed that SARS-CoV-2 can indeed infect insulin-producing pancreatic cells causing them to malfunction or die. In addition, during inflammation, the expression of the ACE2 receptor of SARS-CoV-2 increases several times above the standard values.
Professor Dotta concludes: “This means that these insulin-producing beta cells could be even more susceptible to viral infections when inflamed. This finding is also important from a clinical point of view, as keeping the inflammatory state under control in patients with COVID-19 may reduce the expression of the ACE2 receptor in beta cells with beneficial effects on blood sugar. and metabolic control of patients. “
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