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Source: COVID-19 Research  Jul 27, 2020  3 years, 8 months, 2 weeks, 3 days, 4 hours, 51 minutes ago

COVID-19 Research: Cases Of COVID-19 Patients Developing Diabetes For First Time Can Be Due To High ACE2 Expression In Pancreatic Islet Cells During Infection

COVID-19 Research: Cases Of COVID-19 Patients Developing Diabetes For First Time Can Be Due To High ACE2 Expression In Pancreatic Islet Cells During Infection
Source: COVID-19 Research  Jul 27, 2020  3 years, 8 months, 2 weeks, 3 days, 4 hours, 51 minutes ago
COVID-19 Research:  Researchers from Italy, Belgium and America in a new collaborative study have found the possible causes of numerous COVID-19 patients who never had diabetes before and were healthy prior to contracting the SARS-CoV02 coronavirus suddenly developing diabetes. According to their research findings, the pancreatic islet beta cells which produce insulin could be infected by the virus as it was seen that inflammation during the disease leads to an increased expression of the ACE-2 receptors in these cells. By targeting these receptors, the novel coronavirus ultimately damages the normal functions of the pancreas.

Hence this could explain why high glucose levels are more common in acute COVID-19, even in individuals not known to be diabetic in the past.
The research findings are published on a preprint server and yet to have been peer-reviewed.
Initially, it was shown that poor control of blood sugar increases the risk of severe COVID-19. High blood glucose levels, often seen in diabetes, along with a decline in glycemic control with the onset of infection, causes a higher level of inflammation, impaired coagulation function, and difficulty with breathing. Overall, this worsens the prognosis.
Interestingly however, patients admitted with infection often have a high blood sugar level at admission, irrespective of whether they were already diabetic. This reflects earlier findings in the SARS outbreak in 2003 and points to a possible link between the infection and diabetes of new-onset.
This study aimed to study the expression of ACE2 in human pancreas cells, from non-diabetic individuals, as well as in one type of cells that produce insulin, the EndoC-βH1. They found three cell types that express this receptor. One is the endothelial cells or pericytes found in specific lobules of the pancreas, but not all.
The research finding is significant since it confirms the occurrence of vascular leakage and endothelial inflammation in multiple organs infected with the virus. This promotes the spread of early inflammation localized to an organ and then drives the worsening of immune responses.
The research supports the possibility of local damage to blood vessels along with inflammation resulting from the viral infection of pericytic or endothelial cells expressing ACE2.
Also a few ACE2 positive cells were found in the pancreatic ducts.
During the study, the pancreatic islets also stained positive, and a subset of islet cells was located in the parenchyma. Using immunofluorescence, they found that the receptors were preferentially located on the β-cells secreting insulin. The staining of β-cells was uniformly observed in all pancreatic specimens from the same individual and different cases.
Significantly, transcription of ACE2 mRNA was also found in human pancreatic islets in the same subset of β-cells. This confirms the presence of the protein within the β-cells. In short, the current study indicates the presence of the receptor in β-cells, making them sensitiv e to infection. This agrees with recent reports of in vitro infection of human pancreatic islet cells by the virus.
The study team found that ACE2 staining was within subcellular compartments. The possible explanations for this include the movement of ACE2 to the interior of the cells via endosomes or lysosomes after activation; insulin granules carrying the ACE2 molecules to the cell membrane; or the detection of soluble ACE2 following secretion, after protease-mediated release from the carrier.
Hence this would allow the presence of ACE2 in different compartments of the cell, especially since the virus itself enters the host cells via endosomes or lysosomes.
The study team also found that under conditions of stress, such as abnormal metabolic parameters or inflammation, the expression of ACE2 was altered.
While exposure to certain toxic fatty acids failed to produce significant change, β-cells exposed to a mixture of cytokines found in diabetics, including IL-1β- IFNγ, and TNFα, showed a rise in ACE2 levels.
It was found that the ACE2 mRNA was increased over 12 times in the presence of stress compared to controls. The increased ACE2 expression was confirmed using multiple methods to measure the ACE2 protein content and RNA sequencing data.
Also when either IL-1β+IFNγ or with IFNα was added to the cell culture of EndoC-βH1 cells, the ACE2 mRNA went up by 25- and 55-fold, respectively. Human pancreatic islets also showed the same pattern of expression, but at a tenth of the increase. Overall, the researchers found that ACE2 is upregulated when either EndoC-βH1 cells or human pancreatic islets are exposed to either of these cytokines.
From the study findings, it can be assumed that in the prediabetic patient, the high level of metabolic demand and the increased level of inflammation can cause the level of ACE2 expression to rise in the β-cells. This allows infection by the virus, which increases the quantum and speed of β-cell loss. More research is required to find out if the virus targets these cells, and whether this can lead to autoimmune diabetes in the future.
The research shows that one set of β-cells in the human pancreas express ACE2 and are, therefore, vulnerable to SARS-CoV-2 infection. In general, when these cells and human pancreatic islet cells are exposed to cytokines released during inflammation, ACE2 expression is enhanced.
The researchers say that their data suggest that there may be a potential link between SARS-CoV-2 infection and new-onset diabetes, which deserves further investigation based on long-term follow up of patients recovered from COVID-19 disease.
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