High ACE2 Expression on pancreatic islet cells during inflammation could explain new-onset diabetes in COVID-19

A new study suggests that the SARS-CoV-2 infection may be linked to the onset of diabetes, via the infection of pancreatic islet beta cells, which produce insulin. 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 study was published in the preprint server medRxiv* in July 2020.

ACE2 and insulin double immunofluorescence analysis in EndoC-βH1 cultured cells. Negative isotype primary antibody control (relative to ACE2 primary antibody) is shown in panel-a. Insulin (red) and ACE2 (green) are reported in panel-b and -c, while overlay is reported in panel-d. Zoom-in images are reported from panel-e to -h. Scale bar in panel -h = 15 µm

Virus Tropism and Tissue Receptors

Viruses attack specific host tissues because of the presence of viral receptors on the cells in such tissues. The SARS-CoV-2 virus, which causes severe pneumonic illness and death in a significant minority of cases, is known to bind via its envelope spike glycoprotein to the angiotensin-converting enzyme (ACE) 2 receptor on the human host cell. This interaction is, therefore, key to the entry, replication, and spread of the virus.

While the virus attacks airway epithelium and alveolar cells primarily, other tissues also show ACE2 expression. Prior research shows that the severity of illness is increased with advancing age and in patients who already have cardiovascular disease, lung diseases such as chronic obstructive pulmonary disease, or diabetes, which may accompany either of the other two conditions. Investigators have noted a two-way relationship between COVID-19 and diabetes.

Blood Sugar and Severe COVID-19

Earlier, 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.

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.

The Study: ACE2 Expression in Human Pancreas

The current 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.

This 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 study supports the possibility of local damage to blood vessels along with inflammation resulting from the viral infection of pericytic or endothelial cells expressing ACE2.

A few ACE2 positive cells were found in the pancreatic ducts.

ACE2 Expression in β-cells

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.

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 sensitive to infection. This agrees with recent reports of in vitro infection of human pancreatic islet cells by the virus.

ACE2 Found at Subcellular Locations

The researchers 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.

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.

ACE2 Level Higher in the Presence of Inflammation

The researchers 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.

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.

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.

Implications

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 study 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.

Our 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.

*Important Notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Dr. Liji Thomas

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.

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