How the coronavirus compromises the pancreas

Initially, the Covid-19 pandemic it was considered to be an exclusive lung disease, which ultimately led to severe respiratory symptoms. Meanwhile, the accumulation of experimental and clinical studies suggested that SARS-CoV-2 can also cause damage to the kidneys, heart, brain, and gastrointestinal and endocrine organs.

Pre-existing diabetes is a very common comorbidity observed in 22% of patients and, as such, it increases the risk of serious disease, requiring more interventions and increased mortality. Second, SARS-CoV-2 infection appears to affect the exocrine pancreas, manifesting as pancreatitis in 32.5% of critically ill patients.and pancreatic hypertrophy and abnormal amylase or lipase levels in 17% of patients. Third, it has been observed a metabolic disturbance in COVID-19 patients such as: increased hyperglycemia in patients with type 2 diabetes; ketoacidosis in 6.4% of diabetic and nondiabetic patients and in case studies reporting ketoacidosis on SARS-CoV-2 infection, accompanied by type 1 diabetes mellitus (T1D) in the absence of autoantibodies.

In a cohort study of diabetic patients, hyperglycemia was reported in over 50% of all cases, and nearly a third suffered from diabetic ketoacidosis. Finally, a multicenter study found an 80% increase in newly emerged DM1 in children during the COVID-19 pandemic. A recent meta-analysis summarizes that severe COVID-19 is associated with increased blood sugar. However, formal proof of SARS-CoV-2 as a tropical β-cell virus, which can lead to diabetes, does not yet exist, and the only correlative evidence remains in light of conflicting clinical and experimental results. Both acute and long-term prospectively collected results from new diabetes cases, as well as thoughtful interpretations of emerging data, are warranted until this discussion is finally clarified.

This was the subject of a study carried out by a team from the Institute of Molecular Virology at the University of Ulm, Germany. They defined ACE2 and TMPRSS2 expression profiles in human pancreatic endocrine and exocrine cell types, used human pancreatic islet cultures to demonstrate susceptibility to SARS-CoV-2 infection and viral replication in β cells, and have shown that infection with SARS-CoV-2 affects glucose. -Stimulated insulin secretion (GSIS). In addition, they visualized replicating viral particles in pancreatic endocrine cells and defined their subcellular localization patterns and finally presented examples of multi-organ infection patterns, including the pancreas of patients who died from COVID-19. .

An imperfect couple

According to the current state of knowledge, The expression of ACE2 continues to be the primary determinant of the entry of SARS-CoV-2 and, therefore, of the tropism of the organism. Several proteases can prime the S protein of the coronavirus, whose expression of pancreatic TMPRSS2 also coincided with the infection profile of deceased COVID-19 patients included in the analysis. The researchers found that ACE2 and TMPRSS2 are less colocalized with the marqu and α cell markers. However, this lower frequency does not rule out infection as the previous data suggests.

However, regardless of a possible debate on the expression of the viral entry protein, they observed a productive infection with SARS-CoV-2 of islets cultivated ex vivo using virology-based assays. advanced molecular, providing evidence of the presence. functional input factors.

The most striking finding was an enlarged and vacuolated ER-Golgi intermediate compartment, similar to findings in intestinal, renal, and respiratory epithelial cells infected with SARS-CoV-2. The features of endocrine differentiation, that is, secretory granules, are significantly displaced and reduced. However, a more comprehensive TEM-based analysis throughout a full cycle of viral replication in human islets, as well as more samples from infected patients, is needed to draw definitive conclusions. However, TEM observations are in line with the affected insulin secretion observed in the present study, despite the fact that experimental variations were encountered in the four islet preparations studied.

The results show that viral replication in infected islets ex vivo was effectively inhibited by remdesivir used as a control to prevent SARS-CoV-2 replication. This inhibition of viral replication was not associated with complete rescue of β cell function or complete restoration of transcriptomes. Most likely, say the specialists, this is due to a delay in the total recovery of β cells, which cannot be achieved in the current experimental setting due to the deterioration of islets in prolonged ex vivo culture. However, the effects of remdesivir suggest that the observed changes are specific to SARS-CoV-2 infection.

Investigation into the pancreas of people killed by COVID-19 revealed a scattered distribution of clusters of infected cells throughout the organ in all patients, more visible in the exocrine compartment, but near the islets of Langerhans. Such a pattern could indicate a spread to neighboring pancreatic cells from a few infected cells, which can be reached by viral particles directly in the bloodstream during a temporary viraemia, which usually occurs in severe COVID-19.

For specialists, in particular, insulin might not be an appropriate marker to show colocalization with viral proteins. Therefore, estimating infection rates of the respective cells, within islets or pancreatic tissues, remains a challenge. The precise profile of SARS-CoV-2 infection in human islet subpopulations is still warranted, and it remains to be determined whether the number of cells infected with SARS-CoV-2 and the loss of associated identity of β cells are sufficient to affect endocrine function in healthy and diseased islets.

Therefore, the results of this article raise the question if SARS-CoV-2 directly disrupts the integrity of β cells and potentially leads to endocrine disruption and causes a negative T1DM autoantibody, as shown in recent clinical studies after cronavirus infection. Alternatively, infection with SARS-CoV-2 could be a trigger for autoimmune diabetes mellitus that occurs even years after recovery, justifying the need for long-term follow-up of COVID-19 patients.

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