Beta-cells from patients with COVID-19 and from isolated human islets exhibit ACE2, DPP4, and TMPRSS2 expression, viral infiltration and necroptotic cell death

Abstract

Here we report a possible mechanistic link between coronavirus disease 2019 (COVID-19) and diabetes. In addition to its known role on the respiratory system, the human coronavirus SARS-CoV-2 has been shown to affect the endocrine system including the pancreas 1-4. It has been suggested that the virus can induce type 1 diabetes 5-8. Therefore, we isolated human pancreatic islets and examined the expression of angiotensin-converting enzyme 2 (ACE2) and the protease TMPRSS2, known to be important for SARS-CoV-2 entry 9. Furthermore, we investigated the expression of an alternative entry receptor, dipeptidyl peptidase-4 (DPP4 also known as CD26) 10. We found all three proteins expressed in pancreatic beta-cells and confirmed that beta-cells are permissive to infection with SARS-CoV-2 pseudoviruses. Additionally, we performed a comprehensive analysis of ACE2, TMPRSS2 and DPP4 expression in pancreata of 10 patients who died of COVID-19. We report significant variation between the samples and detected the highest levels of ACE2 and DPP4 expression in patients exhibiting SARS-CoV-2 infiltration shown by confocal microscopy, RNAscope and electron microscopy. Furthermore, necroptotic cell death was observed in beta-cells of the COVID-19 patients. Taken together, these data suggest that SARS-CoV-2 viral infection of pancreatic beta-cells may trigger necroptosis and islet impairment.

Acute and long-term disruption of glycometabolic control after SARS-CoV-2 infection

“…5,6 ); similar data were previously reported in patients affected by SARS-CoV-1, which has been shown to increase the levels of fasting glucose as compared to glucose levels observed in patients with pneumonia unrelated to SARS-CoV-1 infection [7][8][9] . Currently, little evidence exists as to whether the effect of SARS-CoV-2 on beta cell function is direct or indirect 10,11 . It is theoretically possible that SARS-CoV-2 may localize to the endocrine pancreas; indeed, mRNA levels of angiotensin-converting enzyme 2 (ACE2), which is the primary SARS-CoV-2 receptor, were found to be high in both exocrine and endocrine pancreas 8,12 , and immunohistochemistry as well as in situ hybridization studies have identified SARS-CoV-1-related antigen in the pancreases of patients who died of SARS-CoV-1 (refs.…”