SARS-CoV-2 infects human pancreatic β cells and elicits β cell impairment

Abstract

Emerging evidence points towards an intricate relationship between the pandemic of coronavirus disease 2019 (COVID-19) and diabetes. While pre-existing diabetes is associated with severe COVID-19 , it is unclear if COVID-19 severity is a cause or consequence of diabetes . To mechanistically link COVID-19 to diabetes, we tested whether insulin-producing pancreatic β-cells can be infected by SARS-CoV-2 and cause β-cell depletion. We found that the SARS-CoV-2 receptor, ACE2 and related entry factors (TMPRSS2, NRP1, TRFC) are expressed in β-cells, with selectively high expression of NRP1. We discovered that SARS-CoV-2 infects human pancreatic β-cells in patients who succumbed to COVID-19 and selectively infects human islet β-cells in vitro . We demonstrated SARS-CoV-2 infection attenuates pancreatic insulin levels and secretion, and induces β-cell apoptosis, each rescued by NRP1 inhibition. Phosphoproteomic pathway analysis of infected islets indicates apoptotic β-cell signaling, similar to that observed in Type 1 diabetes (T1D). In summary, our study shows SARS-CoV-2 can directly induce β-cell killing.

Epidemiology and Pathophysiology of COVID-19-Associated Mucormycosis: India Versus the Rest of the World

“…Angiotensin-converting enzyme 2 (ACE2) is found in the lungs, and pancreas serves as the entry receptor for COVID-19. The ACE2 protein allows entry of SARS-CoV-2 into pancreatic islet cells and may injure the beta cells [76,77]. Also, severe COVID-19 increases insulin resistance through enhanced secretion of stress hormones (cortisol and others) and cytokines [78].…”

COVID-19 and metabolic disease: mechanisms and clinical management

“…Some reports show no expression of ACE2 in the islets of Langerhans but in pancreatic epithelial cells only, 24 , 25 , 26 whereas other studies in patients without COVID-19 have shown expression of ACE2 in β cells. 27 , 28 , 29 A sub-group of authors of this Review previously investigated expression of ACE2 and SARS-CoV-2 infection of β cells in 11 patients who died due to COVID-19. 30 Compared with other study cohorts of just one to three patients, we observed that only around 30% of the patients expressed ACE2 in β cells, indicating that other factors were also involved in the infection.…”

“…Additional factors expressed in pancreatic β cells have been identified as crucial for infection with SARS-CoV-2 ( figure 1 B). 29 , 30 NRP1, known to bind furin-cleaved substrates, facilitates SARS-CoV-2 entry and infectivity, 60 suggesting that virus entry is increased in cells with a low expression of ACE2 due to promotion of the interaction between SARS-CoV-2 and ACE2 via NRP1. In addition, HMGB1, a DNA-binding protein that regulates chromatin and is known to be proviral, was shown to regulate the expression of ACE2 and be essential for viral entry.…”

Early and late endocrine complications of COVID-19

“…Two further studies also confirmed infection of β-cells in autopsy samples from people who died of COVID-19 and showed that COVID-19 infection leads to reduced production and release of insulin from pancreatic islet tissue. In particular, they showed that SARS-CoV-2 infection leads to the death of some of those all-important β-cells and causes transdifferentiation of the surviving cells ( 61 , 62 ). In addition, several studies in mice support the hypothesis that ACE2 is important in β cell homeostasis.…”