Indirect and Direct Effects of SARS-CoV-2 on Human Pancreatic Islets

Abstract

Recent studies have shown that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may induce metabolic distress, leading to hyperglycemia in patients affected by coronavirus disease 19 (COVID-19). We investigated the potential indirect and direct effects of SARS-CoV-2 on human pancreatic islets in 10 patients who became hyperglycemic after COVID-19. Although there was no evidence of peripheral anti-islet autoimmu- nity, the serum of these patients displayed toxicity on human pancreatic islets, which could be abrogated by the use of anti-interleukin-1 β (IL- β), anti-IL-6, and anti-tu- mor necrosis factor a, cytokines known to be highly upre- gulated during COVID-19. Interestingly, the receptors of those aforementioned cytokines were highly expressed on human pancreatic islets. An increase in peripheral unmethylated INS DNA, a marker of cell death, was evi- dent in several patients with COVID-19. Pathology of the pancreas from deceased hyperglycemic patients who had COVID-19 revealed mild lymphocytic infiltration of pancreatic islets and pancreatic lymph nodes. Moreover, SARS-CoV-2-specrfic viral RNA, along with the presence of several immature insulin granules or proinsulin, was detected in postmortem pancreatic tissues, suggestive of β-cell-attered proinsulin processing, as well as β-cell degeneration and hyperstimulation. These data demon- strate that SARS-CoV-2 may negatively affect human pancreatic islet function and survival by creating inflam- matory conditions, possibly with a direct tropism, which may in turn lead to metabolic abnormalities observed in patie nts with COVID-19.