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

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posted on 02.05.2022, 13:32 authored by Moufida Ben Nasr, Francesca D’Addio, Laura Montefusco, Vera Usuelli, Cristian Loretelli, Antonio Rossi, Ida Pastore, Ahmed Abdelsalam, Anna Maestroni, Marco Dell’Acqua, Elio Ippolito, Emma Assi, Andy Joe Seelam, Roberta Maria Fiorina, Enrica Chebat, Paola Morpurgo, Maria Elena Lunati, Andrea Mario Bolla, Reza Abdi, Joseph V. Bonventre, Stefano Rusconi, Agostino Riva, Domenico Corradi, Pierachille Santus, Pamela Clark, Manuela Nebuloni, Gabriella Baldi, Giovanna Finzi, Franco Folli, Gian Vincenzo Zuccotti, Massimo Galli, Kevan C. Herold, Paolo Fiorina

Recent studies have shown that SARS-CoV-2 infection may induce metabolic distress, leading to hyperglycemia in patients affected by 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. While there was no evidence of peripheral anti-islet autoimmunity, the serum of these patients displayed toxicity on human pancreatic islets, which can be abrogated by the use of anti-IL1b, anti-IL-6 and anti-TNF-a, cytokines known to be highly upregulated 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 evident 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-specific viral RNA, along with the presence of several immature insulin granules or proinsulin, were detected in post-mortem pancreatic tissues, suggestive of β-cell altered proinsulin processing, as well as β-cell degeneration and hyperstimulation. These data demonstrate that SARS-CoV-2 may negatively affect human pancreatic islets function and survival by creating inflammatory conditions and possibly with a direct tropism, which may in turn lead to metabolic abnormalities observed in patients with COVID-19. 

Funding

We thank the Fondazione Romeo and Enrica Invernizzi for outstanding support. P.F. and F.D are supported by the Italian Ministry of Health grant RF-2016-02362512. F.D. is supported by a SID Lombardia Grant and by the EFSD/JDRF/Lilly Programme on Type 1 Diabetes Research 2019. K.C.H is supported by DK R01 DK057846 and P30DK116577. R.A. is supported by K24 AI116925. V.U. is supported by the Fondazione Diabete Ricerca (FO.DI.RI) Società Italiana di Diabetologia (SID) fellowship.

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