COVID-19-related hyperglycemia is associated with infection of hepatocytes and stimulation of gluconeogenesis

Proc Natl Acad Sci U S A. 2023 May 23;120(21):e2217119120. doi: 10.1073/pnas.2217119120.

Ester A Barreto ¹ ², Amanda S Cruz ¹ ², Flavio P Veras ¹ ², Ronaldo Martins ³, Rafaella S Bernardelli ⁴, Isadora M Paiva ¹ ², Thais M Lima ⁵, Youvika Singh ⁶, Raphael C Guimarães ⁷, Samara Damasceno ¹ ², Nayara Pereira ¹ ², João Manoel Alves ¹ ², Tiago T Gonçalves ¹ ², Julia Forato ⁸, Stéfanie P Muraro ⁸, Gabriela F Souza ⁸, Sabrina Setembre Batah ⁵, José L Proenca-Modena ⁸ ⁹, Marcelo A Mori ⁷ ⁹ ¹⁰, Fernando Q Cunha ¹ ², Paulo Louzada-Junior ² ¹¹, Thiago M Cunha ¹ ², Helder I Nakaya ² ⁶, Alexandre Fabro ⁵, Renê D R de Oliveira ¹¹, Eurico Arruda ³, Rosângela Réa ⁴ ¹², Álvaro Réa Neto ⁴ ¹², Miguel M Fernandes da Silva ¹², Luiz Osório Leiria ¹ ²

Affiliations

1 Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14049-900, Brazil.
2 Center for Research in Inflammatory Diseases, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14049-900, Brazil.
3 Department of Cell Biology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14049-900, Brazil.
4 Federal University of Paraná, Center for Study and Research in Intensive Care Medicine, Curitiba 82530-200, Brazil.
5 Department of Pathology and Legal Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14049-900, Brazil.
6 Hospital Israelita Albert Einstein, São Paulo 05652-900, Brazil.
7 Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas 13083-970, Brazil.
8 Department of Genetics, Microbiology and Immunology, Laboratory of Emerging Viruses, Institute of Biology, University of Campinas, Campinas 13083-970, Brazil.
9 Experimental Medicine Research, Cluster University of Campinas, Campinas 13083-970, Brazil.
10 Obesity and Comorbidities Research Center, University of Campinas, Campinas 13083-864, Brazil.
11 Divisions of Clinical Immunology, Emergency, Infectious Diseases, and Intensive Care Unit, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14049-900, Brazil.
12 Hospital de Clínicas da Universidade Federal do Paraná, Curitiba 80060-900, Brazil.

PMID: 37186819 DOI: 10.1073/pnas.2217119120

Abstract

Occurrence of hyperglycemia upon Infection is associated with worse clinical outcome in COVID-19 patients. However, it is still unknown whether SARS-CoV-2 directly triggers hyperglycemia. Herein, we interrogated whether and how SARS-CoV-2 causes hyperglycemia by infecting hepatocytes and increasing glucose production. We performed a retrospective cohort study including patients that were admitted at a hospital with suspicion of COVID-19. Clinical and laboratory data were collected from the chart records and daily blood glucose values were analyzed to test the hypothesis on whether COVID-19 was independently associated with hyperglycemia. Blood glucose was collected from a subgroup of nondiabetic patients to assess pancreatic Hormones. Postmortem liver biopsies were collected to assess the presence of SARS-CoV-2 and its transporters in hepatocytes. In human hepatocytes, we studied the mechanistic Bases of SARS-CoV-2 entrance and its gluconeogenic effect. SARS-CoV-2 Infection was independently associated with hyperglycemia, regardless of diabetic history and beta cell function. We detected replicating viruses in human hepatocytes from postmortem liver biopsies and in primary hepatocytes. We found that SARS-CoV-2 variants infected human hepatocytes in vitro with different susceptibility. SARS-CoV-2 Infection in hepatocytes yields the release of new infectious viral particles, though not causing cell damage. We showed that infected hepatocytes increase glucose production and this is associated with induction of PEPCK activity. Furthermore, our results demonstrate that SARS-CoV-2 entry in hepatocytes occurs partially through ACE2- and GRP78-dependent mechanisms. SARS-CoV-2 infects and replicates in hepatocytes and exerts a PEPCK-dependent gluconeogenic effect in these cells that potentially is a key cause of hyperglycemia in infected patients.

Keywords

SARS-CoV-2; glucose; liver.

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HY-125974

HM03

99.34%, HSPA5 Inhibitor

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