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

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Barreto, Ester A. ; Cruz, Amanda S. ; Veras, Flavio P. ; Martins, Ronaldo ; Bernardelli, Rafaella S. ; Paiva, Isadora M. ; Lima, Thais M. ; Singh, Youvika ; Guimaraes, Raphael C. ; Damasceno, Samara ; Pereira, Nayara ; Alvesa, Joao Manoel ; Goncalves, Tiago T. ; Forato, Julia ; Muraro, Stefanie P. ; Souza, Gabriela F. ; Batah, Sabrina Setembre ; Proenca-Modena, Jose L. ; Mori, Marcelo A. ; Cunha, Fernando Q. ; Louzada-Junior, Paulo ; Cunha, Thiago M. ; Nakay, Helder I. ; Fabro, Alexandre ; de Oliveira, Rene D. R. ; Arruda, Eurico ; Rea, Rosangela ; Neto, Alvaro Rea ; da Silva, Miguel M. Fernandes ; Leiria, Luiz Osorio

• Document type: Journal article
• Source: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA; v. 120, n. 21, p. 10-pg., 2023-05-15.

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. (AU)

• FAPESP's process: 16/00194-8 - Pathogenesis and neurovirulence of emerging viruses in Brazil
• Grantee: José Luiz Proença Módena
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 20/05040-4 - Translational study on the role of specialised pro-resolving lipid mediators in the tolerance against CARS-CoV-2 infection
• Grantee: Luiz Osório Silveira Leiria
• Support Opportunities: Regular Research Grants
• FAPESP's process: 17/08264-8 - Investigation on the mechanisms underlying brown adipose tissue/liver crosstalk for the regulation of hepatic de novo lipogenesis and glucose production
• Grantee: Luiz Osório Silveira Leiria
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 20/04558-0 - Characterization of intrinsic risk factors and the development of new diagnostic and treatment alternatives for COVID-19
• Grantee: José Luiz Proença Módena
• Support Opportunities: Regular Research Grants