Busca avançada
Ano de início
Entree


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

Texto completo
Autor(es):
Mostrar menos -
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
Número total de Autores: 30
Tipo de documento: Artigo Científico
Fonte: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA; v. 120, n. 21, p. 10-pg., 2023-05-15.
Resumo

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)

Processo FAPESP: 16/00194-8 - Patogênese e neurovirulência de vírus emergentes no Brasil
Beneficiário:José Luiz Proença Módena
Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores
Processo FAPESP: 20/05040-4 - Estudo translacional sobre o papel dos lipídios pró-resolução como mediadores da tolerância à infecção por SARS-CoV-2
Beneficiário:Luiz Osório Silveira Leiria
Modalidade de apoio: Auxílio à Pesquisa - Regular
Processo FAPESP: 17/08264-8 - Estudo dos mecanismos de intercomunicação entre tecido adiposo marrom e fígado com impacto na regulação da lipogênese hepática e produção endógena de glicose
Beneficiário:Luiz Osório Silveira Leiria
Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores
Processo FAPESP: 20/04558-0 - Caracterização de fatores de risco intrínsecos e o desenvolvimento de novas alternativas de diagnóstico e tratamento para COVID-19
Beneficiário:José Luiz Proença Módena
Modalidade de apoio: Auxílio à Pesquisa - Regular