COVID-19 tied to in-hospital hyperglycaemia

A retrospective study combining ex vivo and in vitro assays showed an independent association between COVID-19 and the onset of hyperglycaemia.

“We propose that this occurs as a result of the direct action of the virus in hepatocytes,” said the researchers. “SARS-CoV-2 infects and replicates in hepatocytes and exerts a PEPCK*-dependent gluconeogenic effect that [could be] a key cause of hyperglycaemia in infected patients.”

“This study also demonstrated that the cooperation of the transporters GRP78 and the short ACE2 isoform is partially responsible for the entry of SARS-CoV-2 into hepatocytes,” they added.

Data were collected from 269 patients from Clinics Hospital of Ribeirão Preto Medical School, University of Sao Paulo and 663 from the Center for Study and Research in Intensive Care Medicine of Curitiba. The rate of glycaemia on admission was higher among COVID-19-positive patients (p=0.003). [Proc Natl Acad Sci U S A 2023;120:e2217119120]

On Cox regression analysis, the hazard ratio (HR) for developing hyperglycaemia in COVID-positive patients was 2.27 (p<0.001). The HR was 2.89 (p<0.001) after adjusting for sex, age, gender, BMI, diabetes, and corticosteroid use. Additional adjustment for SOFA** score yielded an HR of 2.62 (p=0.001). “These data indicate that COVID-19 holds a strong and independent correlation with the occurrence of hyperglycaemia,” said the researchers.

SARS-CoV-2 a direct trigger of hepatic glucose production

“We analysed biopsies and found the virus in hepatocytes, and it was replicating … This was most interesting, mainly because the virus did not cause the death of these hepatocytes but used them to replicate and increased the amount of glucose produced,” said study author Dr Luiz Osório Leiria from the Ribeirão Preto Medical School, University of São Paulo, Brazil, in a press release.

In the plaque-forming unit assay, the ancestral SARS-CoV-2 B lineage was replicating in hepatocytes and generating infective viral particles, thus corroborating the findings in biopsies, they added.

At 48 hours post infection, there were increases in glucose production and in PEPCK activity.

“Collectively, these findings indicate that SARS-CoV-2 exerts a pro-gluconeogenic effect associated with the activation of PEPCK … All variants (Delta, Gamma, and Omicron) were equally able to stimulate both hepatic glucose production and PEPCK activity,” said the researchers.

ACE2-, GRP78-dependent mechanisms

The chaperone glucose-regulated protein 78 (GRP78) was the most highly expressed transporter found in the hepatocytes. Although ACE2 expression was low, both receptors were present on the cell membrane and colocalized with spike protein. “[This suggests that both] interact with viral particles during SARS-CoV-2 adsorption,” they said.

Blocking both receptors individually inhibited virus entry into hepatocytes, but concomitant blockage did not produce an additive or synergistic blocking effect, the researchers noted. “[This finding supports evidence showing] that these receptors likely cooperate in the same pathway for internalizing the virus.”

Hepatic glucose control is important

“Confirming the link with GRP78 and ACE2 was the cherry on the cake for our study, but the most significant result was that SARS-CoV-2 causes hyperglycaemia directly, regardless of corticoid use, stress due to hospitalization, body weight, and diabetes,” said Leiria. “It is the first time the virus has been shown to cause hyperglycaemia directly.”

“Our data provide mechanistic insights on how COVID-19 pathophysiology impact glucose metabolism and shed light on the importance of in-hospital control of hepatic glucose production to achieve better clinical outcomes in COVID-19 patients [and protect them] against the detrimental effects of in-hospital hyperglycaemia,” the researchers concluded.