Covid-19 infects the liver and causes hyperglycemia – 05/16/2023 – Health

Research carried out at USP (University of São Paulo) shows that SARS-CoV-2, the virus that causes Covid-19, is capable of infecting liver cells (hepatocytes), stimulating the production of glucose and causing a condition similar to that of diabetes in hospitalized patients – even if they did not show changes in blood glucose levels before.

The results of the study, published yesterday (15) in the journal Proceedings of the National Academy of Sciences (PNAS), reveal part of the mechanism that the virus uses to infect these cells, with an impact on glucose metabolism, and point to ways for treatments capable of prevent the worsening of the clinical condition of these patients.

The findings also suggest that virus entry into hepatocytes is partially mediated by cooperation between the receptors (proteins) GRP78 and ACE2, the latter being present on the surface of human hepatocytes as a different isoform, of low molecular weight, and with the which SARS-CoV-2 binds to enable infection. This data is one of the innovations of the research, since previous works indicated that liver cells would not express the ACE2 protein.

High blood sugar (hyperglycemia), prevalent in hospitalized patients with Covid-19, occurs regardless of diabetes history and is associated with a worse clinical outcome, possibly leading to death. Since the beginning of the pandemic, in 2020, diabetes was identified as a risk factor for people with Covid-19, but there were gaps in relation to the mechanisms related to this condition.

Previous scientific publications even pointed out that patients with type 1 diabetes were at risk of death 3.5 times greater than those with Covid-19 without diabetes. In the case of those suffering from type 2 diabetes, the risk was twice as high.

“Making the connection with the GRP78 and ACE2 receptors was a kind of ‘icing on the cake’ of our work. But the great finding was showing that SARS-CoV-2 is a direct cause of hyperglycemia, regardless of the use of corticosteroids, stress caused by hospitalization, body weight and whether the person is diabetic or not. Demonstrating that the virus is a direct inducing agent of hyperglycemia is a very new fact”, explains Luiz Osório Silveira Leiria, professor at the Department of FMRP-USP to FAPESP (Pharmacology, Faculty of Medicine of Ribeirão Preto, University of São Paulo) and corresponding author of the article.

The research received support from FAPESP through four projects (20/05040-4, 17/08264-8, 16/00194-8 and 20/04558-0).

Hyperglycemia (in the case of type 1 diabetes) can occur when an individual’s immune system attacks the cells in the pancreas – which “manufacture” insulin -, eliminating or reducing the ability to produce this hormone and causing an imbalance in glucose metabolism. However, the researchers detected that the pancreas of the analyzed patients was preserved. Therefore, they began to evaluate the liver, which, among its functions, extracts the ingested glucose, storing it in the form of glycogen.

LONG WAY

The scientists combined a retrospective clinical study with ex vivo and in vitro experiments (in hepatocytes isolated from patients), pointing out that SARS-CoV-2 infects liver cells through ACE2 and GRP78 receptors, thus generating an increase in glucose production. liver.

The work involved a group of 269 patients from the ICU (Intensive Care Unit) of the HC (Hospital das Clínicas) in Ribeirão Preto, linked to USP, and 663 patients from the Cepeti (Center for Studies and Research in Intensive Care Medicine) in Curitiba, hospitalized with suspected Covid-19, between March and August 2020, and submitted to a PCR test.

The control group consisted of patients with other types of respiratory diseases, hospitalized in the ICU during the same period. “We got an almost perfect control group, since the symptoms were similar, with negative PCR, and similar hospitalization environment”, completes Leiria.

The researchers analyzed primary human hepatocytes and realized that SARS-CoV-2 infected these cells. “We also evaluated patient biopsies and saw that the virus was in the hepatocytes. In both cases it is replicative. And that was very interesting, mainly because the virus did not cause these hepatocytes to die, but used them to replicate, also increasing the amount of glucose produced”, explains the professor.

After obtaining the results, the behavior with other variants of SARS-CoV-2, such as delta, gamma and omicron, was followed in vitro, and the outcomes were similar.

To indicate lines of possible treatments, compounds that can inhibit the pair of GRP78 and ACE2 receptors were tested and the use, for example, of metformin, which inhibits the hepatic function of glucose, was reached.

“Other studies have found that intensive insulin therapy in the hospital is not necessarily protective for these patients. Using a drug like metformin has a more interesting effect than insulin. provide additional protection to patients”, says Leiria.

On May 5, the WHO (World Health Organization) announced that the Covid-19 pandemic no longer represents a global health emergency, after just over three years. There were trillions of dollars in economic losses and about 7 million deaths worldwide, according to official data, of which at least 702 thousand lives were lost in Brazil. The country has just over 37.48 million cases of Covid-19, according to the Coronavirus Panel, from the Ministry of Health.

ORIGIN

Leiria recalls that the study began in 2020, when diabetes and obesity were considered the main risk factors for the development of the most serious forms of Covid-19. “It turned on a light that perhaps this diabetic state could be aggravated inside the hospital. In the same period, a Brazilian article was published showing that, when the virus infected monocytes in cell culture, viral replication increased the more glucose was added to the culture medium “, he states.

The professor refers to the research that revealed that the highest level of glucose in the blood is captured by monocytes and serves as an extra energy source, allowing the coronavirus to replicate more than in a healthy organism. In response to the increasing viral load, monocytes release a large amount of cytokines (proteins with an inflammatory action), which cause effects such as the death of lung cells. Read more here.

Last year, the group from Leiria was part of a task force, led by scientists from Unicamp (State University of Campinas) and FMRP-USP, which studied the connection between visceral fat, which involves vital organs, and the worsening from Covid-19. The work concluded that it contributes more to the worsening of the disease than the fat under the skin. Read more here.

The team of one of the leaders of this research, professor at the Institute of Biology at Unicamp Marcelo Mori, was the first to demonstrate, in July 2020, that SARS-CoV-2 was capable of infecting human fat cells and to suggest that adipose tissue would serve as a reservoir for the virus. Read more here.

The article COVID-19-related hyperglycemia is associated with infection of hepatocytes and stimulation of gluconeogenesis can be read at: www.pnas.org/doi/10.1073/pnas.2217119120.