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Pathological Glucose Levels Enhance Entry Factor Expression and Hepatic SARS‐CoV‐2 Infection

Rao et al., Journal of Cellular and Molecular Medicine, doi:10.1111/jcmm.70581, May 2025
https://c19early.org/rao3ins.html
Analysis of high glucose levels on SARS-CoV-2 infection, showing that hyperglycemia significantly increases expression of viral entry factors (ACE2, TMPRSS2, TMPRSS4, FURIN, NRP1) in liver cells but not in lung and pancreatic cells, which enhances SARS-CoV-2 pseudovirus infection in hepatocytes. Authors show that glucose-lowering drugs (metformin, dapagliflozin, sitagliptin, and exenatide) can reduce viral entry factor expression and SARS-CoV-2 infection under high glucose conditions.
Rao et al., 29 May 2025, China, peer-reviewed, 8 authors. Contact: tyfxh@163.com, xfu@scu.edu.cn.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
Pathological Glucose Levels Enhance Entry Factor Expression and Hepatic SARS‐CoV‐2 Infection
Guocheng Rao, Xiongbo Sang, Xinyue Zhu, Sailan Zou, Yanyan Zhang, Wei Cheng, Yan Tian, Xianghui Fu
Journal of Cellular and Molecular Medicine, doi:10.1111/jcmm.70581
Accumulating clinical evidence suggests an intricate relationship between severe COVID-19 and preexisting metabolic complications, which share some metabolic dysregulations, including hyperglycaemia, hyperinsulinaemia and hyperlipidaemia. However, the potential role of these metabolic risk factors in SARS-CoV-2 infection and entry factor expression remains unknown. Here we report the implication of hyperglycaemia in SARS-CoV-2 infection and therapy. Hyperglycaemia, instead of hyperinsulinaemia and hyperlipidaemia, can significantly induce the expression of SARS-CoV-2 entry factors (Ace2, Tmprss2, Tmprss4, Furin and Nrp1) in liver cells, but not in lung and pancreatic cells, which is attenuated by mTOR inhibition. Correspondingly, pathological glucose levels promote SARS-CoV-2 entry into cultured hepatocytes in pseudovirus cell systems. Conversely, representative glucose-lowering drugs (metformin, dapagliflozin, sitagliptin and exenatide) are able to diminish the enhancement of entry factor expression and SARS-CoV-2 infection in cultured hepatocytes under pathological glucose conditions. Intriguingly, SARS-CoV-2 entry factors are increased in the livers of nonalcoholic fatty liver disease and diabetes patients. These results define hyperglycaemia as a key susceptibility factor for hepatic SARS-CoV-2 infection, and provide insights into the clinical application of glucose-lowering therapies in COVID-19 patients under comorbid hyperglycaemia conditions. | Introduction Coronavirus disease 2019 (COVID-19), caused by the SARS-CoV-2 virus, first emerged in December 2019. Despite the development of vaccines and improved therapies, global infections still spread at an alarming rate. Owing to its high contagiousness, the occurrence of asymptomatic carriers, and the rise of viral variants, SARS-CoV-2 remains a devastating threat to human lives, the
Author Contributions Guocheng Rao: investigation (lead), methodology (lead), writing -original draft (lead). Xiongbo Sang: conceptualization (equal), methodology (equal), writing -original draft (equal). Xinyue Zhu: investigation (equal), supervision (equal), writing -original draft (equal). Sailan Zou: formal analysis (equal), software (equal). Yanyan Zhang: formal analysis (equal), software (equal). Wei Cheng: data curation (equal). Yan Tian: methodology (equal), visualization (equal). Xianghui Fu: conceptualization (lead), project administration (lead), resources (lead), writing -review and editing (lead). Ethics Statement The study was performed in accordance with the principles of the Declaration of Helsinki and approved by the Institutional Review Board and Biomedical Ethics Committee of West China Hospital of Sichuan University (WCH/SCU). Consent Fully informed consent was obtained from all patients. Conflicts of Interest The authors declare no conflicts of interest. Supporting Information Additional supporting information can be found online in the Supporting Information section.
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DOI record: { "DOI": "10.1111/jcmm.70581", "ISSN": [ "1582-1838", "1582-4934" ], "URL": "http://dx.doi.org/10.1111/jcmm.70581", "abstract": "<jats:title>ABSTRACT</jats:title><jats:p>Accumulating clinical evidence suggests an intricate relationship between severe COVID‐19 and preexisting metabolic complications, which share some metabolic dysregulations, including hyperglycaemia, hyperinsulinaemia and hyperlipidaemia. However, the potential role of these metabolic risk factors in SARS‐CoV‐2 infection and entry factor expression remains unknown. Here we report the implication of hyperglycaemia in SARS‐CoV‐2 infection and therapy. Hyperglycaemia, instead of hyperinsulinaemia and hyperlipidaemia, can significantly induce the expression of SARS‐CoV‐2 entry factors (<jats:italic>Ace2</jats:italic>, <jats:italic>Tmprss2</jats:italic>, <jats:italic>Tmprss4</jats:italic>, <jats:italic>Furin</jats:italic> and <jats:italic>Nrp1</jats:italic>) in liver cells, but not in lung and pancreatic cells, which is attenuated by mTOR inhibition. Correspondingly, pathological glucose levels promote SARS‐CoV‐2 entry into cultured hepatocytes in pseudovirus cell systems. Conversely, representative glucose‐lowering drugs (metformin, dapagliflozin, sitagliptin and exenatide) are able to diminish the enhancement of entry factor expression and SARS‐CoV‐2 infection in cultured hepatocytes under pathological glucose conditions. Intriguingly, SARS‐CoV‐2 entry factors are increased in the livers of nonalcoholic fatty liver disease and diabetes patients. These results define hyperglycaemia as a key susceptibility factor for hepatic SARS‐CoV‐2 infection, and provide insights into the clinical application of glucose‐lowering therapies in COVID‐19 patients under comorbid hyperglycaemia conditions.</jats:p>", "alternative-id": [ "10.1111/jcmm.70581" ], "assertion": [ { "group": { "label": "Publication History", "name": "publication_history" }, "label": "Received", "name": "received", "order": 0, "value": "2024-10-16" }, { "group": { "label": "Publication History", "name": "publication_history" }, "label": "Accepted", "name": "accepted", "order": 2, "value": "2025-04-23" }, { "group": { "label": "Publication History", "name": "publication_history" }, "label": "Published", "name": "published", "order": 3, "value": "2025-05-29" } ], "author": [ { "affiliation": [ { "name": "Department of Endocrinology and Metabolism, Department of Biotherapy, Center for Diabetes and Metabolism Research, State Key Laboratory of Biotherapy and Cancer Center, 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