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

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, West China Hospital Sichuan University Chengdu Sichuan China" } ], "family": "Rao", "given": "Guocheng", "sequence": "first" }, { "affiliation": [ { "name": "Department of Endocrinology and Metabolism, Department of Biotherapy, Center for Diabetes and Metabolism Research, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital Sichuan University Chengdu Sichuan China" } ], "family": "Sang", "given": "Xiongbo", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Endocrinology and Metabolism, Department of Biotherapy, Center for Diabetes and Metabolism Research, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital Sichuan University Chengdu Sichuan China" } ], "family": "Zhu", "given": "Xinyue", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Endocrinology and Metabolism, Department of Biotherapy, Center for Diabetes and Metabolism Research, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital Sichuan University Chengdu Sichuan China" } ], "family": "Zou", "given": "Sailan", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Endocrinology and Metabolism, Department of Biotherapy, Center for Diabetes and Metabolism Research, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital Sichuan University Chengdu Sichuan China" }, { "name": "Department of Endocrinology and Metabolism Gansu Provincial Hospital Lanzhou China" } ], "family": "Zhang", "given": "Yanyan", "sequence": "additional" }, { "affiliation": [ { "name": "Division of Pulmonary and Critical Care Medicine, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital Sichuan University Chengdu Sichuan China" } ], "family": "Cheng", "given": "Wei", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Endocrinology and Metabolism, Department of Biotherapy, Center for Diabetes and Metabolism Research, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital Sichuan University Chengdu Sichuan China" } ], "family": "Tian", "given": "Yan", "sequence": "additional" }, { "ORCID": "https://orcid.org/0000-0001-9808-3892", "affiliation": [ { "name": "Department of Endocrinology and Metabolism, Department of Biotherapy, Center for Diabetes and Metabolism Research, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital Sichuan University Chengdu Sichuan China" } ], "authenticated-orcid": false, "family": "Fu", "given": "Xianghui", "sequence": "additional" } ], "container-title": "Journal of Cellular and Molecular Medicine", "container-title-short": "J Cellular Molecular Medi", "content-domain": { "crossmark-restriction": true, "domain": [ "onlinelibrary.wiley.com" ] }, "created": { "date-parts": [ [ 2025, 5, 30 ] ], "date-time": "2025-05-30T04:54:18Z", "timestamp": 1748580858000 }, "deposited": { "date-parts": [ [ 2025, 5, 30 ] ], "date-time": "2025-05-30T04:54:27Z", "timestamp": 1748580867000 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