{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T06:09:20Z","timestamp":1789711760107,"version":"4.0.1"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T00:00:00Z","timestamp":1789689600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Diabetic patients face elevated risks of severe COVID-19, yet the molecular underpinnings of disease progression, particularly for Omicron subvariants, which have predominated since late 2021, remain poorly defined. This observational study leverages a cohort recruited during China\u2019s Omicron peak (December 2022\u2013February 2023) to delineate multi-omic signatures underlying severe diabetic COVID-19.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We enrolled 55 patients across five clinical strata: non-diabetic mild\/severe, diabetic mild\/severe\/fatal. Integrated 4D-DIA proteomics and LC\/GC-MS metabolomics were applied, adjusting for confounders while retaining secondary infections as integral disease features.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Diabetic patients exhibited immune exhaustion with elevated IL-6\/IL-10, blunted antiviral responses, and high secondary infection rates. We identified 62 diabetes-unique molecules associated with coordinated dysregulation across six pathways: oxidative stress, ferroptosis, glycolytic dysfunction, lipid remodeling, insulin signaling, and endothelial injury. A graded molecular signature tracked clinical deterioration: progressive depletion of GP1BB and PRG3, coupled with stepwise elevation of MMP-3\/LOXL1 and Dl-Xylose. Fatal cases further revealed a metabolic substrate misalignment, glycolytic flux adduct accumulation paradoxically coexisting with glucose, lactate, ornithine depletion, suggesting terminal fuel utilization failure. Stage-dependent shifts of stress mediators (e.g., GSK3B, ALDH9A1) distinguished severe from fatal outcomes, implying transition from compensatory adaptation to homeostatic exhaustion.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Severe diabetic COVID-19 is characterized by progressive immune-metabolic collapse. GP1BB, MMP-3, and Dl-Xylose warrant evaluation as early-warning biomarkers, while ornithine and PC(18:2) may track homeostatic reserve depletion in terminal disease. Together, these findings identify candidate biomarkers and pathway nodes that, with further validation, could contribute to risk-stratification and therapeutic strategies for diabetic patients with severe viral infections.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1871190","type":"journal-article","created":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T05:36:19Z","timestamp":1789709779000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Multi-omics reveals regulatory networks and critical early-warning factors for severe disease progression in diabetic patients infected with SARS-CoV-2"],"prefix":"10.3389","volume":"17","author":[{"given":"Lei","family":"Dong","sequence":"first","affiliation":[{"name":"Department of Clinical Laboratory, Air Force Medical Center, Air Force Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongshan","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, The Second Affiliated Hospital of Nanchang University","place":["Nanchang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunfeng","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Hospital of the Shaanxi Provincial Corps of The Chinese People\u2019s Armed Police Force","place":["Xi\u00b4an, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianjie","family":"Zhou","sequence":"additional","affiliation":[{"name":"Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinhua","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Air Force Medical Center, Air Force Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, The Second Affiliated Hospital of Nanchang University","place":["Nanchang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shijie","family":"Qin","sequence":"additional","affiliation":[{"name":"Innovative Vaccine and Immunotherapy Research Center, The Second Affiliated Hospital Zhejiang University School of Medicine","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yueyun","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Air Force Medical Center, Air Force Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanhua","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Air Force Medical Center, Air Force Medical University","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1016\/s0140-6736(20)30183-5","article-title":"Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China","volume":"395","author":"Huang","year":"2020","journal-title":"Lancet"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/s2213-8587(20)30271-0","article-title":"Risk factors for Covid-19-related mortality in people with type 1 and type 2 diabetes in England: A population-based cohort study","volume":"8","author":"Holman","year":"2020","journal-title":"Lancet Diabetes Endocrinol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2022.113089","article-title":"Covid-19 and diabetes: Association intensify risk factors for morbidity and mortality","volume":"151","author":"Sharma","year":"2022","journal-title":"BioMed Pharmacother"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/s2213-2600(20)30558-0","article-title":"Continuation versus discontinuation of renin-angiotensin system inhibitors in patients admitted to hospital with Covid-19: A prospective, randomised, open-label trial","volume":"9","author":"Cohen","year":"2021","journal-title":"Lancet Respir Med"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2022.919223","article-title":"Respiratory tract infections in diabetes - 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