Frontiers in immunology · 2026
Multi-omics reveals regulatory networks and critical early-warning factors for severe disease progression in diabetic patients infected with SARS-CoV-2.
СтатьяНаблюдательное исследованиеНазвание и аннотация: Перевод пока не подготовлен
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Dong Lei, Yu Dongshan, Xiao Yunfeng, Zhou Jianjie, Tang Jinhua, Li Ying, Qin Shijie, Ma Yueyun, Li Yanhua
Аннотация
BACKGROUND: 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's Omicron peak (December 2022-February 2023) to delineate multi-omic signatures underlying severe diabetic COVID-19.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.