tetano
Editor, Senior Moderator
Front Immunol
. 2026 Sep 18:17:1871190.
doi: 10.3389/fimmu.2026.1871190. eCollection 2026.
Lei Dong # 1 , Dongshan Yu # 2 , Yunfeng Xiao # 3 , Jianjie Zhou # 4 , Jinhua Tang 1 , Ying Li 2 , Shijie Qin 5 , Yueyun Ma 1 , Yanhua Li 1
Affiliations Expand
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.
Keywords: COVID-19; Omicron variant; biomarkers; diabetes mellitus; disease progression; multi-omics.
. 2026 Sep 18:17:1871190.
doi: 10.3389/fimmu.2026.1871190. eCollection 2026.
Multi-omics reveals regulatory networks and critical early-warning factors for severe disease progression in diabetic patients infected with SARS-CoV-2
Lei Dong # 1 , Dongshan Yu # 2 , Yunfeng Xiao # 3 , Jianjie Zhou # 4 , Jinhua Tang 1 , Ying Li 2 , Shijie Qin 5 , Yueyun Ma 1 , Yanhua Li 1
Affiliations Expand
- PMID: 42827770
- PMCID: PMC13630745
- DOI: 10.3389/fimmu.2026.1871190
Abstract
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.
Keywords: COVID-19; Omicron variant; biomarkers; diabetes mellitus; disease progression; multi-omics.