Preexisting Type 2 Diabetes and hypertension hinder physiological resolution of metabolic and lipid dysregulation in critical COVID-19 patients, providing proteomic evidence for distinct mortality risks associated with failure to restore metabolic homeostasis in comorbid versus non-comorbid patients.
Key Findings
Results
Critical COVID-19 patients exhibited a systemic proteomic shift at ICU admission characterized by upregulated immune responses and downregulated metabolic processes regardless of comorbidity status.
Analysis was performed on plasma proteins from ICU patients on the first and last days of ICU stay.
Two groups were compared: a COVID-only group (COG) and a COVID comorbid group (CTHG) with Type 2 Diabetes and hypertension.
The systemic shift was observed across all patients at admission, suggesting a common acute-phase response to severe COVID-19.
Both upregulated immune responses and downregulated metabolic processes were identified as hallmarks of the admission proteomic profile.
Results
Survival in critical COVID-19 patients was fundamentally defined by the restoration of homeostasis, with liver-derived proteins LPA, TTR, and AHSG initially suppressed but rebounding significantly in survivors.
Liver-derived proteins including LPA (lipoprotein(a)), TTR (transthyretin), and AHSG (alpha-2-HS-glycoprotein) were initially suppressed at ICU admission.
These proteins rebounded significantly in survivors by the last day of ICU stay.
The rebound of these metabolic markers distinguished survivors from nonsurvivors across both patient groups.
The pattern indicates that recovery of liver function and metabolic homeostasis is a key determinant of survival in critical COVID-19.
Results
Homeostatic recovery was impaired in the comorbid group (CTHG) compared to the COVID-only group (COG), with CTHG survivors showing attenuated recovery of metabolic markers.
CTHG patients had preexisting Type 2 Diabetes and hypertension.
Even among survivors, CTHG patients showed attenuated recovery of metabolic markers compared to COG survivors.
This suggests that preexisting T2D and HTN impair the physiological resolution of metabolic dysregulation even in patients who ultimately survive.
The finding indicates a comorbidity-specific deficit in homeostatic restoration during ICU recovery.
Results
COG nonsurvivors exhibited liver failure and severe hemolysis marked by persistent suppression of haptoglobin (HP).
Haptoglobin (HP) suppression persisted in COG nonsurvivors, indicating ongoing hemolysis.
This pattern was characterized as liver failure and severe hemolysis.
The mortality signature in COG was distinct from that observed in the comorbid group.
Persistent HP suppression rather than rebound distinguished COG nonsurvivors from COG survivors.
Results
CTHG mortality was driven by lipid metabolism dysregulation, with CD5L and APOA2 levels dropping specifically in comorbid nonsurvivors.
CD5L (CD5 antigen-like) and APOA2 (apolipoprotein A-II) levels dropped specifically in CTHG nonsurvivors.
This lipid metabolism dysregulation was not observed in COG nonsurvivors, indicating a comorbidity-specific mortality mechanism.
CTHG nonsurvivors also showed a paradoxical elevation in APOA4 (apolipoprotein A-IV).
The APOA4 elevation was interpreted as likely reflecting impaired renal clearance rather than restored lipid homeostasis.
These findings suggest that failure to restore lipid homeostasis is a key driver of mortality specifically in comorbid COVID-19 patients.
Results
The study identified distinct mortality-associated proteomic signatures between comorbid and non-comorbid critical COVID-19 patients.
COG and CTHG nonsurvivors had qualitatively different proteomic mortality signatures.
COG mortality signature centered on liver failure and hemolysis (HP suppression).
These distinct signatures provide proteomic evidence that preexisting T2D and HTN alter the pathophysiological mechanisms leading to death in severe COVID-19.
What This Means
This research suggests that when patients with Type 2 Diabetes and high blood pressure (hypertension) develop severe COVID-19 requiring intensive care, their bodies struggle to recover in ways that are measurably different from COVID-19 patients without these conditions. By analyzing hundreds of proteins in the blood of ICU patients at the time of admission and again at the end of their stay, the researchers found that all critically ill COVID-19 patients initially showed a similar pattern: the immune system was in overdrive while normal metabolic functions were suppressed. In patients who survived, key proteins made by the liver — which help regulate metabolism — bounced back to normal levels. However, patients with diabetes and hypertension showed a weaker version of this recovery even when they survived, suggesting their underlying conditions hamper the body's ability to fully restore normal function.
The study also found that the biological reasons for death differed between the two groups. COVID-19 patients without comorbidities who died showed signs of liver failure and red blood cell breakdown, marked by persistently low levels of a protein called haptoglobin. In contrast, patients with diabetes and hypertension who died showed a distinct pattern of disrupted fat (lipid) metabolism, with specific proteins (CD5L and APOA2) falling to very low levels and another protein (APOA4) rising in a way that likely signals kidney impairment rather than recovery.
This research suggests that having diabetes and hypertension does not just increase the risk of dying from severe COVID-19 in a general way — it actually changes the specific biological pathway through which the disease becomes fatal. These findings could help clinicians better understand why comorbid patients face higher risks and may point toward protein markers that could be monitored to track recovery or predict outcomes in ICU patients, though further research would be needed to translate these findings into clinical tools.
Taleb S, Stephan N, Vemulapalli P, Suhre K, Hssain A, Schmidt F, et al.. (2026). Plasma Proteomic Profiling of Comorbid and Noncomorbid COVID-19 Patients in ICU.. Journal of proteome research. https://doi.org/10.1021/acs.jproteome.6c00467