Abstract Background Ischaemia–reperfusion injury (IRI) is a key factor in early morbidity and graft loss after pancreas transplantation. Oxygenated hypothermic machine perfusion (HMPO₂) has been shown to mitigate the consequences of IRI in liver and kidney preservation and is promising preclinically in pancreas preservation. The metabolic mechanisms underlying the benefit of HMPO₂ are poorly defined. This study aimed to highlight the key metabolites and pathways involved using metabolomic profiling. Methods 18 porcine pancreases, with 19 min of warm ischaemia, were preserved in three groups (n = 6): 8h static cold storage (SCS), 6 h SCS followed by 2 h HMPO2 and 8 h HMPO2, and then assessed by 60-minute normothermic reperfusion (NR) with whole blood. Human validation cohort: seven pancreases declined for transplantation arrived in SCS, underwent 2h HMPO₂ followed by 60-minute NR. Tissue samples were collected at start and end of cold preservation, and end of NR for untargeted metabolomics analysis using liquid chromatography-mass spectrometry (LC-MS). Results Key porcine tissue metabolic findings included:Succinate, a mitochondrial marker of ischaemia, increased during SCS and decreased during HMPO₂.Malate, a TCA metabolite, was consumed during HMPO₂ relative to SCS.S-adenosylmethionine was lower in continuous HMPO₂ than SCS, indicating methylation demand.L-cystine, a glutathione precursor, was lower in HMPO₂ than SCS.Human graft metabolite trends mirrored the porcine HMPO₂ groups, supporting translational relevance. Conclusions Compared with SCS, HMPO₂ was associated with changes in key metabolites involved in energy metabolism and respiration. This supports that oxygen delivery during HMPO₂ sustains residual metabolism under hypothermia and may mitigate IRI.
Elzawahry et al. (2026) studied this question.