Transcending metabolic acidosis: lactate as an epigenetic signal reprogramming diabetes-sepsis immunity

Patients with diabetic sepsis exhibit a paradoxical state characterised by persistently elevated inflammatory cytokines and severely impaired antigen presentation, with substantially elevated mortality rates compared to non-diabetic patients. This review assesses the strength of evidence for lactate-epigenetic-immune dysfunction. Immune cells from diabetic patients exhibit basal glycolytic activity 2-3 times higher than healthy controls. Blood lactate levels rise markedly during sepsis, exceeding 10 mmol/L in critically ill patients-50-80% higher than non-diabetics. Hyperlactataemia states have been associated with activation of GPR81 receptors and induction of lactylation at histone H3K18. This modification selectively activates inflammatory genes while suppressing antigen-presentation pathways, thereby providing a molecular basis for the paradoxical coexistence of inflammation and immunosuppression observed clinically. Preliminary clinical studies (n = 48) demonstrate a correlation between H3K18la levels and disease severity (r = 0.63). In addition, lactate clearance of <30% within 6 hours is associated with poor prognosis. Current therapeutic evidence remains limited: dichloroacetic acid reduces serum lactate by 20-30% but shows no proven survival benefit; GPR81 modulators remain in development; GM-CSF may increase HLA-DR expression but demonstrates inconsistent effects on infection and mortality. This review identifies three potential therapeutic targets: metabolic regulation to reduce lactate production, intervention in the GPR81-H3K18la signalling axis, and personalised therapy based on immune phenotypes. However, these strategies require validation through high-quality clinical trials.