Metabolic-epigenetic crosstalk in latent autoimmune diabetes in adults: potential roles of lactate-induced histone lactylation in immune regulation and pancreatic β-cell fate.

Latent autoimmune diabetes in adults (LADA) is clinically between type 2 and type 1 diabetes with progressive autoimmune loss of β-cells and variable insulin dependence. Lactate was once thought to be a glucan byproduct and is now recognized as a signaling enzyme regulating gene expression via lysine lactylation. One of these marks is histone H3 lysine 18 lactylation (H3K18la), which is enriched at active enhancers and links immune genes. We examined literature and systematically distinguished direct LADA evidence from inferences from studies of type 1 diabetes, β-cell biology, autoimmune disease, and cancer. Present data posits elevated lactate and H3K9la in cell dedifferentiation, and H3K18la has stronger mechanistic support in immune regulation and enhancer activity. Cell-type-specific validation in longitudinal LADA cohorts and disease-specific experiments is lacking. We consider H3K18la a biologically plausible mechanism of LADA pathogenesis rather than an established driver. We emphasize that biomarker development or therapeutic translation will require strict LADA-specific evidence.