d-Threitol alleviates symptoms of diabetes in db/db mice by reducing hepatic ceramide levels

Hepatic manifestations of type 2 diabetes, including steatosis, represent a major complication driven by hepatic lipotoxicity and ceramide accumulation, yet few targeted interventions are available. This study investigated whether dietary intake of d -threitol, a naturally occurring four‑carbon sugar alcohol, could alleviate metabolic disorders by modulating hepatic sphingolipid metabolism. An 8-week d -threitol intervention improved systemic metabolism in db/db mice, indicated by stabilised body weight, enhanced insulin sensitivity, and reduced hepatic steatosis. Untargeted serum metabolomics revealed systemic lipid remodelling and enriched glycerophospholipid metabolism. Crucially, quantitative hepatic lipidomics identified ceramides as the most strongly downregulated lipid class. Through transcriptomics and qRT-PCR analyses, d -threitol was confirmed to downregulate the expression of genes associated with de novo ceramide synthesis while upregulating those associated with ceramide degradation and conversion. Integration of multi-omics data indicated the coordinated regulation of pathways related to sphingolipid metabolism, AGE–RAGE signalling, and diabetic complications. In summary, the finding that dietary d -threitol can alleviate hepatic lipotoxicity by regulating ceramide metabolism identifies it as a novel bioactive dietary regulator and a promising functional sugar alternative for diabetes-related complications. • First study showing d -threitol ameliorates diabetes in db/db mice. • Hepatic ceramide reduction identified as the core mechanism. • d -threitol inhibits ceramide synthesis and promotes its degradation. • Multi-omics integration reveals coordinated sphingolipid pathway regulation. • Positions d -threitol as a novel dietary regulator for metabolic health.