Multi-omics analysis identifies SMPD1 as a key contributor in sphingolipid pathway for Type 2 diabetes pathogenesis.

BACKGROUND: Type 2 diabetes (T2D) is a complex and heterogeneous metabolic disorder that presents significant challenges in treatment development. Emerging evidence indicates that T2D is closely associated with dysregulation of the sphingolipid metabolic pathway, which plays crucial roles in cellular signaling, membrane structure, and metabolic homeostasis. OBJECTIVE: To identify and characterize key sphingolipid pathway components that contribute to the pathogenesis of T2D. METHODS: We employed a multi-omics approach integrating genomic, transcriptomic, and metabolomic datasets. Two-sample Mendelian randomization analysis was performed using genome-wide association study data. For functional validation, we conducted in vivo experiments using both lean and ob/ob mice treated with recombinant sphingomyelin phosphodiesterase 1 (SMPD1). RESULTS: A mouse phenome-liver transcriptome analysis initially identified SMPD1, which converts sphingomyelin to ceramide, as a potential significant factor in T2D. Further investigation using human T2D blood lipid metabolome revealed a decrease of sphingomyelin in T2D patients, strongly suggesting SMPD1's involvement. Two-sample Mendelian randomization, utilizing genome-wide association studies, established a causal effect between SMPD1 gene expression and diabetic traits. Additionally, bulk and single-cell RNA-seq datasets from liver tissues with metabolic dysfunction-associated steatotic liver disease (MASLD) showed that SMPD1 was upregulated in MASLD hepatocytes. Critically, administering recombinant SMPD1 to both lean and ob/ob mice increased hepatic ceramide levels and worsened glucose intolerance and insulin resistance, definitively confirming SMPD1's pathogenic role. CONCLUSION: Our findings strongly indicate that SMPD1, as part of the sphingolipid pathway, represents a promising therapeutic target for both T2D and MASLD.