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

Area of Science:

• Biochemistry and Molecular Biology
• Metabolic Disorders
• Genetics

Background:

• Type 2 Diabetes (T2D) is a complex metabolic disorder with significant treatment challenges.
• Emerging evidence links T2D to dysregulation of the sphingolipid metabolic pathway.
• Sphingolipids are crucial for cellular signaling, membrane structure, and metabolic homeostasis.

Purpose of the Study:

• Identify and characterize sphingolipid pathway components involved in T2D pathogenesis.
• Investigate the role of sphingomyelin phosphodiesterase 1 (SMPD1) in T2D and related liver conditions.

Main Methods:

• Utilized a multi-omics approach integrating genomic, transcriptomic, and metabolomic data.
• Performed two-sample Mendelian randomization using genome-wide association study data.
• Conducted in vivo functional validation in lean and ob/ob mice treated with recombinant SMPD1.

Main Results:

• Identified SMPD1, an enzyme converting sphingomyelin to ceramide, as a key factor in T2D.
• Observed decreased sphingomyelin in T2D patients and established a causal link between SMPD1 expression and diabetic traits.
• Demonstrated that SMPD1 upregulation in metabolic dysfunction-associated steatotic liver disease (MASLD) hepatocytes worsens glucose intolerance and insulin resistance in mice.

Conclusions:

• SMPD1 plays a critical pathogenic role in T2D and MASLD.
• SMPD1 represents a promising therapeutic target for T2D and MASLD.