Reduced Sphingosine-1-Phosphate Levels Exacerbate Type 2 Diabetes Mellitus and Associated Complications in a High-Fat Diet Mouse Model.
Groundbreaking study reveals how reduced levels of the bioactive lipid sphingosine-1-phosphate (S1P) worsen type 2 diabetes and its complications in a high-fat diet mouse model, paving the way for targeted therapies.
This study used S1P lyase knock-in (S1PLC317A KI) mice, which have reduced S1P levels due to impaired degradation, to investigate the impact of decreased S1P on the development of type 2 diabetes mellitus (T2DM) and associated complications. Compared to wild-type mice, the S1PLC317A KI mice exhibited greater body weight, more pronounced insulin resistance, higher blood glucose levels, increased hepatic fat deposition, and worsened diabetic kidney disease when fed a high-fat diet. Transcriptomic analysis identified 4,656 differentially expressed genes, including 133 diabetes-related genes, with notable enrichment in mitochondrial and bioenergetic pathways. These findings suggest that therapeutic targeting of S1P pathways could offer promising strategies for treating T2DM and its complications.