Serine palmitoyltransferase-mediated de novo sphingolipid biosynthesis is required for normal insulin production and glucose tolerance.

AIMS/HYPOTHESIS: The importance for normal insulin secretion of ceramide synthesis is unclear. ceramide synthesis requires serine palmitoyl transferase, SPT2, encoded by .

METHODS

We generated β-cell-selective null mice by crossing animals with alleles to mice expressing recombinase from the locus. Metabolic phenotyping, transcriptomic, functional analyses and histology were performed using standard approaches.

RESULTS

Islets from mice displayed marked alterations in ceramide and sphingomyelin levels: ceramide content: p=0.016 and p=0.109; sphingomyelin content: p=0.016 and p=0.004 in vs mice under regular and high fat diet, respectively, despite compensatory increases in the expression of enzymes in the salvage and sphingomyelinase pathways. Correspondingly, profound abnormalities were observed in glucose-regulated insulin secretion and glucose tolerance , both on a regular chow and high fat diet. These changes were associated with a drastic (~80%) lowering in β-cell numbers, and a more minor increase in delta cell numbers. They were also preserved in animals maintained on a ketogenic diet, consistent with a cell autonomous effect on the β-cell. Despite normal glucose-regulated intracellular calcium dynamics and insulin secretion, marked transcriptomic changes were observed in mouse islets, with affected GO terms including lysosome organisation and regulation of autophagy. Consistent with roles for compromised SPT2 function in diseased β-cells, expression in Balbc and DBA2J mouse islets was lowered by a high fat-diet. Moreover, mRNA tended to be lower, and mRNA was significantly decreased, in islets from human subjects with type 2 diabetes normoglycemic individuals.

CONCLUSIONS

Preserved ceramide synthesis is required to maintain normal β-cell mass and thus insulin secretion in mice. Therapeutic approaches which seek to target this process systemically using pharmacological SPT2 inhibitors should thus be treated with caution.