Diminished sphingolipid metabolism, a hallmark of future type 2 diabetes pathogenesis, is linked to pancreatic beta-cell dysfunction

Summary Gestational diabetes mellitus (GDM) is the top risk factor for the future Type 2 diabetes (T2D) development. Ethnicity profoundly influences who will transition from GDM to T2D, with high risk observed in Hispanic women. To better understand this risk, a nested 1:1 pair-matched, Hispanic-specific, case-control design was applied to a prospective cohort with GDM history. Women who were non-diabetic 6-9 weeks postpartum (baseline) were monitored for the development of T2D. Metabolomics was performed on baseline plasma to identify metabolic pathways associated with T2D risk. Notably, diminished sphingolipid metabolism was highly associated with future T2D. Defects in sphingolipid metabolism were further implicated by integrating metabolomics and genome-wide-association data, which identified two significantly enriched T2D-linked genes, CERS2 and CERS4. Follow-up experiments in mice and cells demonstrated that inhibiting sphingolipid metabolism impaired pancreatic beta-cell function. These data suggest early postpartum alterations in sphingolipid biosynthesis contribute to beta-cell dysfunction and T2D risk.