Khan 2020_Diminished sphingolipid metabolism, a hallmark of future type 2 diabetes pathogenesis, is linked to pancreatic beta-cell dysfunction

Pancreatic beta-cell dysfunction and loss of mass are essential mechanisms for Type 2 diabetes (T2D) development. We present several pieces of evidence supporting the pivotal role of diminished sphingolipid metabolism in these mechanistic aspects of T2D; this is accomplished using an omics-derived precision medicine approach on a subset of gestational diabetes mellitus (GDM) women of the SWIFT cohort, coupled with subsequent system biology, in vivo and in vitro studies. We have also devised a mapping strategy for standalone metabolomics on genome-wide association study data, which has identified two sphingolipid metabolism-re¬¬lated genes (i.e., CERS2 and CERS4) with five risk-alleles for T2D development and overall biochemical phenotype. Furthermore, incorporating sphingolipid sphingomyelin (SM) C16:10 level was found to significantly enhance the ability of an oral glucose tolerance test to predict future T2D in this sub-cohort. Taken together, these data suggest that early-stage alterations in sphingolipid biosynthesis contribute to future T2D risk.