Reduced circulating sphingolipids and <i>CERS2</i> activity are linked to T2D risk and impaired insulin secretion

Gestational diabetes mellitus (GDM), a transient form of diabetes that resolves postpartum, is a major risk factor for type 2 diabetes (T2D) in women. While the progression from GDM to T2D is not fully understood, it involves both genetic and environmental components. By integrating clinical, metabolomic, and genome-wide association study (GWAS) data, we identified associations between decreased sphingolipid biosynthesis and future T2D, in part through the <i>rs267738</i> allele of the <i>CERS2</i> gene in Hispanic women shortly after a GDM pregnancy. To understand the impact of the <i>CERS2</i> gene and risk allele on glucose regulation, we examined whole-body <i>Cers2</i> knockout and <i>rs267738</i> knock-in mice. Both models exhibited glucose intolerance and impaired insulin secretion in vivo. Islets isolated from these models also demonstrated reduced β cell function, as shown by decreased insulin secretion ex vivo. Overall, reduced circulating sphingolipids may indicate a high risk of GDM-to-T2D progression and reflect deficits in <i>CERS2</i> activity that negatively affect glucose homeostasis and β cell function.