Reduced circulating sphingolipids and CERS2 activity are linked to T2D risk and impaired insulin secretion

作者：Saifur Rahman Khan, Wenyue W. Ye, Julie A.D. Van, Ishnoor Singh, Yasmin Rabiee, Kaitlyn L. Rodricks, Xiangyu Zhang, Rebekah J. Nicholson, Babak Razani, Scott A. Summers, Anthony H. Futerman, Erica P. Gunderson, Michael B. Wheeler · 发表于：Science Advances · 年份：2025 · DOI：10.1126/sciadv.adr1725 · 被引用次数：12 · 研究领域：Pancreatic function and diabetes、Gestational Diabetes Research and Management、Liver Disease Diagnosis and Treatment

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 rs267738 allele of the CERS2 gene in Hispanic women shortly after a GDM pregnancy. To understand the impact of the CERS2 gene and risk allele on glucose regulation, we examined whole-body Cers2 knockout and rs267738 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 CERS2 activity that negatively affect glucose homeostasis and β cell function.