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.

妊娠糖尿病 (GDM) 是未来 2 型糖尿病 (T2D) 发展的首要危险因素。种族对从 GDM 过渡到 T2D 的人群有着深远的影响，在西班牙裔女性中观察到的风险很高。为了更好地了解这种风险，我们对具有 GDM 病史的前瞻性队列应用了针对西班牙裔的嵌套 1:1 配对病例对照设计。对产后 6-9 周（基线）没有糖尿病的女性进行 T2D 的发展监测。对基线血浆进行代谢组学，以确定与 T2D 风险相关的代谢途径。值得注意的是，鞘脂代谢减弱与未来的 T2D 高度相关。通过整合代谢组学和全基因组关联数据，进一步揭示了鞘脂代谢的缺陷，该数据确定了两个显着富集的 T2D 相关基因CERS2和CERS4。小鼠和细胞的后续实验表明，抑制鞘脂代谢会损害胰腺β细胞功能。这些数据表明产后早期鞘脂生物合成的改变会导致 β 细胞功能障碍和 T2D 风险。