Introduction and Objective: The classical Pedersen hypothesis cannot explain why some offspring of pregnancies complicated by type 2 diabetes mellitus (T2DM) are small for gestational age (SGA) or develop fetal growth restriction (FGR). We investigated whether hyperglycemia-induced placental lipid dysregulation contributes to these adverse outcomes independently of fetal insulin signaling. Methods: Multicenter cohort analysis, a T2DM pregnancy mouse model, human placental samples, and high-glucose-treated trophoblasts were used to assess placental lipid metabolism and its molecular regulation. Results: Offspring of T2DM pregnancies remained at risk of SGA regardless of maternal glycemic control. T2DM mice showed placental structural abnormalities, increased lipid accumulation, impaired angiogenesis, altered fatty acid transport, and reduced fetal weight and placental efficiency. SREBP1 was upregulated in both mouse and human T2DM placentas. In trophoblasts, high glucose activated the PI3K/AKT/mTOR-SREBP1-ACLY/FASN pathway, promoting de novo lipogenesis and lipid accumulation. Conclusion: Hyperglycemia induces placental lipid metabolic dysregulation in T2DM, which may impair placental function and affect pregnancy outcomes independently of fetal insulin signaling. Disclosure S. Wan: None. H. Yang: None.
WAN et al. (Fri,) studied this question.