Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research, Singapore.
J Physiol. 2023 Sep;601(18):4151-4169. doi: 10.1113/JP285036. Epub 2023 Aug 21.
Well-regulated placental palmitic acid (PA) and oleic acid (OA) metabolism is vital for optimal placental function and fetal development, but dysregulation occurs with gestational diabetes (GDM). We hypothesized that such dysregulation might arise from increased maternofetal glucose, leptin or insulin concentrations present in GDM, and that dysregulated PA and OA lipid metabolism could be moderated by myo-inositol, a natural polyol and potential GDM intervention. Placental explants from 21 women were incubated with stable isotope-labelled C-PA or C-OA for 48 h. Explants were treated with glucose (5, 10 mm) or leptin (13 nm) or insulin (150 nm) in combination with myo-inositol (0.3, 30, 60 μm). Forty-seven C-PA lipids and 37 C-OA lipids were measured by liquid chromatography-mass spectrometry (LCMS). Compared with controls (5 mm glucose), glucose (10 mm) increased 19 C-OA lipids and nine C-PA lipids, but decreased C-OA phosphatidylethanolamine 38:5 and C-PA phosphatidylethanolamine 36:4. The effects of leptin and insulin were less prominent than glucose, with leptin increasing C-OA acylcarnitine 18:1, and insulin increasing four C-PA triacylglycerides. Most glucose, leptin and insulin-induced alterations in lipids were attenuated by co-incubation with myo-inositol (30 or 60 μm), with attenuation also occurring in all subgroups stratified by GDM status and fetal sex. However, glucose-induced increases in acylcarnitine were not attenuated by myo-inositol and were even exaggerated in some instances. Myo-inositol therefore appears to generally act as a moderator, suppressing the perturbation of lipid metabolic processes by glucose, leptin and insulin in placenta in vitro. Whether myo-inositol protects the fetus and pregnancy from unfavourable outcomes requires further research. KEY POINTS: Incubation of placental explants with additional glucose, or to a lesser extent insulin or leptin, alters the placental production of C-lipids from C-palmitic acid (PA) and C-oleic acid (OA) in vitro compared with untreated controls from the same placenta. Co-incubation with myo-inositol attenuated most alterations induced by glucose, insulin or leptin in C-lipids, but did not affect alterations in C-acylcarnitines. Alterations induced by glucose and leptin in C-PA triacylglycerides and C-PA phospholipids were influenced by fetal sex and gestational diabetes status, but were all still attenuated by myo-inositol co-incubation. Insulin differently affected C-PA triacylglycerides and C-PA phospholipids depending on fetal sex, with alterations also attenuated by myo-inositol co-incubation.
胎盘棕榈酸（PA）和油酸（OA）的代谢受到良好调节对胎盘功能和胎儿发育至关重要，但在妊娠糖尿病（GDM）中会出现失调。我们假设这种失调可能源于 GDM 中存在的母胎葡萄糖、瘦素或胰岛素浓度增加，而通过肌醇（一种天然多元醇和潜在的 GDM 干预物）可以调节失调的 PA 和 OA 脂质代谢。用稳定同位素标记的 C-PA 或 C-OA 孵育 21 名妇女的胎盘组织 48 小时。用葡萄糖（5、10mm）或瘦素（13nm）或胰岛素（150nm）与肌醇（0.3、30、60μm）联合处理组织。通过液相色谱-质谱法（LCMS）测量了 47 种 C-PA 脂质和 37 种 C-OA 脂质。与对照组（5mm 葡萄糖）相比，葡萄糖（10mm）增加了 19 种 C-OA 脂质和 9 种 C-PA 脂质，但降低了 C-OA 磷脂酰乙醇胺 38:5 和 C-PA 磷脂酰乙醇胺 36:4。瘦素和胰岛素的作用不如葡萄糖明显，瘦素增加了 C-OA 酰基辅酶 A18:1，胰岛素增加了四种 C-PA 三酰甘油。用肌醇（30 或 60μm）共孵育可减轻葡萄糖、瘦素和胰岛素引起的大多数脂质变化，根据 GDM 状态和胎儿性别分层的所有亚组也发生了减弱。然而，肌醇不能减轻葡萄糖诱导的酰基辅酶 A 的增加，在某些情况下甚至加剧了这种增加。因此，肌醇似乎通常作为一种调节剂，抑制葡萄糖、瘦素和胰岛素在体外胎盘脂质代谢过程中的扰动。肌醇是否能保护胎儿和妊娠免受不良结局的影响还需要进一步研究。
与来自同一胎盘的未处理对照相比，体外培养的胎盘组织与额外的葡萄糖孵育，或在较小程度上与胰岛素或瘦素孵育，改变了 C-棕榈酸（PA）和 C-油酸（OA）从 C-棕榈酸（PA）和 C-油酸（OA）产生的 C-脂的产生。与葡萄糖、胰岛素或瘦素诱导的变化相比，与肌醇共孵育减弱了大多数 C-脂的变化，但不影响 C-酰基辅酶 A 的变化。葡萄糖和瘦素诱导的 C-PA 三酰甘油和 C-PA 磷脂的变化受胎儿性别和妊娠糖尿病状态的影响，但仍被肌醇共孵育所减弱。胰岛素对 C-PA 三酰甘油和 C-PA 磷脂的影响取决于胎儿性别，肌醇共孵育也减弱了这些变化。
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