Abstract
Gestational diabetes mellitus (GDM) results in reduced docosahexaenoic acid (DHA) transfer to the fetus, likely due to placental dysfunction. Sirtuin-1 (SIRT1) is a nutrient sensor and regulator of lipid metabolism. This study investigated whether the high glucose and insulin condition of GDM regulates DHA transfer and expression of fatty acid transporters and if this effect is related to SIRT1 expression and function. Syncytialized primary human trophoblasts were treated with and without glucose (25 mmol/L) and insulin (10−7 mol/L) for 72 h to mimic the insulin-resistance conditions of GDM pregnancies. In control conditions, DHA transfer across trophoblasts increased in a time- and dose-dependent manner. Exposure to GDM conditions significantly decreased DHA transfer, but increased triglyceride accumulation and fatty acid transporter expression (CD36, FABP3, and FABP4). GDM conditions significantly suppressed SIRT1 mRNA and protein expression. The SIRT1 inhibitor decreased DHA transfer across control trophoblasts, and recombinant SIRT1 and SIRT1 activators restored the decreased DHA transport induced by GDM conditions. The results demonstrate a novel role of SIRT1 in the regulation of DHA transfer across trophoblasts. The suppressed SIRT1 expression and the resultant decrease in placental DHA transfer caused by high glucose and insulin levels suggest new insights of molecular mechanisms linking GDM to fetal DHA deficiency.
Highlights
Gestational diabetes mellitus (GDM) is a common metabolic disorder affecting 5–20% of all pregnancies, depending on the diagnosis method and ethnicity [1]
SIRT1 mRNA and protein levels were significantly reduced by 30% and 68%, respectively, in the trophoblasts from GDM conditions relative to controls (p < 0.05) (Figure 5a,b), which indicates that insulin resistance (IR)
SIRT1 mRNA and protein levels were significantly reduced by 30% and 68%, respectively, in the trophoblasts from GDM conditions relative to controls (p < 0.05) (Figure 5a,b), which indicates the trophoblasts from GDM conditions relative to controls (p < 0.05) (Figure 5a,b), which indicates
Summary
Gestational diabetes mellitus (GDM) is a common metabolic disorder affecting 5–20% of all pregnancies, depending on the diagnosis method and ethnicity [1]. GDM is characterized by glucose intolerance diagnosed for the first time during pregnancy caused due to reduced responsiveness to insulin [2]. This insulin resistance (IR) induces alterations in lipid metabolism leading to dyslipidemia in GDM women [3]. GDM increases perinatal morbidity and increases the risk of developing type 2 diabetes mellitus later in life [4,5,6]. Docosahexaenoic acid (DHA, 22:6 n − 3) is a long-chain polyunsaturated fatty acid that is essential for neurogenesis and brain development during the early stages of fetal life [9,10]
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