Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands.
Laboratory of Clinical Chemistry and Hematology, Jeroen Bosch Hospital, 's-Hertogenbosch, Netherlands.
Front Endocrinol (Lausanne). 2022 Aug 25;13:986616. doi: 10.3389/fendo.2022.986616. eCollection 2022.
Type 2 diabetes (T2D) is characterized by a decreased insulin sensitivity. Magnesium (Mg) deficiency is common in people with T2D. However, the molecular consequences of low Mg levels on insulin sensitivity and glucose handling have not been determined in adipocytes. The aim of this study is to determine the role of Mg in the insulin-dependent glucose uptake.
First, the association of low plasma Mg with markers of insulin resistance was assessed in a cohort of 395 people with T2D. Secondly, the molecular role of Mg in insulin-dependent glucose uptake was studied by incubating 3T3-L1 adipocytes with 0 or 1 mmol/L Mg for 24 hours followed by insulin stimulation. Radioactive-glucose labelling, enzymatic assays, immunocytochemistry and live microscopy imaging were used to analyze the insulin receptor phosphoinositide 3-kinases/Akt pathway. Energy metabolism was assessed by the Seahorse Extracellular Flux Analyzer.
In people with T2D, plasma Mg concentration was inversely associated with markers of insulin resistance; i.e., the lower Mg, the more insulin resistant. In Mg-deficient adipocytes, insulin-dependent glucose uptake was decreased by approximately 50% compared to control Mgcondition. Insulin receptor phosphorylation Tyr1150/1151 and PIP3 mass were not decreased in Mg-deficient adipocytes. Live imaging microscopy of adipocytes transduced with an Akt sensor (FoxO1-Clover) demonstrated that FoxO1 translocation from the nucleus to the cytosol was reduced, indicting less Akt activation in Mg-deficient adipocytes. Immunocytochemistry using a Lectin membrane marker and at the membrane located Myc epitope-tagged glucose transporter 4 (GLUT4) demonstrated that GLUT4 translocation was diminished in insulin-stimulated Mg-deficient adipocytes compared to control conditions. Energy metabolism in Mg deficient adipocytes was characterized by decreased glycolysis, upon insulin stimulation.
Mg increases insulin-dependent glucose uptake in adipocytes and suggests that Mg deficiency may contribute to insulin resistance in people with T2D.
2 型糖尿病（T2D）的特征是胰岛素敏感性降低。镁（Mg）缺乏在 T2D 患者中很常见。然而，低镁水平对胰岛素敏感性和葡萄糖处理的分子后果在脂肪细胞中尚未确定。本研究旨在确定 Mg 在胰岛素依赖性葡萄糖摄取中的作用。
首先，在 395 名 T2D 患者的队列中评估低血浆 Mg 与胰岛素抵抗标志物的关联。其次，通过将 3T3-L1 脂肪细胞在 0 或 1 mmol/L Mg 中孵育 24 小时，然后进行胰岛素刺激，研究 Mg 在胰岛素依赖性葡萄糖摄取中的分子作用。放射性葡萄糖标记、酶测定、免疫细胞化学和活细胞显微镜成像用于分析胰岛素受体磷酸肌醇 3-激酶/Akt 途径。通过 Seahorse 细胞外通量分析仪评估能量代谢。
在 T2D 患者中，血浆 Mg 浓度与胰岛素抵抗标志物呈负相关；即 Mg 越低，胰岛素抵抗越严重。在缺镁脂肪细胞中，与对照 Mg 条件相比，胰岛素依赖性葡萄糖摄取减少了约 50%。在缺镁脂肪细胞中，胰岛素受体磷酸化 Tyr1150/1151 和 PIP3 质量没有降低。用 Akt 传感器（FoxO1-Clover）转导的脂肪细胞的活细胞显微镜成像表明，FoxO1 从细胞核向细胞质的易位减少，表明 Akt 在缺镁脂肪细胞中的激活减少。用凝集素膜标记和位于膜上的 Myc 表位标记的葡萄糖转运蛋白 4（GLUT4）的免疫细胞化学表明，与对照条件相比，胰岛素刺激下缺镁脂肪细胞中的 GLUT4 易位减少。缺镁脂肪细胞的能量代谢表现为胰岛素刺激下糖酵解减少。
Mg 增加了脂肪细胞中胰岛素依赖性葡萄糖摄取，并表明 Mg 缺乏可能导致 T2D 患者的胰岛素抵抗。
