Key Laboratory of Hormones and Development (Ministry of Health), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Metabolic Diseases Hospital, Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300070, China.
Key Laboratory of Immuno Microenvironment and Disease of the Educational Ministry of China, Department of Immunology, Tianjin Medical University, Tianjin, 300070, China.
J Endocrinol Invest. 2018 Sep;41(9):1097-1102. doi: 10.1007/s40618-018-0836-x. Epub 2018 Jan 27.
OBJECTIVE: A reduction in insulin-stimulated glucose uptake in skeletal muscles is a characteristic of insulin resistance and type 2 diabetes mellitus (T2DM). The glucagon-like peptide (GLP)-1 agonist liraglutide can reduce blood glucose levels in individuals with T2DM. However, its effect on insulin-induced glucose metabolism in the skeletal muscle of insulin resistance is unknown. We investigated the effects and action mechanisms of liraglutide on insulin resistance (IR) in the skeletal muscle cells treatment with palmitic acid (PA). METHODS: The cell-surface GLUT4myc levels were determined by an antibody-coupled colorimetric assay. The phosphorylation levels of Akt, PI3K(p85α), AS160, IRS1, IKK, and JNK were determined by western blotting. The quantifications of mRNA levels of TNFα, IL-1β, and IL-6 were determined by real-time PCR. Analysis of variance was used for data analysis. RESULTS: PA elevated not only phosphorylation of JNK, IRS1 serines, and IKKα/β, but also the expression of IL-6, TNFα and IL-1β in C2C12-GLUT4myc cells. PA can reduce phosphorylation of IRS1 tyrosine. These effects of PA were reversed by liraglutide. In addition, liraglutide can reverse PA-decreased insulin-stimulated cell-surface GLUT4 levels, Akt, PI3K(p85α), and AS160 phosphorylation. CONCLUSIONS: Liraglutide can enhance insulin-induced GLUT4 translocation by inhibiting IRS1 serine phosphorylation in PA-treated muscle cells.
目的：骨骼肌中胰岛素刺激的葡萄糖摄取减少是胰岛素抵抗和 2 型糖尿病（T2DM）的特征。胰高血糖素样肽（GLP）-1 激动剂利拉鲁肽可降低 T2DM 患者的血糖水平。然而，其对胰岛素抵抗患者骨骼肌中胰岛素诱导的葡萄糖代谢的影响尚不清楚。我们研究了利拉鲁肽对棕榈酸（PA）处理的骨骼肌细胞胰岛素抵抗的作用及其作用机制。
方法：通过抗体偶联比色法测定细胞表面 GLUT4myc 水平。通过 Western blot 测定 Akt、PI3K（p85α）、AS160、IRS1、IKK 和 JNK 的磷酸化水平。通过实时 PCR 测定 TNFα、IL-1β 和 IL-6 的 mRNA 水平。采用方差分析进行数据分析。
结果：PA 不仅升高了 JNK、IRS1 丝氨酸和 IKKα/β的磷酸化，还升高了 C2C12-GLUT4myc 细胞中 IL-6、TNFα 和 IL-1β 的表达。PA 可降低 IRS1 酪氨酸的磷酸化。这些 PA 的作用被利拉鲁肽逆转。此外，利拉鲁肽可逆转 PA 降低的胰岛素刺激的细胞表面 GLUT4 水平、Akt、PI3K（p85α）和 AS160 磷酸化。
结论：利拉鲁肽可通过抑制 PA 处理的肌肉细胞中 IRS1 丝氨酸磷酸化来增强胰岛素诱导的 GLUT4 易位。
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