Meuillet E J, Wiernsperger N, Mania-Farnell B, Hubert P, Cremel G
Children's Memorial Hospital-CMIER, Pediatric Brain Tumor Research Program, Chicago, IL 60614, USA.
Eur J Pharmacol. 1999 Jul 21;377(2-3):241-52. doi: 10.1016/s0014-2999(99)00386-6.
The effects of the biguanide anti-hyperglycemic agent, metformin (N,N'-dimethyl-biguanide), on insulin signaling was studied in a human hepatoma cell line (HepG2). Cells were cultured in the absence (control cells) or in the presence of 100 microM of a cholesterol derivative, hemisuccinate of cholesterol. Cholesterol hemisuccinate-treatment alters cholesterol and lipid content of HepG2 and modulates membrane fluidity. Cholesterol hemisuccinate-treatment induces a decrease in insulin responsiveness and creates an 'insulin-resistant' state in these cells. Exposure to 100 microM of metformin resulted in a significant enhancement of insulin-stimulated lipogenesis in control and cholesterol hemisuccinate-treated cells. In control cells, metformin altered glycogenesis in a biphasic manner. In cholesterol hemisuccinate-treated cells, metformin inhibited basal glycogenesis but restored insulin-stimulated glycogenesis. Hence, to understand the mechanism of metformin action, we analyzed early steps in the insulin signaling pathway, including insulin receptor autophosphorylation, mitogen-activated-protein kinase and phosphatidylinositol 3-kinase activities, in both control and cholesterol hemisuccinate-treated cells. Overall, the results suggest that metformin may interact with the insulin receptor and/or a component involved in the early steps of insulin signal transduction.
在人肝癌细胞系（HepG2）中研究了双胍类抗高血糖药物二甲双胍（N，N'-二甲基双胍）对胰岛素信号传导的影响。细胞在无（对照细胞）或存在100微摩尔胆固醇衍生物胆固醇半琥珀酸酯的情况下培养。胆固醇半琥珀酸酯处理改变了HepG2的胆固醇和脂质含量，并调节膜流动性。胆固醇半琥珀酸酯处理导致胰岛素反应性降低，并在这些细胞中产生“胰岛素抵抗”状态。暴露于100微摩尔二甲双胍导致对照细胞和胆固醇半琥珀酸酯处理细胞中胰岛素刺激的脂肪生成显著增强。在对照细胞中，二甲双胍以双相方式改变糖原生成。在胆固醇半琥珀酸酯处理的细胞中，二甲双胍抑制基础糖原生成，但恢复胰岛素刺激的糖原生成。因此，为了解二甲双胍的作用机制，我们分析了对照细胞和胆固醇半琥珀酸酯处理细胞中胰岛素信号通路的早期步骤，包括胰岛素受体自磷酸化、丝裂原活化蛋白激酶和磷脂酰肌醇3激酶活性。总体而言，结果表明二甲双胍可能与胰岛素受体和/或参与胰岛素信号转导早期步骤的成分相互作用。
