Terasaki J, Anai M, Funaki M, Shibata T, Inukai K, Ogihara T, Ishihara H, Katagiri H, Onishi Y, Sakoda H, Fukushima Y, Yazaki Y, Kikuchi M, Oka Y, Asano T
Institute for Adult Diseases, Asahi Life Foundation, Tokyo, Japan.
Diabetologia. 1998 Apr;41(4):400-9. doi: 10.1007/s001250050922.
JTT-501 is an insulin-sensitising compound with an isoxazolidinedione rather than a thiazolidionedione structure. Sprague-Dawley rats fed a high fat diet for 2 weeks were used as an animal model of insulin resistance, and JTT-501 was administered for the final week of the diet. An euglycaemic glucose clamp study showed that the glucose infusion rate (GIR) required to maintain euglycaemia was 57% lower in rats fed a high fat diet than in control rats, and that JTT-501 treatment restored the reduction in GIR produced by the high fat diet. To explain the mechanisms underlying the effects of a high fat diet and JTT-501 treatment, epididymal fat pads were excised and used in the analysis of insulin action. The high fat diet caused: (1) a 58% decrease in insulin receptor substrate-1 (IRS-1) content with a 58% decrease in IRS-1 tyrosine phosphorylation; (2) reductions of 56% and 73% respectively in insulin-induced maximal PI 3-kinase activation in anti-phosphotyrosine and anti-IRS-1 antibody immunoprecipitates; (3) a 46% reduction in the glucose transporter protein, GLUT4 content and, consequently, (4) severely impaired insulin-induced GLUT4 translocation to the plasma membrane and glucose uptake in adipocytes. JTT-501 treatment restored appreciably the protein content and tyrosine phosphorylation level of IRS-1. Insulin-stimulated PI 3-kinase activation was also restored in anti-phosphotyrosine and anti-IRS-1 antibody immunoprecipitates. As reflected by these improvements in insulin signalling, JTT-501 treatment improved considerably insulin-induced GLUT4 translocation to the plasma membrane as well as insulin-induced glucose uptake. However, JTT-501 had no effect on the decrease in GLUT4 content produced by the high fat diet. These observations suggest that JTT-501 enhances insulin signalling and may be effective in reducing insulin resistance.
JTT - 501是一种具有异恶唑烷二酮结构而非噻唑烷二酮结构的胰岛素增敏化合物。将喂食高脂饮食2周的斯普拉格 - 道利大鼠用作胰岛素抵抗动物模型，在饮食的最后一周给予JTT - 501。正常血糖葡萄糖钳夹研究表明，维持正常血糖所需的葡萄糖输注率（GIR）在喂食高脂饮食的大鼠中比对照大鼠低57%，并且JTT - 501治疗恢复了高脂饮食导致的GIR降低。为了解释高脂饮食和JTT - 501治疗效果的潜在机制，切除附睾脂肪垫并用于胰岛素作用分析。高脂饮食导致：（l）胰岛素受体底物 - 1（IRS - 1）含量降低58%，IRS - 1酪氨酸磷酸化降低58%；（2）抗磷酸酪氨酸和抗IRS - 1抗体免疫沉淀物中胰岛素诱导的最大PI 3 - 激酶激活分别降低56%和73%；（3）葡萄糖转运蛋白GLUT4含量降低46%，因此，（4）胰岛素诱导的GLUT4向质膜的转位以及脂肪细胞中葡萄糖摄取严重受损。JTT - 501治疗明显恢复了IRS - 1的蛋白质含量和酪氨酸磷酸化水平。抗磷酸酪氨酸和抗IRS - 1抗体免疫沉淀物中胰岛素刺激的PI 3 - 激酶激活也得以恢复。如这些胰岛素信号转导的改善所反映，JTT - 501治疗显著改善了胰岛素诱导的GLUT4向质膜的转位以及胰岛素诱导的葡萄糖摄取。然而，JTT - 501对高脂饮食导致的GLUT4含量降低没有影响。这些观察结果表明，JTT - 501增强胰岛素信号转导，可能对降低胰岛素抵抗有效。
