Shimaya A, Noshiro O, Hirayama R, Yoneta T, Niigata K, Shikama H
Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co. Ltd., Ibaraki, Japan.
Eur J Endocrinol. 1997 Dec;137(6):693-700. doi: 10.1530/eje.0.1370693.
Genetically obese Zucker rats exhibit mild hyperglycaemia and hyperinsulinaemia suggesting the existence of peripheral insulin resistance. We have examined the effects of YM268, an analogue of thiazolidinedione, on the content and translocation of a glucose transporter (GLUT4) in epididymal adipose tissue in 11-week-old obese and lean Zucker rats. The administration of YM268 at a dose of 10 mg/kg for 2 weeks ameliorated hyperglycaemia, hyperinsulinaemia, and impaired glucose tolerance after glucose load in obese rats. The GLUT4 content per fat pad in obese rats was reduced to 36% of that in lean littermates. Obese rats treated with YM268 increased GLUT4 concentrations in their fat pads from a basal value of 36% up to 191% of the level in lean rats. Furthermore, in adipocytes prepared from obese rats, an increase in the ratio of GLUT4 in plasma membrane to the total amount of GLUT4 (PM-GLUT4 ratio) induced by the submaximal concentration of insulin (0.3 nmol/l) was significantly attenuated compared with that in lean rats. But the maximum effect of insulin (3 nmol/l) was not attenuated. Meanwhile, YM268 had no significant effect on the attenuated PM-GLUT4 ratio in response to insulin in obese rats. These data suggested that one of the mechanisms by which YM268 improved insulin resistance in obese Zucker rats was to normalize the decreased GLUT4 content in the adipose tissue.
遗传性肥胖的 Zucker 大鼠表现出轻度高血糖和高胰岛素血症，提示存在外周胰岛素抵抗。我们研究了噻唑烷二酮类似物 YM268 对 11 周龄肥胖和瘦 Zucker 大鼠附睾脂肪组织中葡萄糖转运蛋白（GLUT4）含量和转位的影响。以 10 mg/kg 的剂量给予 YM268 两周，可改善肥胖大鼠的高血糖、高胰岛素血症以及葡萄糖负荷后受损的糖耐量。肥胖大鼠每个脂肪垫中的 GLUT4 含量降至同窝瘦鼠的 36%。用 YM268 治疗的肥胖大鼠脂肪垫中的 GLUT4 浓度从基础值（为瘦鼠水平的 36%）增加到瘦鼠水平的 191%。此外，与瘦鼠相比，在肥胖大鼠制备的脂肪细胞中，次最大浓度胰岛素（0.3 nmol/l）诱导的质膜 GLUT4 与 GLUT4 总量之比（PM-GLUT4 比）的增加明显减弱。但胰岛素的最大效应（3 nmol/l）未减弱。同时，YM268 对肥胖大鼠胰岛素反应减弱的 PM-GLUT4 比无显著影响。这些数据表明，YM268 改善肥胖 Zucker 大鼠胰岛素抵抗的机制之一是使脂肪组织中降低的 GLUT4 含量正常化。
