Russell J C, Shillabeer G, Bar-Tana J, Lau D C, Richardson M, Wenzel L M, Graham S E, Dolphin P J
Department of Surgery, University of Alberta, Edmonton, Canada.
Diabetes. 1998 May;47(5):770-8. doi: 10.2337/diabetes.47.5.770.
The JCR:LA-cp rat develops an extreme obese/insulin-resistant syndrome such that by 12 weeks of age, there is no longer any insulin-mediated glucose turnover. At 4 weeks of age, obese and lean rats have essentially identical basal and insulin-mediated glucose uptake in skeletal muscle. By 8 weeks of age, however, the obese rats no longer exhibit such intake. Plasma insulin concentrations in the normal fed state show only small increases up to 4 weeks, with a rapid rise to a marked hyperinsulinemia thereafter, with an age at half-development of 5.5 weeks. Plasma triacylglycerol concentrations in fed obese rats are elevated at 3 weeks and rise rapidly thereafter. The triacylglycerol content of skeletal muscle is significantly elevated in the obese rats at 4 weeks of age. Histological examination of Oil Red O-stained muscle tissue and transmission electron microscopy shows the presence of intracellular lipid droplets. Treatment with the potent triacylglycerol-lowering agent MEDICA 16 (beta,beta'-tetramethylhexadecanedioic acid) from 6 weeks of age reduces plasma lipids markedly, but it reduces body weight and insulin resistance only modestly. In contrast, treatment with MEDICA 16 from the time of weaning at 3 weeks of age results in the normalization of food intake and body weight to over 8 weeks of age. The development of hyperinsulinemia is also delayed until 8.5 weeks of age, and insulin levels remain strongly reduced. Plasma triacylglycerol concentrations remain at the same level as in lean rats, and neither an elevated muscle triacylglycerol content nor intracellular lipid droplets are found at 4 weeks of age. The results indicate that insulin resistance develops in the young animals and is not directly due to a genetically determined defect in insulin metabolism. The mechanism of induction instead appears to be related to an exaggerated triacylglycerol metabolism.
LA-cp大鼠会发展出一种极端肥胖/胰岛素抵抗综合征，到12周龄时，不再有任何胰岛素介导的葡萄糖周转。4周龄时，肥胖大鼠和瘦大鼠在骨骼肌中的基础葡萄糖摄取和胰岛素介导的葡萄糖摄取基本相同。然而，到8周龄时，肥胖大鼠不再表现出这种摄取。正常进食状态下的血浆胰岛素浓度在4周龄前仅略有升高，此后迅速上升至明显的高胰岛素血症，半数发育年龄为5.5周。喂食的肥胖大鼠血浆三酰甘油浓度在3周龄时升高，此后迅速上升。4周龄时，肥胖大鼠骨骼肌中的三酰甘油含量显著升高。用Oil Red O染色的肌肉组织进行组织学检查和透射电子显微镜检查显示存在细胞内脂滴。从6周龄开始用强效降三酰甘油剂MEDICA 16（β,β'-四甲基十六烷二酸）治疗可显著降低血浆脂质，但仅适度降低体重和胰岛素抵抗。相比之下，从3周龄断奶时开始用MEDICA 16治疗可使8周龄以上的食物摄入量和体重恢复正常。高胰岛素血症的发展也延迟至8.5周龄，胰岛素水平仍大幅降低。血浆三酰甘油浓度保持在与瘦大鼠相同的水平，4周龄时未发现肌肉三酰甘油含量升高或细胞内脂滴。结果表明，胰岛素抵抗在幼年动物中出现，并非直接由于胰岛素代谢的基因缺陷所致。相反，诱导机制似乎与三酰甘油代谢过度有关。
