Jeanrenaud B
Laboratoires de Recherches Métaboliques, Faculty of Medicine, University of Geneva, Switzerland.
Diabetologia. 1994 Sep;37 Suppl 2:S170-8.
To study the impact on glucose handling of the observed hyperinsulinaemia and hypercorticism of the genetically obese fa/fa rats, simplified animal models were used. In the first model, normal rats were exposed to hyperinsulinaemia for 4 days and compared to saline-infused controls. At the end of this experimental period, the acute effect of insulin was assessed during euglycaemic-hyperinsulinaemic clamps. White adipose tissue lipogenic activity was much more insulin responsive in the "insulinized" than in the control groups. Conversely muscles from "insulinized" rats became insulin resistant. Such divergent consequences of prior "insulinization" on white adipose tissue and muscle were corroborated by similar divergent changes in glucose transporter (GLUT 4) mRNA and protein levels in these respective tissues. In the second model, normal rats were exposed to stress levels of corticosterone for 2 days. This resulted in an insulin resistance of all muscle types that was due to an increased glucose-fatty acid cycle, without measurable alteration of the GLUT 4 system. In genetically obese (fa/fa) rats, local cerebral glucose utilization was decreased compared to lean controls. This could be the reason for adaptive changes leading to increased levels in their hypothalamic neuropeptide Y levels and median eminence corticotropin-releasing-factor. Thus, in a third model, neuropeptide Y was administered intracerebroventricularly to normal rats for 7 days. This produced hyperinsulinaemia, hypercorticosteronaemia, as well as most of the metabolic changes observed in the genetically obese fa/fa rats, including muscle insulin resistance. These data together suggest that the aetiology of obesity-insulin resistance of genetically obese rodents has to be searched within the brain, not peripherally.
为了研究遗传性肥胖fa/fa大鼠中观察到的高胰岛素血症和高皮质醇血症对葡萄糖代谢的影响，使用了简化的动物模型。在第一个模型中，正常大鼠暴露于高胰岛素血症4天，并与输注生理盐水的对照组进行比较。在这个实验期结束时，在正常血糖-高胰岛素血症钳夹期间评估胰岛素的急性作用。白色脂肪组织的脂肪生成活性在“胰岛素处理”组中比对照组对胰岛素的反应性更强。相反，“胰岛素处理”大鼠的肌肉出现胰岛素抵抗。在白色脂肪组织和肌肉中，先前的“胰岛素处理”所产生的这种不同后果，在这些相应组织中葡萄糖转运蛋白（GLUT 4）的mRNA和蛋白质水平的类似不同变化中得到了证实。在第二个模型中，正常大鼠暴露于应激水平的皮质酮2天。这导致了所有肌肉类型的胰岛素抵抗，这是由于葡萄糖-脂肪酸循环增加所致，而GLUT 4系统没有可测量的改变。与瘦对照组相比，遗传性肥胖（fa/fa）大鼠的局部脑葡萄糖利用率降低。这可能是导致其下丘脑神经肽Y水平和正中隆起促肾上腺皮质激素释放因子水平升高的适应性变化的原因。因此，在第三个模型中，向正常大鼠脑室内注射神经肽Y 7天。这产生了高胰岛素血症、高皮质醇血症，以及在遗传性肥胖fa/fa大鼠中观察到的大多数代谢变化，包括肌肉胰岛素抵抗。这些数据共同表明，遗传性肥胖啮齿动物的肥胖-胰岛素抵抗病因必须在大脑中寻找，而不是在外周。
