Cameron C M, Kostyo J L, Adamafio N A, Dunbar J C
Endocrinology. 1987 Apr;120(4):1568-75. doi: 10.1210/endo-120-4-1568.
The ob/ob mouse responds predictably to chronic treatment with large doses of pituitary GH with marked hyperglycemia and decreased glucose tolerance. The purpose of the present study was to characterize the metabolic alterations produced by GH that lead to this diabetogenic response in the ob/ob mouse in order to determine whether this animal might serve as a useful model for the study of the cellular mechanisms involved in the diabetogenic action of GH. Female ob/ob mice were treated sc for 3 days with either saline or 200 micrograms/day S-carboxymethylated human GH (RCM-hGH), a diabetogenic GH derivative lacking significant growth-promoting or insulin-like activities. Six hours before the start of the experiment, the animals were given a sc injection of 2 micrograms dexamethasone and deprived of food. RCM-hGH treatment produced marked increases in fasting blood glucose and plasma insulin concentrations, but had no effect on plasma glucagon or serum insulin-like growth factor I levels. It had no effect on liver glycogen level or in vitro hepatic glucose production in the absence or presence of pyruvate and lactate added to the incubation medium. By contrast, the in vitro stimulatory effects of insulin on [14C] glucose oxidation by isolated soleus muscle or segments of parametrial fat were greatly attenuated by RCM-hGH treatment, without changes in rates of basal glucose oxidation. This change in peripheral tissue responsiveness to insulin does not appear to involve glucose transport, since the in vitro stimulation by insulin of 3-O-[14C]methylglucose transport into isolated diaphragm muscle was not altered by RCM-hGH treatment. Moreover, the RCM-hGH-induced reduction in adipose tissue responsiveness to insulin does not appear to be mediated by a reduction in insulin binding, since [125I]iodoinsulin binding to adipocytes isolated from RCM-hGH-treated mice was similar to that to cells from saline-treated animals. Interestingly, the reduction in responsiveness to insulin seen with segments of adipose tissue from RCM-hGH-treated animals was not found with isolated adipocytes prepared from such tissue by collagenase digestion. These results suggest that the hyperglycemia and glucose intolerance produced in ob/ob mice by chronic GH treatment result primarily from increased peripheral tissue insulin resistance. Therefore, the ob/ob mouse provides a useful model to elucidate the cellular mechanism(s) of this aspect of the diabetogenic action of GH.
ob/ob小鼠对大剂量垂体生长激素（GH）的长期治疗反应可预测，会出现明显的高血糖和葡萄糖耐量降低。本研究的目的是描述GH产生的代谢改变，这些改变导致ob/ob小鼠出现这种致糖尿病反应，以确定这种动物是否可作为研究GH致糖尿病作用所涉及的细胞机制的有用模型。雌性ob/ob小鼠皮下注射生理盐水或200微克/天的S-羧甲基化人GH（RCM-hGH，一种缺乏显著促生长或胰岛素样活性的致糖尿病GH衍生物），持续3天。在实验开始前6小时，给动物皮下注射2微克地塞米松并禁食。RCM-hGH治疗使空腹血糖和血浆胰岛素浓度显著升高，但对血浆胰高血糖素或血清胰岛素样生长因子I水平无影响。在孵育培养基中添加或不添加丙酮酸和乳酸的情况下，它对肝糖原水平或体外肝葡萄糖生成均无影响。相比之下，RCM-hGH治疗极大地减弱了胰岛素对分离的比目鱼肌或子宫旁脂肪段[14C]葡萄糖氧化的体外刺激作用，而基础葡萄糖氧化速率未改变。外周组织对胰岛素反应性的这种变化似乎不涉及葡萄糖转运，因为胰岛素对3-O-[14C]甲基葡萄糖转运到分离的膈肌中的体外刺激作用未被RCM-hGH治疗改变。此外，RCM-hGH诱导的脂肪组织对胰岛素反应性降低似乎不是由胰岛素结合减少介导的，因为[125I]碘胰岛素与从RCM-hGH治疗小鼠分离的脂肪细胞的结合与与生理盐水处理动物的细胞的结合相似。有趣的是，用胶原酶消化从RCM-hGH治疗动物的脂肪组织制备的分离脂肪细胞时，未发现RCM-hGH治疗动物的脂肪组织段对胰岛素反应性的降低。这些结果表明，慢性GH治疗在ob/ob小鼠中产生的高血糖和葡萄糖耐量异常主要源于外周组织胰岛素抵抗增加。因此，ob/ob小鼠为阐明GH致糖尿病作用这一方面的细胞机制提供了一个有用的模型。
