Moller D E, Chang P Y, Yaspelkis B B, Flier J S, Wallberg-Henriksson H, Ivy J L
Department of Medicine, Beth Israel Hospital, Boston, Massachusetts, USA.
Endocrinology. 1996 Jun;137(6):2397-405. doi: 10.1210/endo.137.6.8641192.
Impaired skeletal muscle insulin receptor function is a feature of common forms of insulin resistance, including obesity and noninsulin-dependent diabetes mellitus. However, the extent to which this defect accounts for impaired muscle glucose disposal or altered in vivo glucose homeostasis remains to be established. We recently showed that transgenic mice that overexpress dominant-negative insulin receptors specifically in striated muscle have a severe defect in muscle insulin receptor-mediated signaling and modest hyperinsulinemia. Here we performed hindlimb perfusion studies to determine the impact of this defect on muscle glucose uptake and metabolism. Maximal rates of insulin-stimulated muscle 3-O-methylglucose transport were reduced by 32-40% in transgenic mice with proportional defects involving total hindlimb [14C]glucose uptake, lactate production, and muscle glycogen synthesis. To address the hypothesis that muscle insulin resistance could promote an increase in the accretion of body fat, carcass analysis was performed using two independent lines of transgenic mice. Although body weights were normal, transgenic mice had a 22-38% increase in body fat, with a reciprocal decrease (10-15%) in body protein. Mean gonadal fat pad weight was also increased in transgenic mice. Skeletal muscle histology and fiber type distribution were not affected. To determine whether muscle-specific insulin resistance was sufficient to cause impaired glucose tolerance, oral glucose tolerance tests were performed with 6-month-old transgenic and control mice. Fasting glucose levels were increased by 25%, and peak values were 22-40% higher in transgenic mice. Transgenic mice also had a 37% decrease in plasma lactate levels and modest increases in levels of plasma triglycerides and FFA (29% and 15%, respectively). We conclude that 1) severe defects in muscle insulin receptor function result in impaired insulin-stimulated glucose uptake and metabolism in this tissue; 2) muscle-specific insulin resistance can contribute to the development of obesity; and 3) a "pure" defect in insulin-mediated muscle glucose disposal is sufficient to result in impaired glucose tolerance and other features of the insulin resistance syndrome, including hyperinsulinemia and dyslipidemia.
骨骼肌胰岛素受体功能受损是常见形式胰岛素抵抗的一个特征，包括肥胖症和非胰岛素依赖型糖尿病。然而，这种缺陷在多大程度上导致肌肉葡萄糖代谢受损或体内葡萄糖稳态改变仍有待确定。我们最近发现，在横纹肌中特异性过表达显性负性胰岛素受体的转基因小鼠，其肌肉胰岛素受体介导的信号传导存在严重缺陷，并伴有轻度高胰岛素血症。在此，我们进行了后肢灌注研究，以确定这种缺陷对肌肉葡萄糖摄取和代谢的影响。在涉及整个后肢[14C]葡萄糖摄取、乳酸生成和肌肉糖原合成存在相应缺陷的转基因小鼠中，胰岛素刺激的肌肉3 - O - 甲基葡萄糖转运的最大速率降低了32 - 40%。为了验证肌肉胰岛素抵抗可能促进体脂增加这一假说，我们使用两个独立品系的转基因小鼠进行了胴体分析。尽管体重正常，但转基因小鼠的体脂增加了22 - 38%，同时体蛋白相应减少（10 - 15%）。转基因小鼠的平均性腺脂肪垫重量也增加了。骨骼肌组织学和纤维类型分布未受影响。为了确定肌肉特异性胰岛素抵抗是否足以导致葡萄糖耐量受损，我们对6月龄的转基因小鼠和对照小鼠进行了口服葡萄糖耐量试验。转基因小鼠的空腹血糖水平升高了25%，峰值比对照小鼠高22 - 40%。转基因小鼠的血浆乳酸水平也降低了37%，同时血浆甘油三酯和游离脂肪酸水平适度升高（分别为29%和15%）。我们得出以下结论：1）肌肉胰岛素受体功能的严重缺陷导致该组织中胰岛素刺激的葡萄糖摄取和代谢受损；2）肌肉特异性胰岛素抵抗可导致肥胖症的发生；3）胰岛素介导的肌肉葡萄糖代谢的“单纯”缺陷足以导致葡萄糖耐量受损以及胰岛素抵抗综合征的其他特征，包括高胰岛素血症和血脂异常。
