Contrasting effects of IRS-1 versus IRS-2 gene disruption on carbohydrate and lipid metabolism in vivo
Contrasting effects of IRS-1 versus IRS-2 gene disruption on carbohydrate and lipid metabolism in vivo
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DOI：
10.1074/jbc.m006490200
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发表时间：
2000-12-15
影响因子：
4.8
通讯作者：
Shulman, GI
中科院分区：
文献类型：
--
作者：
Previs, SF;Withers, DJ;Shulman, GI
研究胰岛素受体底物（IRS）-1纯合子遗传破坏对（IRS-1（-/-））或IRS-S（IRS-2（-/-））对基础和胰岛素刺激的体内碳水化合物和脂质代谢的影响，我们向禁食18小时的小鼠（野生型（WT）、IRS-1（-/-）和IRS-2（-/-））与[3-H-3]葡萄糖和[H-2（5）]甘油的混合物中，并评估基础胰岛素水平下葡萄糖和甘油的周转率。（0-90 min）和高胰岛素-正常血糖钳夹（90-210 min; 5 mM葡萄糖和5毫单位胰岛素kg（-1）.min（-1））条件。与WT小鼠相比，IRS-1（-/-）和IRS-2（-/-）小鼠均存在胰岛素抵抗，这反映在胰岛素刺激的全身葡萄糖利用率明显受损。IRS-1（-/-）小鼠的胰岛素抵抗主要归因于胰岛素刺激的外周葡萄糖代谢降低。相比之下，IRS-2（-/-）小鼠在胰岛素介导的碳水化合物代谢中表现出多种缺陷，反映为（i）外周葡萄糖利用减少，（ii）内源性葡萄糖产生抑制减少，（iii）肝糖原合成减少。此外，IRS-2（-/-）小鼠在脂肪组织中也表现出明显的胰岛素抵抗，这反映在高胰岛素-正常血糖钳夹期间血浆游离脂肪酸浓度和甘油周转的抑制减少。这些数据表明IRS-1和IRS-2在介导胰岛素对小鼠体内碳水化合物和脂质代谢的影响中具有重要的组织特异性作用。IRS-1似乎主要作用于肌肉，而IRS-2似乎影响肝脏、肌肉和脂肪组织。
To examine the impact of homozygous genetic disruption of insulin receptor substrate (IRS)-1 (IRS-1(-/-)) or IRS-S (IRS-2(-/-)) on basal and insulin-stimulated carbohydrate and lipid metabolism in vivo, we infused 18-h fasted mice (wild-type (WT), IRS-1(-/-), and IRS-2(-/-)) with [3-H-3]glucose and [H-2(5)]glycerol and assessed rates of glucose and glycerol turnover under basal (0-90 min) and hyperinsulinemic-euglycemic clamp (90-210 min; 5 mM glucose, and 5 milliunits of insulin kg(-1).min(-1)) conditions. Both IRS-1(-/-) and IRS-2(-/-) mice were insulin-resistant as reflected by markedly impaired insulin-stimulated whole-body glucose utilization compared with WT mice. Insulin resistance in the IRS-1(-/-) mice could be ascribed mainly to decreased insulin-stimulated peripheral glucose metabolism. In contrast, IRS-2(-/-) mice displayed multiple defects in insulin-mediated carbohydrate metabolism as reflected by (i) decreased peripheral glucose utilization, (ii) decreased suppression of endogenous glucose production, and (iii) decreased hepatic glycogen synthesis. Additionally, IRS-2(-/-) mice also showed marked insulin resistance in adipose tissue as reflected by reduced suppression of plasma free fatty acid concentrations and glycerol turnover during the hyperinsulinemic-euglycemic clamp. These data suggest important tissue-specific roles for IRS-1 and IRS-2 in mediating the effect of insulin on carbohydrate and Lipid metabolism in vivo in mice. IRS-1 appears to have its major role in muscle, whereas IRS-2 appears to impact on liver, muscle, and adipose tissue.