Decreased IRS-2 and increased SREBP-1c lead to mixed insulin resistance and sensitivity in livers of lipodystrophic and ob/ob mice
Decreased IRS-2 and increased SREBP-1c lead to mixed insulin resistance and sensitivity in livers of lipodystrophic and ob/ob mice
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DOI：
10.1016/s1097-2765(00)00009-5
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发表时间：
2000-07-01
期刊：
影响因子：
16
通讯作者：
Goldstein, JL
中科院分区：
文献类型：
--
作者：
Shimomura, I;Matsuda, M;Goldstein, JL
在脂肪过少（脂肪营养不良）或脂肪过多（肥胖症/肥胖症）的小鼠中，瘦素缺乏导致高血糖症、高胰岛素血症和胰岛素抵抗。在这两种疾病中，肝脏过度产生葡萄糖，这是由于对胰岛素抑制促胰岛素酶mRNA的正常作用的抵抗。在这里，我们表明，慢性高胰岛素血症下调IRS-2的mRNA，在肝脏中的胰岛素信号通路的重要组成部分，从而产生胰岛素抵抗。尽管IRS-2缺乏，胰岛素继续刺激SREBP-1c的产生，SREBP-1c是一种激活脂肪酸合成的转录因子。胰岛素抵抗（不适当的胰岛素生成）和胰岛素敏感性（升高的脂肪生成）的组合建立了恶性循环，其加重脂肪营养不良和ob/ob小鼠中的高胰岛素血症和胰岛素抵抗。
In mice with too little fat (lipodystrophy) or too much fat (ob/ob), leptin deficiency leads to hyperglycemia, hyperinsulinemia, and insulin resistance, In both disorders, the liver overproduces glucose as a result of resistance to the normal action of insulin in repressing mRNAs for gluconeogenic enzymes. Here we show that chronic hyperinsulinemia downregulates the mRNA for IRS-2, an essential component of the insulin-signaling pathway in liver, thereby producing insulin resistance. Despite IRS-2 deficiency, insulin continues to stimulate production of SREBP-1c, a transcription factor that activates fatty acid synthesis. The combination of insulin resistance (inappropriate gluconeogenesis) and insulin sensitivity (elevated lipogenesis) establishes a vicious cycle that aggravates hyperinsulinemia and insulin resistance in lipodystrophic and ob/ob mice.