Shimomura I, Matsuda M, Hammer R E, Bashmakov Y, Brown M S, Goldstein J L
Department of Molecular Genetics, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas 75390, USA.
Mol Cell. 2000 Jul;6(1):77-86.
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.
在脂肪过少（脂肪营养不良）或脂肪过多（ob/ob）的小鼠中，瘦素缺乏会导致高血糖、高胰岛素血症和胰岛素抵抗。在这两种病症中，由于肝脏对胰岛素抑制糖异生酶mRNA正常作用产生抵抗，导致肝脏过度生成葡萄糖。我们在此表明，慢性高胰岛素血症会下调肝脏中胰岛素信号通路的重要组成部分IRS-2的mRNA，从而产生胰岛素抵抗。尽管缺乏IRS-2，但胰岛素仍继续刺激SREBP-1c的生成，SREBP-1c是一种激活脂肪酸合成的转录因子。胰岛素抵抗（不适当的糖异生）和胰岛素敏感性（脂肪生成增加）共同作用形成恶性循环，加重了脂肪营养不良和ob/ob小鼠的高胰岛素血症和胰岛素抵抗。
