The novel roles of liver for compensation of insulin resistance in human growth hormone transgenic rats
The novel roles of liver for compensation of insulin resistance in human growth hormone transgenic rats
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DOI：
10.1210/en.2006-0518
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发表时间：
2006-11-01
期刊：
影响因子：
4.8
通讯作者：
Takahashi, Shin-Ichiro
中科院分区：
文献类型：
--
作者：
Cho, Yoshitake;Ariga, Miyako;Takahashi, Shin-Ichiro
长期过量生长激素已知会导致高胰岛素血症和胰岛素抵抗。我们开发了人GH转基因（TG）大鼠，其特点是高血浆水平的人GH和IGF-I。这些TG大鼠的血浆胰岛素水平较高，与对照同窝仔相比，而血糖浓度正常。胰岛素依赖性葡萄糖摄取到脂肪细胞和肌肉受损，这表明这些大鼠发展胰岛素抵抗。与此相反，胰岛素非依赖性葡萄糖摄取到肝细胞从TG大鼠显着增加，和糖原和脂质水平在TG大鼠的肝脏显着高。由于GH诱导的胰岛素抵抗的肝脏的作用是知之甚少，我们研究了胰岛素信号在早期阶段和胰岛素作用的肝脏和原代培养的肝细胞制备的TG大鼠。TG和对照大鼠之间胰岛素诱导的胰岛素受体激酶活性无差异;然而，TG大鼠肝细胞中胰岛素依赖性胰岛素受体底物-2酪氨酸磷酸化、糖原合酶激活和诱导脂质合成的酶表达增强。这些结果表明，在脂肪组织和肌肉中GH过量对胰岛素依赖性葡萄糖摄取的损害通过肝脏中葡萄糖摄取的上调得到补偿，并且在经历GH过量的肝脏中通过胰岛素受体底物-2增强胰岛素信号传导导致糖原和脂质合成从并入的葡萄糖增加，导致糖原和脂质在肝脏中积累。这种新的机制至少部分解释了GH过量模型中血糖水平的正常化。
Chronic excess of GH is known to cause hyperinsulinemia and insulin resistance. We developed human GH transgenic (TG) rats, which were characterized by high plasma levels of human GH and IGF-I. These TG rats showed higher levels of plasma insulin, compared with control littermates, whereas ;plasma glucose concentrations were normal. Insulin-dependent glucose uptake into adipocytes and muscle was impaired, suggesting that these rats developed insulin resistance. In contrast, insulin-independent glucose uptake into hepatocytes from TG rats was significantly increased, and glycogen and lipid levels in livers of TG rats were remarkably high. Because the role of liver in GH-induced insulin resistance is poorly understood, we studied insulin signaling at early stages and insulin action in liver and primary cultures of hepatocytes prepared from TG rats. There was no difference in insulin receptor kinase activity induced by insulin between TG and control rats; however, insulin-dependent insulin receptor substrate-2 tyrosine phosphorylation, glycogen synthase activation, and expression of enzymes that induce lipid synthesis were potentiated in hepatocytes of TG rats. These results suggest that impairment of insulin-dependent glucose uptake by GH excess in adipose tissue and muscle is compensated by up-regulation of glucose uptake in liver and that potentiation of insulin signaling through insulin receptor substrate-2 in liver experiencing GH excess causes an increase in glycogen and lipid synthesis from incorporated glucose, resulting in accumulation of glycogen and lipids in liver. This novel mechanism explains normalization of plasma glucose levels at least in part in a GH excess model.