Studies on mechanisms underlying the induction of insulin resistance using transgenic rats

GH过量已被证明会导致胰岛素抵抗，但其分子机制仍有待阐明。本研究以本实验室培育的人生长激素（hGH）转基因大鼠（TG大鼠）为研究对象，探讨了GH对细胞内胰岛素信号及胰岛素依赖性糖代谢调节的影响。TG大鼠的特点是高水平的血清hGH。和IGF-I，导致体长和体重增加。在10周龄的TG大鼠中，与非转基因同窝大鼠（对照大鼠）相比，检测到较高水平的血清胰岛素，但血清葡萄糖水平正常，表明高水平的血清GH引起轻度胰岛素抵抗。然后，我们从10周龄的TG或对照大鼠分离和培养肝细胞。用胰岛素处理血清饥饿的肝细胞，并分析胰岛素受体、IRS-1和IRS-2的酪氨酸磷酸化以及各种酶的活性或mRNA水平。在TG肝细胞中，胰岛素依赖性受体 ...更多信息 与对照肝细胞相比，ptor自身磷酸化减少;然而，IRS-1和IRS-2酪氨酸磷酸化增加。胰岛素诱导的葡萄糖摄取也被上调，这可能是由于胰岛素依赖性IRS酪氨酸磷酸化的增加。与此相反，糖原合成酶活性显着降低，PEPCK和FAS的mRNA水平，在TG肝细胞升高，表明胰岛素抵抗至少发生在这些酶。另一方面，胰岛素诱导的TG脂肪细胞的葡萄糖摄取减少，表明高水平的血清GH损害脂肪细胞中的胰岛素作用。总之，我们的研究结果表明，GH在外周组织（如脂肪组织）中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来补偿，从而使葡萄糖水平正常化。我们的GH转基因大鼠模型表明，GH损害胰岛素的作用在不同的步骤，在组织特异性的方式。少

GH excess has been shown to lead insulin resistance; however, the molecular mechanisms remain to be elucidated. This study was undertaken to investigate the effects of GH on intracellular signals of insulin and insulin-dependent regulation of, glucose metabolism using human GH (hGH) transgenic rats (TG rats) developed in our laboratory. The TG rats were characterized by high levels of serum hGH. and IGF-I, resulting in an increase in body length and weight. In 10 weeks old TG rats, higher levels of serum insulin were detected compared with non-transgenic littermates (control rats), but serum glucose levels were normal, suggesting high levels of serum GH cause mild insulin resistance. We then isolated and cultured hepatocytes from 10 weeks old TG or control rats. Serum starved hepatocytes were treated with insulin, and tyrosine phosphorylation of insulin receptor, IRS-1 arid IRS-2, arid activities or mRNA levels of various enzymes were analyzed. In TG hepatocytes, insulin-dependent rece … More ptor autophosphorylation was reduced compared with control hepatocytes; however, IRS-1 and IRS-2 tyrosine phosphorylation increased. Glucose uptake induced by insulin was also up-regulated, which may be due to increases in insulin-dependent IRSs tyrosine phosphorylation. In contrast, glycogen synthase activity was significantly lower and the mRNA levels of PEPCK and FAS were, elevated in TG hepatocytes, suggesting that insulin resistance occurs at least on these enzymes. On the other hand, insulin-induced glucose uptake decreased in TG adipocytes, showing that high levels of serum GH impaired insulin action in adipocytes. Taken together, our results suggest that impairment of insulin-dependent glucose uptake by GH in peripheral tissues, such as adipose tissues, is compensated by up-regulation of glucose uptake in the liver in response to insulin, resulting in normalizing glucose levels. Our GH transgenic rats model shows that GH impairs insulin action at the different steps in tissue specific manners. Less