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

使用转基因大鼠诱导胰岛素抵抗的机制研究

• 批准号: 11480248
• 负责人: NISHIHARA Masugi
• 金额: $ 9.6万
• 依托单位: THE UNIVERSITY OF TOKYO
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11480248/
• 关键词: Obesity; Diabetes; Insulin; Growth hormone; Transgenic rat; Signal transduction; Insulin receptor substrate; tyrosin phosphrylation; インスリン受容体基質; 成長ホルモン受容体

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

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。总而言之，我们的结果表明，外周组织（例如脂肪组织）中GH对胰岛素依赖性葡萄糖摄入的损害可以通过响应胰岛素而上调肝脏中的葡萄糖摄入来补偿，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

项目成果

Furuhata Y, 他: "Impaired insulin signaling in the liver of transgenic rats with low circulating growth hormone levels"J Endocrinol. 172. 127-136 (2002)

Furuhata Y 等人：“循环生长激素水平低的转基因大鼠肝脏中胰岛素信号传导受损”J Endocrinol. 172. 127-136 (2002)

Hu JM,他: "Effect of taurin in rat milk on the growth of offspring"J Vet Med Sci. (印刷中). (2000)

Hu JM 等：“大鼠乳汁中牛磺酸对后代生长的影响”J Vet Med Sci（出版中）。

Kuranaga E, 他: "Requirement of the Fas ligand-expressing luteal immune cells for regression of corpus luteum"FEBS Lett. 472. 137-142 (2000)

Kuranaga E 等人：“黄体退化需要表达 Fas 配体的黄体免疫细胞”FEBS Lett. 472. 137-142 (2000)

Yonezawa T, et al.: "Detection of transgene in progeny at different developmental stages following testis-mediated gene transfer"Mol Reprod Dev. 60. 196-201 (2001)

Yonezawa T 等人：“睾丸介导的基因转移后不同发育阶段后代中转基因的检测”Mol Reprod Dev。

Furuhata Y, et al.: "Impaired insulin signaling in the liver of transgenic rats with low circulating growth hormone levels"J Endocrinol. 172. 127-136 (2002)

Furuhata Y 等人：“循环生长激素水平较低的转基因大鼠肝脏中的胰岛素信号受损”J Endocrinol。