Meg1/Grb10 overexpression causes postnatal growth retardation and insulin resistance via negative modulation of the IGF1R and IR cascades
Meg1/Grb10 overexpression causes postnatal growth retardation and insulin resistance via negative modulation of the IGF1R and IR cascades
复制标题
DOI：
10.1016/j.bbrc.2005.02.047
复制
发表时间：
2005-04-15
影响因子：
3.1
通讯作者：
Kaneko-Ishino, T
中科院分区：
文献类型：
--
作者：
Shiura, H;Miyoshi, N;Kaneko-Ishino, T
Meg 1/Grb 10蛋白在体外被认为是胰岛素受体（IR）和胰岛素样生长因子1受体（IGF 1 R）信号通路中的衔接蛋白。为了阐明其在体内的功能，建立了4个独立的Meg 1/Grb 10转基因小鼠品系，并研究了过量Meg 1/Grb 10对出生后生长和葡萄糖代谢的影响。所有Meg 1/Grb 10转基因小鼠在断奶后（3-4周）表现出生长迟缓，这表明Meg 1/Grb 10的异位过表达抑制了由IGF 1通过IGF 1 R介导的出生后生长。此外，小鼠由于高水平的胰岛素抵抗而变得高胰岛素血症，这表明Meg 1/Grb 10也在体内负向调节胰岛素受体级联反应。II型糖尿病在两个转基因品系中频繁出现，这两个品系也显示出葡萄糖耐量受损。在这些小鼠中，胰腺腺泡细胞的严重萎缩与胰腺中Meg 1/Grb 10的高水平产生相关。这些结果表明，Meg 1/Grb 10抑制这些细胞中胰岛素和IGF 1受体的功能，因为Ir和Igf 1 r双敲除小鼠报告了类似的表型。总之，这些结果表明，Meg 1/Grb 10在体内与胰岛素和IGF 1受体相互作用，并通过这些受体负调控IGF生长途径。(c)2005年爱思唯尔公司All rights reserved.
The Meg1/Grb10 protein has been implicated as an adapter protein in the signaling pathways from insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF1R) in vitro. To elucidate its in vivo function, four independent Meg1/Grb10 transgenic mouse lines were established, and the effects of excess Meg1/Grb10 on both postnatal growth and glucose metabolism were examined. All of the Meg1/Grb10 transgenic mice showed growth retardation after weaning (3-4 weeks), which indicates that ectopic overexpression of Meg1/Grb10 inhibits postnatal growth that is mediated by IGF1 via IGF1R. In addition, the mice became hyperinsulinemic owing to high levels of insulin resistance, which demonstrates that Meg1/Grb10 also modulates the insulin receptor cascade negatively in vivo. Type II diabetes arose frequently in the two transgenic lines, which also showed impaired glucose tolerance. In these mice, severe atrophy of the pancreatic acinus cells was associated with high-level production of Meg1/Grb10 in the pancreas. These results suggest that Meg1/Grb10 inhibits the function of both insulin and IGF1 receptors in these cells, since a similar phenotype has been reported for Ir and Igf1r double knockout mice. Taken together, these results indicate that Meg1/Grb10 interacts with both insulin and IGF1 receptors in vivo, and negatively regulates the IGF growth pathways via these receptors. (c) 2005 Elsevier Inc. All rights reserved.