Degradation of IRS1 leads to impaired glucose uptake in adipose tissue of the type 2 diabetes mouse model TALLYHO/Jng.
Degradation of IRS1 leads to impaired glucose uptake in adipose tissue of the type 2 diabetes mouse model TALLYHO/Jng.
复制标题
DOI：
10.1677/joe-09-0026
复制
发表时间：
2009-10
期刊：
影响因子：
--
通讯作者：
Naggert JK
中科院分区：
文献类型：
--
作者：
Wang Y;Nishina PM;Naggert JK
Tallyho/JNG(Th)小鼠品系是以中度肥胖、糖耐量和摄取受损、胰岛素抵抗和高胰岛素血症为特征的2型糖尿病的多基因模型。本研究的目的是阐明该模型脂肪组织葡萄糖摄取减少和胰岛素抵抗的分子机制。与对照组C57BL6/J(B6)小鼠相比，TH小鼠GLUT4在脂肪细胞质膜上的转位和定位受到损害。这些缺陷与GLUT4蛋白减少、PI3激酶活性降低和IRS1的磷酸化状态改变有关。在TH小鼠中，能够磷酸化Ser307上的IRS1的JNK1/2的活性显著高于B6对照组。TH组小鼠的IRS1蛋白表达水平低于对照组，但未见表达水平。抗泛素免疫沉淀和蛋白质印迹分析显示，TH小鼠脂肪组织中总的IRS1泛素化增加。SOCS1，已知促进IRS1泛素化和随后的降解，在TH小鼠中被发现比B6的水平要高得多。免疫组织化学显示IRS1与20S蛋白酶体共定位于TH脂肪细胞的蛋白酶体结构中，支持IRS1被主动降解的观点。我们的发现表明，IRS1降解增加和随后GLUT4动员受损在胰岛素抵抗TH小鼠的葡萄糖摄取减少中起作用。由于在人类2型糖尿病中经常观察到低水平的IRS1，TH小鼠是研究胰岛素抵抗机制和探索新的治疗方法的有吸引力的模型。
The TALLYHO/Jng (TH) mouse strain is a polygenic model for type 2 diabetes characterized by moderate obesity, impaired glucose tolerance and uptake, insulin resistance, and hyperinsulinemia. The goal of this study was to elucidate the molecular mechanisms responsible for the reduced glucose uptake and insulin resistance in the adipose tissue of this model. The translocation and localization of GLUT4 to the adipocyte plasma membrane were impaired in TH mice compared to control C57BL6/J (B6) mice. These defects were associated with decreased GLUT4 protein, reduced PI3 kinase activity and alterations in the phosphorylation status of IRS1. Activation of JNK 1/2, which can phosphorylate IRS1 on Ser307, was significantly higher in TH mice compared to B6 controls. IRS1 protein but not mRNA levels were found to be lower in TH mice than controls. Immunoprecipitation with anti-ubiquitin and western blot analysis of IRS1 protein revealed increased total IRS1 ubiquitination in adipose tissue of TH mice. SOCS1, known to promote IRS1 ubiquitination and subsequent degradation, was found at significantly higher levels in TH mice compared to B6. Immunohistochemistry showed that IRS1 co-localized with the 20S proteasome in proteasomal structures in TH adipocytes, supporting the notion that IRS1 is actively degraded. Our findings suggest that increased IRS1 degradation and subsequent impaired GLUT4 mobilization play a role in the reduced glucose uptake in insulin resistant TH mice. Since low IRS1 levels are often observed in human type 2 diabetes, the TH mouse is an attractive model to investigate mechanisms of insulin resistance and explore new treatments.