Wang Yun, Nishina Patsy M, Naggert Jürgen K
The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine 04609, USA.
J Endocrinol. 2009 Oct;203(1):65-74. doi: 10.1677/JOE-09-0026. Epub 2009 Jul 8.
The TALLYHO/Jng (TH) mouse strain is a polygenic model for type 2 diabetes (T2D) 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 glucose transporter 4 (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 phosphatidylinositol 3-kinase activity, and alterations in the phosphorylation status of insulin receptor substrate 1 (IRS1). Activation of c-Jun N-terminal kinase 1/2, which can phosphorylate IRS1 on Ser307, was significantly higher in TH mice compared with B6 controls. IRS1 protein but not mRNA levels was 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. Suppressor of cytokine signaling 1, known to promote IRS1 ubiquitination and subsequent degradation, was found at significantly higher levels in TH mice compared with B6. Immunohistochemistry showed that IRS1 colocalized 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 T2D, the TH mouse is an attractive model to investigate mechanisms of insulin resistance and explore new treatments.
TALLYHO/Jng（TH）小鼠品系是2型糖尿病（T2D）的多基因模型，其特征为中度肥胖、糖耐量受损及摄取减少、胰岛素抵抗和高胰岛素血症。本研究的目的是阐明该模型脂肪组织中葡萄糖摄取减少和胰岛素抵抗的分子机制。与对照C57BL6/J（B6）小鼠相比，TH小鼠中葡萄糖转运蛋白4（GLUT4）向脂肪细胞质膜的转位和定位受损。这些缺陷与GLUT4蛋白减少、磷脂酰肌醇3激酶活性降低以及胰岛素受体底物1（IRS1）磷酸化状态改变有关。与B6对照相比，TH小鼠中可使IRS1在Ser307位点磷酸化的c-Jun氨基末端激酶1/2的激活显著更高。发现TH小鼠中IRS1蛋白水平低于对照，但mRNA水平无差异。用抗泛素进行免疫沉淀并对IRS1蛋白进行蛋白质印迹分析显示，TH小鼠脂肪组织中总IRS1泛素化增加。已知可促进IRS1泛素化及随后降解的细胞因子信号转导抑制因子1在TH小鼠中的水平显著高于B6小鼠。免疫组织化学显示，在TH脂肪细胞的蛋白酶体结构中，IRS1与20S蛋白酶体共定位，支持IRS1被主动降解的观点。我们的研究结果表明，IRS1降解增加及随后GLUT4动员受损在胰岛素抵抗的TH小鼠葡萄糖摄取减少中起作用。由于在人类T2D中常观察到低IRS1水平，TH小鼠是研究胰岛素抵抗机制和探索新治疗方法的有吸引力的模型。
