Elucidation of abnormality of plasma membrane microdomain in type 2 diabetes mellitus

2型糖尿病质膜微区异常的阐明

基本信息

批准号：
16390259
负责人：
SUZUKI Susumu
金额：
$ 9.28万
依托单位：
Tohoku University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390259/
关键词：
diabetes ganglioside sialidase adenovirus vector glucose tolerance insulin resistance insulin receptor insulin receptor substrate 1

项目摘要

Membrane microdomains rich in gangliosides are recognized as being critical for proper compartmentalization of insulin signaling. Plasma membrane-associated sialidase, NEU3, is a key enzyme for ganglioside hydrolysis. We previously reported that the mice overexpressing NEU3 developed severe insulin-resistant diabetes. To examine possible the contributions of NEU3 to in vivo insulin sensitivity and glucose tolerance, NEU3 was expressed using adenoviral vectors in the livers of C57BL/6 mice on standard and high-fat diets, and insulin-resistant KKAy mice on standard diets. Hepatic NEU3 overexpression significantly improved glucose tolerance and insulin sensitivity in the C57BL/6 mice fed standard diets, and glucose tolerance in the C57BL/6 mice fed high-fat diets and in KKAy mice. Hepatic NEU3 overexpression increased hepatic glycogen deposition and triglyceride accumulation, and enhanced the hepatic PPARg and fetuin expression in the C57BL/6 mice on standard and high-fat diets, and in KKAy mice. TLC analysis demonstrated increased levels of GM1 and markedly reduced GM3 in the livers of mice with hepatic NEU3 overexpression (NEU3 mice). Basal and insulin-stimulated tyrosine phosphorylations of insulin receptor substrate 1 (IRS1) were significantly increased, but tyrosine phosphorylations of the insulin receptor and IRS2 in the NEU3 liver were unchanged. Insulin-stimulated tyrosine phosphorylations of the insulin receptor were increased in adipose tissues of NEU3 mice. These results suggest that hepatic NEU3 overexpression improves insulin sensitivity and glucose tolerance through modification of ganglioside composition and PPARγ signaling. Our findings also provide further evidence that NEU3 is an important regulator of insulin sensitivity and glucose tolerance.

富含神经节剂的膜微区域被认为对于适当的胰岛素信号隔室化至关重要。质膜相关的唾液酸酶Neu3是神经节水解的关键酶。我们先前报道说，过表达NEU3的小鼠会出现严重的胰岛素糖尿病。为了检查NEU3对体内胰岛素敏感性和葡萄糖耐量的可能贡献，使用腺病毒载体肝NEU3过表达表达NEU3显着提高了C57BL/6小鼠在C57BL/6小鼠中添加标准饮食和Glucose Tolerance in C57BL/6 MICE中的葡萄糖耐受性和胰岛素敏感性。肝NEU3过表达增加了肝糖原的沉积和甘油三酸酯的积累，并增强了C57BL/6小鼠在标准和高脂饮食中以及KKAY小鼠中C57BL/6小鼠中的肝PPARG和胎儿表达。 TLC分析表明，GM1水平升高，并在肝脏NEU3过表达（NEU3小鼠）的生活中显着降低了GM3。胰岛素受体底物1（IRS1）的基底和胰岛素刺激的酪氨酸磷酸化显着增加，但是胰岛素受体和NEU3肝脏中胰岛素受体的酪氨酸磷酸化却没有改变。在NEU3小鼠的脂肪组织中，胰岛素刺激的酪氨酸磷酸化增加了。这些结果表明，肝NEU3过表达通过修饰神经节组成和PPARγ信号传导来提高胰岛素敏感性和葡萄糖耐受性。我们的发现还提供了进一步的证据，表明NEU3是胰岛素敏感性和葡萄糖耐受性的重要调节剂。