The association of adipose-derived dimethylarginine dimethylaminohydrolase-2 with insulin sensitivity in experimental type 2 diabetes mellitus
The association of adipose-derived dimethylarginine dimethylaminohydrolase-2 with insulin sensitivity in experimental type 2 diabetes mellitus
复制标题
脂肪源性二甲基精氨酸二甲氨基水解酶-2 与实验性 2 型糖尿病胰岛素敏感性的关系
DOI：
10.1093/abbs/gmt058
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发表时间：
2013-08-01
影响因子：
3.7
通讯作者：
Yang, Zhichun
中科院分区：
文献类型：
--
作者：
Zheng, Jie;Wang, Kuansong;Yang, Zhichun
不对称二甲基精氨酸（ADMA）是一种内源性一氧化氮合酶（NOS）抑制剂，可被二甲基精氨酸-二甲氨基水解酶（DDAH）水解。据报道，脂肪细胞可以产生DDAH/ADMA，但其作用尚不清楚。在本研究中，我们通过动物和细胞模型研究了脂肪细胞来源的DDAH/ADMA对胰岛素敏感性的影响。结果表明，在高脂饮食喂养的糖尿病大鼠脂肪组织中，以及高糖（25 mM）加胰岛素（100 nM）处理的3T3-L1脂肪细胞中，胰岛素受体物质-1 （IRS-1）、葡萄糖转运蛋白-4 （GLUT-4）和DDAH亚型-2 （DDAH-2）的表达水平与对照组相比下调，但DDAH-1的表达无显著变化。我们还观察到，在糖尿病脂肪组织中，一氧化氮的生物利用度、DDAH和NOS活性随之降低，而局部ADMA含量升高。将人DDAH-2基因转染高糖和胰岛素处理的3T3-L1脂肪细胞，可显著改善DDAH活性，降低ADMA含量，上调IRS-1和GLUT-4 mRNA表达水平。这些结果提示，在2型糖尿病的发展过程中，脂肪细胞中局部的DDAH-2可能在调节胰岛素敏感性中起重要作用。
Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase (NOS), which can be hydrolyzed by dimethylarginine-dimethylaminohydrolase (DDAH). It has been reported that adipocytes can produce DDAH/ADMA, but its role remains unknown. In the present study, we examined the effects of adipocyte-derived DDAH/ADMA on insulin sensitivity using animal and cell models. Results showed that in adipose tissue of high fat diet-fed diabetic rats, as well as in high glucose (25 mM) plus insulin (100 nM)-treated 3T3-L1 adipocytes, expression levels of insulin receptor substance-1 (IRS-1), glucose transporter-4 (GLUT-4), and DDAH isoform-2 (DDAH-2) were down-regulated compared with control, although DDAH-1 expression showed no significant changes. We also observed that nitric oxide bioavailability, DDAH and NOS activities were subsequently decreased, while the local ADMA content was elevated in diabetic adipose tissue. Transfection of human DDAH-2 gene into high glucose- and insulin-treated 3T3-L1 adipocytes significantly ameliorated DDAH activity, reduced ADMA contents, and up-regulated the mRNA expression levels of IRS-1 and GLUT-4. These findings suggested that in the development of type 2 diabetes mellitus, local DDAH-2 in adipocytes might play an important role in regulating insulin sensitivity.