Center for Biomedical Sciences, National Institute of Health, Osong Health Technology Administration Complex, Chungcheongbuk-do, South Korea.
Division of Food Microbiology, Ministry of Food and Drug Safety, Osong Health Technology Administration Complex, Chungcheongbuk-do, South Korea.
Sci Rep. 2018 Feb 1;8(1):2133. doi: 10.1038/s41598-018-20549-0.
To unravel metabolic determinats of insulin resistance, we performed a targeted metabolomics analysis in Korean Children-Adolescent Cohort Study (KoCAS, n = 430). Sixty-seven metabolites were associated with insulin resistance in adolescents and the association also found in an adult population (KoGES, n = 2,485). Functional interactions of metabolites with gene/proteins using biological pathway with insulin resistance were not identified biological significance and regulatory effects of asymmetric dimethylarginine (ADMA). However, ADMA showed a higher association with adolescent obesity (P < 0.001) and adult diabetes (P = 0.007) and decreased after obesity intervention program. Functional studies in cellular and mouse models demonstrated that an accumulation of ADMA is associated with the regulation of obesity-induced insulin resistance in skeletal muscle. ADMA treatment inhibited dimethylarginine-dimethylaminohydrolase (DDAH) activity and mRNA expression in insulin resistance muscle cell. Moreover, the treatment led to decrease of phosphorylation of insulin receptor (IR), AKT, and GLUT4 but increase of protein-tyrosine phosphatase 1B (PTP1B). Accordingly, increased ADMA significantly inhibited glucose uptake in myotube cell. We suggest that accumulation of ADMA is associated with modulation of insulin signaling and insulin resistance. ADMA might expand the possibilities of new therapeutic target for functional and clinical implications in the control of energy and metabolic homeostasis in humans.
为了解胰岛素抵抗的代谢决定因素，我们在韩国儿童青少年队列研究（KoCAS，n=430）中进行了靶向代谢组学分析。67 种代谢物与青少年的胰岛素抵抗有关，这种关联在成人人群（KoGES，n=2485）中也存在。使用与胰岛素抵抗相关的生物学途径的代谢物与基因/蛋白质的功能相互作用没有确定生物学意义和精氨酸双甲基化（ADMA）的调节作用。然而，ADMA 与青少年肥胖（P<0.001）和成人糖尿病（P=0.007）的相关性更高，并且在肥胖干预计划后降低。细胞和小鼠模型的功能研究表明，ADMA 的积累与骨骼肌中肥胖诱导的胰岛素抵抗的调节有关。ADMA 处理抑制了胰岛素抵抗肌肉细胞中二甲基精氨酸二甲胺水解酶（DDAH）的活性和 mRNA 表达。此外，该处理导致胰岛素受体（IR）、AKT 和 GLUT4 的磷酸化减少，而蛋白酪氨酸磷酸酶 1B（PTP1B）的增加。因此，ADMA 的增加显著抑制了肌管细胞中的葡萄糖摄取。我们认为，ADMA 的积累与胰岛素信号转导和胰岛素抵抗的调节有关。ADMA 可能为控制人类能量和代谢稳态的新治疗靶点提供了更多的可能性，具有功能和临床意义。
