Volume 23, No 11, Nov 2013
ISSN: 1001-0602
EISSN: 1748-7838 2018
impact factor 17.848*
(Clarivate Analytics, 2019)
Volume 23 Issue 11, November 2013: 1310-1231
ORIGINAL ARTICLES
Deficiency of IRTKS as an adaptor of insulin receptor leads to insulin resistance
Li-Yu Huang1,2,*, Yu-Ping Wang1,2,7,*, Bao-Feng Wei1,2, Jian Yang3, Ji-Qiu Wang3, Bing-Hao Wu1,2, Zhuang-Zhuang Zhang1,2, Ying-Yong Hou4, Wei-Ming Sun5, Ren-Ming Hu6, Guang Ning3 and Ze-Guang Han1,2
1Key Laboratory of Systems Biomedicine (Ministry of Education) of Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Rui-Jin 2nd Road, Shanghai 200025, China
2Shanghai-MOST Key Laboratory for Disease and Health Genomics, Chinese National Human Genome Center at Shanghai, 351 Guo Shou-Jing Road, Shanghai 201203, China
3Department of Endocrinology and Metabolism, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, 197 Rui-Jin 2nd Road, Shanghai 200025, China
4Department of pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
5Department of Endocrinology, The First Hospital of Lanzhou University, 1 Dong-Gang West Road, Lanzhou, Gansu 730000, China
6Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai 200040, China
7Department of Medical Biochemistry and Molecular Biology, School of Basic Medical Sciences, Lanzhou University, 199 Dong-Gang West Road, Lanzhou, Gansu 730000, China
Correspondence: Ze-Guang Han, Tel: +86-21-50801325; Fax: +86-21-50800402(hanzg@chgc.sh.cn)
IRTKS encodes a member of the IRSp53/MIM homology domain family, which has been shown to play an important role in the formation of plasma membrane protrusions. Although the phosphorylation of IRTKS occurs in response to insulin stimulation, the role of this protein in insulin signaling remains unknown. Here we show that IRTKS-deficient mice exhibit insulin resistance, including hyperglycemia, hyperinsulinemia, glucose intolerance, decreased insulin sensitivity, and increased hepatic glucose production. The administration of ectopic IRTKS can ameliorate the insulin resistance of IRTKS-deficient and diabetic mice. In parallel, the expression level of IRTKS was significantly decreased in diabetic mouse model. Furthermore, DNA hypermethylation of the IRTKS promoter was also observed in these subjects. We also show that IRTKS, as an adaptor of the insulin receptor (IR), modulates IR-IRS1-PI3K-AKT signaling via regulating the phosphorylation of IR. These findings add new insights into our understanding of insulin signaling and resistance.
10.1038/cr.2013.99
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