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The current study was designed to investigate the impact of <jats:italic>KCNQ1<\/jats:italic> genetic polymorphism on the efficacy of repaglinide and furthermore to identify the potential mechanism of action in patients with type 2 diabetes. A total of 305 patients and 200 healthy subjects were genotyped for the <jats:italic>KCNQ1<\/jats:italic> rs2237892 polymorphism, and 82 patients with T2DM were randomized for the oral administration of repaglinide for 8 weeks. HepG2 cells were incubated with repaglinide in the absence or presence of a KCNQ1 inhibitor or the pcDNA3.1-hKCNQ1 plasmid, after which the levels of Akt, IRS-2 and PI(3)K were determined. Our data showed that repaglinide significantly decreased HOMA-IR in patients with T2DM. Furthermore, the level of HOMA-IR was significantly reduced in those patients with CT or TT genotypes than CC homozygotes. The KCNQ1 inhibitor enhanced repaglinide efficacy on insulin resistance, with IRS-2\/PI(3)K\/Akt signaling being up-regulated markedly. As in our clinical experiment, these data strongly suggest that <jats:italic>KCNQ1<\/jats:italic> genetic polymorphism influences repaglinide response due to the pivotal role of <jats:italic>KCNQ1<\/jats:italic> in regulating insulin resistance through the IRS-2\/PI(3)K\/Akt signaling pathway. This study was registered in the Chinese Clinical Trial Register on May 14, 2013. (No. ChiCTR-CCC13003536).<\/jats:p>","DOI":"10.1038\/srep37293","type":"journal-article","created":{"date-parts":[[2016,11,18]],"date-time":"2016-11-18T10:09:19Z","timestamp":1479463759000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["A variation in KCNQ1 gene is associated with repaglinide efficacy on insulin resistance in Chinese Type 2 Diabetes Mellitus Patients"],"prefix":"10.1038","volume":"6","author":[{"given":"Xueyan","family":"Zhou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zejun","family":"Bao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenhai","family":"Shang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinfang","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Temitope Isaac","family":"Adelusi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongmei","family":"Lv","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxing","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,11,18]]},"reference":[{"key":"BFsrep37293_CR1","doi-asserted-by":"publisher","first-page":"1777","DOI":"10.2337\/dci15-0012","volume":"38","author":"CS Fox","year":"2015","unstructured":"Fox, C. 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