title: A variation in KCNQ1 gene is associated with repaglinide efficacy on insulin resistance in Chinese Type 2 Diabetes Mellitus Patients.
abstract: Repaglinide is an insulin secretagogue that often exhibits considerable interindividual variability in therapeutic efficacy. The current study was designed to investigate the impact of KCNQ1 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 KCNQ1 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 KCNQ1 genetic polymorphism influences repaglinide response due to the pivotal role of KCNQ1 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).
authors.affiliation: Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, People's Republic of China.
authors.forename: Xueyan
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, People's Republic of China.
authors.forename: Zejun
authors.initials: Z
authors.lastname: Bao
authors.affiliation: Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, People's Republic of China.|Department of Pharmacy, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, People's Republic of China.
authors.forename: Zhenhai
authors.initials: Z
authors.lastname: Shang
authors.affiliation: Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, People's Republic of China.|Department of Pharmacy, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, People's Republic of China.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, People's Republic of China.
authors.forename: Jinfang
authors.initials: J
authors.lastname: Song
authors.affiliation: Department of Endocrinology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, People's Republic of China.
authors.forename: Juan
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Endocrinology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, People's Republic of China.
authors.forename: Temitope Isaac
authors.initials: TI
authors.lastname: Adelusi
authors.affiliation: Department of Pharmacy, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, People's Republic of China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmacy, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, People's Republic of China.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Lv
authors.affiliation: Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, People's Republic of China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Lu
authors.affiliation: Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, People's Republic of China.
authors.forename: Xiaoxing
authors.initials: X
authors.lastname: Yin
mesh_terms: D000328:Adult; D044466:Asian People / Q000235:genetics; D002219:Carbamates / Q000008:administration & dosage*; D002681:China; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D051657:KCNQ1 Potassium Channel / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010880:Piperidines / Q000008:administration & dosage*; D011110:Polymorphism, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D002219:Carbamates; D055504:Insulin Receptor Substrate Proteins; D051657:KCNQ1 Potassium Channel; D019869:Phosphatidylinositol 3-Kinases; D010880:Piperidines; D051057:Proto-Oncogene Proteins c-akt; C526297:IRS2 protein, human; C496909:KCNQ1 protein, human; C072379:repaglinide