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).
Highlights
Repaglinide is an insulin secretagogue that often exhibits considerable interindividual variability in therapeutic efficacy
Study indicated that patients with Type 2 diabetes mellitus (T2DM) with the KCNQ1 rs2237892 T allele were more likely to have a positive response to repaglinide in terms of postprandial plasma glucose (PPG) levels rather than HOMA-insulin resistance (IR) levels[14]
An association between KCNQ1 rs2237892 and repaglinide efficacy was observed with respect to homeostasis model assessment insulin resistance (HOMA-IR) in newly identified Chinese type 2 diabetes patients
Summary
Repaglinide is an insulin secretagogue that often exhibits considerable interindividual variability in therapeutic efficacy. Several studies have demonstrated that repaglinide can improve insulin sensitivity and decrease homeostasis model assessment insulin resistance (HOMA-IR) in patients with T2DM5,6. It has been widely used clinically and displays excellent safety and efficacy, the response to repaglinide varies among individuals, and genetic variation within KQT-like subfamily, member 1 (KCNQ1) has been suggested[7]. A clinical study demonstrated that diabetic patients with the KCNQ1 rs2237892 T allele were more likely to have a positive response to repaglinide, while patients with the KCNQ1 rs2237892 C allele exhibited larger increases in HOMA-IR13. The relationship between KCNQ1 rs2237892 polymorphism and repaglinide efficacy on IR needs to be re-evaluated
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