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MTNR1B Gene Polymorphisms Are Associated With the Therapeutic Responses to Repaglinide in Chinese Patients With Type 2 Diabetes Mellitus.

ABSTRACT: The objective of this study was to investigate whether MTNR1B gene variants influence repaglinide response in Chinese patients with newly diagnosed type 2 diabetes mellitus (T2DM). A total of 300 patients with T2DM and 200 control subjects were enrolled to identify MTNR1B rs10830963 and rs1387153 genotypes by real-time polymerase chain reaction (PCR), with subsequent high-resolution melting (HRM) analysis. Ninety-five patients with newly diagnosed T2DM were randomly selected to undergo 8 weeks of repaglinide treatment (3 mg/day). After 8-week repaglinide monotherapy, patients with at least one G allele of MTNR1B rs10830963 showed a smaller decrease in fasting plasma glucose (FPG) (P = 0.031) and a smaller increase in homeostasis model assessment for beta cell function (HOMA-B) (P = 0.002) levels than those with the CC genotype did. The T allele carriers at rs1387153 exhibited a smaller decrease in FPG (P = 0.007) and smaller increases in postprandial serum insulin (PINS) (P = 0.016) and HOMA-B (P < 0.001) levels compared to individuals with the CC genotype. These data suggest that the MTNR1B rs10830963 and rs1387153 polymorphisms are associated with repaglinide monotherapy efficacy in Chinese patients with T2DM.

SUBMITTER: Wang T

PROVIDER: S-EPMC6855210 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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MTNR1B Gene Polymorphisms Are Associated With the Therapeutic Responses to Repaglinide in Chinese Patients With Type 2 Diabetes Mellitus.

Wang Tao T Wang Xiao-Tong XT Lai Ran R Ling Hong-Wei HW Zhang Fan F Lu Qian Q Lv Dong-Mei DM Yin Xiao-Xing XX

Frontiers in pharmacology 20191107

The objective of this study was to investigate whether MTNR1B gene variants influence repaglinide response in Chinese patients with newly diagnosed type 2 diabetes mellitus (T2DM). A total of 300 patients with T2DM and 200 control subjects were enrolled to identify MTNR1B rs10830963 and rs1387153 genotypes by real-time polymerase chain reaction (PCR), with subsequent high-resolution melting (HRM) analysis. Ninety-five patients with newly diagnosed T2DM were randomly selected to und ...[more]

PMID: 31787898

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Project description:KCNQ1 channel is a member of the voltage-gated potassium channel KQT-like subfamily. The KCNQ1 gene has recently been identified as a susceptibility locus for type 2 diabetes mellitus (T2DM). In the present study, we examined the effects of KCNQ1 variants on the therapeutic response to modified-release gliclazide (gliclazide MR) treatment in Chinese patients newly diagnosed with T2DM. A total of 100 newly diagnosed T2DM patients without a history of any anti-diabetic medications were treated with gliclazide MR for 16 weeks, but 91 patients completed the entire study. The anthropometric parameters were determined at baseline and at the final visit, while clinical laboratory tests were performed at baseline and on weeks 2, 4, 6, 12, 16. Two SNPs, rs2237892 and rs2237895, in the region of the KCNQ1 gene were genotyped in all the participants. All calculations and statistical analyses were conducted using SPSS. The rs2237892 TT homozygotes exhibited significantly higher 2-h glucose levels at baseline (P<0.05) and a lower cumulative attainment rate of the target 2-h glucose level (Plog-rank=0.020) than the C allele carriers. Patients with greater numbers of rs2237892 T alleles exhibited larger augmentations (Δ) in the 2-h glucose levels (P=0.027); and patients with the rs2237892 TT genotype exhibited a higher Δ homeostasis model assessment of β-cell function (HOMA-β) than CC and CT genotype carriers (P=0.021 and P=0.043, respectively). Moreover, the rs2237895 C allele was associated with a greater decrement in Δ glycated hemoglobin (HbA1c) (P=0.024); and patients with the CC genotype exhibited greater variance than those with the AA and AC genotypes (P=0.005 and 0.021, respectively). Compared with the C allele, the odds ratio for treatment success among carriers of the rs2237892 T allele was 2.533 (P=0.007); and the rs2237895 C allele was associated with a 2.360-fold decrease in HbA1c compared with the A allele (P=0.009). KCNQ1 polymorphisms are associated with gliclazide MR efficacy in Chinese patients with type 2 diabetes.

Project description:BackgroundExenatide is a GLP-1R agonist that often exhibits considerable interindividual variability in therapeutic efficacy. However, there is no evidence about the impact of genetic variants in the PPARD on the therapeutic efficacy of exenatide. This research was aimed to explore the influence of PPARD gene polymorphism on the therapeutic effect of exenatide, and to identify the potential mechanism futher.MethodsA total of 300 patients with T2DM and 200 control subjects were enrolled to identify PPARD rs2016520 and rs3777744 genotypes. A prospective clinical study was used to collect clinical indicators and peripheral blood of T2DM patients treated with exenatide monotherapy for 6 months. The SNaPshot method was used to identify PPARD rs2016520 and rs3777744 genotypes, and then we performed correlation analysis between PPARD gene variants and the efficacy of exenatide, and conducted multiple linear regression analysis of factors affecting the therapeutic effect of exenatide. HepG2 cells were incubated with exenatide in the absence or presence of a PPARδ agonist or the siPPARδ plasmid, after which the levels of GLP-1R and the ratio of glucose uptake were determined.ResultsAfter 6 months exenatide monotherapy, we observed that homeostasis model assessment for insulin resistance (HOMA-IR) levels of the subjects with at least one C allele of the PPARD rs2016520 were significantly lower than those with the TT genotype, which suggested that the PPARD rs2016520 TT genotype conferred the poor exenatide response through a reduction of insulin resistance, as measured by HOMA-IR. The carriers of G alleles at rs3777744 exhibited higher levels of in waist to hip ratio (WHR), fasting plasma glucose (FPG), hemoglobin A1c (HbA1c) and HOMA-IR compared to individuals with the AA genotype following 6 months of exenatide treatment, potentially accounting for the lower failure rate of exenatide therapy among the AA homozygotes. In an insulin resistant HepG2 cell model, the PPARδ agonists enhanced exenatide efficacy on insulin resistance, with the expression of GLP-1R being up-regulated markedly.ConclusionThese data suggest that the PPARD rs2016520 and rs3777744 polymorphisms are associated with exenatide monotherapy efficacy, due to the pivotal role of PPARδ in regulating insulin resistance through affecting the expression of GLP-1R. This study was registered in the Chinese Clinical Trial Register (No. ChiCTR-CCC13003536).

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MTNR1B Gene Polymorphisms Are Associated With the Therapeutic Responses to Repaglinide in Chinese Patients With Type 2 Diabetes Mellitus.

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<i>MTNR1B</i> Gene Polymorphisms Are Associated With the Therapeutic Responses to Repaglinide in Chinese Patients With Type 2 Diabetes Mellitus.

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