Effects of PPARD gene variants on the therapeutic responses to exenatide in chinese patients with type 2 diabetes mellitus.
Effects of PPARD gene variants on the therapeutic responses to exenatide in chinese patients with type 2 diabetes mellitus.
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DOI：
10.3389/fendo.2022.949990
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发表时间：
2022
影响因子：
5.2
通讯作者：
中科院分区：
文献类型：
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作者：
艾塞那肽是一种GLP-1 R激动剂，通常在治疗疗效方面表现出相当大的个体间差异。然而，没有证据表明PPARD中的遗传变异对艾塞那肽的治疗效果有影响。本研究旨在探讨PPARD基因多态性对艾塞那肽疗效的影响，并进一步探讨其可能的作用机制。共招募了300例T2 DM患者和200例对照受试者，以确定PPARD rs 2016520和rs3777744基因型。采用前瞻性临床研究方法，收集接受艾塞那肽单药治疗6个月的2型糖尿病患者的临床指标和外周血。采用SNaPshot法检测PPARD基因rs 2016520和rs3777744基因型，并对PPARD基因变异与艾塞那肽疗效进行相关性分析，对影响艾塞那肽疗效的因素进行多元线性回归分析。在不存在或存在PPARδ激动剂或siPPARδ质粒的情况下，将HepG 2细胞与艾塞那肽孵育，然后测定GLP-1 R水平和葡萄糖摄取率。在6个月的exenetrine单药治疗后，我们观察到具有PPARD rs 2016520的至少一个C等位基因的受试者的胰岛素抵抗的稳态模型评估（HOMA-IR）水平显著低于具有TT基因型的受试者，这表明PPARD rs 2016520 TT基因型通过降低胰岛素抵抗而赋予差的exenetrine应答，rs3777744处的G等位基因的携带者在6个月的exenlavin治疗后与具有AA基因型的个体相比表现出更高水平的腰臀比（WHR）、空腹血糖（FPG）、血红蛋白A1 c（HbA 1c）和HOMA-IR，这可能解释了AA纯合子中外照射治疗失败率较低的原因。在胰岛素抵抗的HepG 2细胞模型中，PPARδ激动剂增强了胰岛素抵抗的疗效，GLP-1 R的表达显著上调。这些数据表明，PPARD rs 2016520和rs3777744多态性与艾塞那肽单药治疗疗效相关，这是由于PPARδ通过影响GLP-1 R的表达在调节胰岛素抵抗中发挥关键作用。本研究已在中国临床试验注册中心注册（注册号：ChiCTR-CCC 13003536）。
Exenatide 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. A 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. After 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. These 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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影响因子：
8.2
作者：
Pilgaard, K.;Jensen, C. B.;Vaag, A. A.
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影响因子：
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作者：
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DOI：
10.1152/ajpendo.00309.2012
发表时间：
2012-11-01
影响因子：
5.1
作者：
Greene, Nicholas P.;Fluckey, James D.;Crouse, Stephen F.
通讯作者：
Crouse, Stephen F.