Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, China.
Department of Pharmacy, Affiliated Hospital of Jiangnan University, Wuxi, China.
Front Endocrinol (Lausanne). 2022 Aug 16;13:949990. doi: 10.3389/fendo.2022.949990. eCollection 2022.
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 on the therapeutic efficacy of exenatide. This research was aimed to explore the influence of 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 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 rs2016520 and rs3777744 genotypes, and then we performed correlation analysis between 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 rs2016520 were significantly lower than those with the TT genotype, which suggested that the 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 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).
Exenatide 是一种 GLP-1R 激动剂，在治疗效果上常常表现出相当大的个体间变异性。然而，目前尚无证据表明 基因中的遗传变异会影响 exenatide 的治疗效果。本研究旨在探讨 基因多态性对 exenatide 治疗效果的影响，并进一步确定潜在的机制。
共纳入 300 例 T2DM 患者和 200 例对照者，以鉴定 rs2016520 和 rs3777744 基因型。采用前瞻性临床研究收集 exenatide 单药治疗 6 个月的 T2DM 患者的临床指标和外周血。采用 SNaPshot 方法鉴定 rs2016520 和 rs3777744 基因型，然后进行 基因变异与 exenatide 疗效的相关性分析，并对影响 exenatide 治疗效果的因素进行多线性回归分析。用 exenatide 孵育 HepG2 细胞，无或有 PPARδ 激动剂或 siPPARδ 质粒，测定 GLP-1R 水平和葡萄糖摄取率的比值。
经过 6 个月的 exenatide 单药治疗，我们观察到 rs2016520 至少有一个 C 等位基因的受试者的稳态模型评估胰岛素抵抗（HOMA-IR）水平明显低于 TT 基因型，这表明 rs2016520 TT 基因型通过降低胰岛素抵抗来改善 exenatide 反应，这是通过 HOMA-IR 来衡量的。与 exenatide 治疗 6 个月后 AA 基因型的个体相比，rs3777744 的 G 等位基因携带者的腰围臀围比（WHR）、空腹血糖（FPG）、糖化血红蛋白（HbA1c）和 HOMA-IR 水平更高，这可能是 AA 纯合子 exenatide 治疗失败率较低的原因。在胰岛素抵抗的 HepG2 细胞模型中，PPARδ 激动剂增强了 exenatide 对胰岛素抵抗的疗效，GLP-1R 的表达明显上调。
这些数据表明， rs2016520 和 rs3777744 多态性与 exenatide 单药治疗效果有关，因为 PPARδ 通过影响 GLP-1R 的表达在调节胰岛素抵抗方面起着关键作用。本研究在中国临床试验注册中心（注册号：ChiCTR-CCC13003536）注册。
