Effects of PPARD gene variants on the therapeutic responses to exenatide in chinese patients with type 2 diabetes mellitus
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...
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Frontiers Media S.A.
2022-08-01
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| Series: | Frontiers in Endocrinology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fendo.2022.949990/full |
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| author | Jinfang Song Jinfang Song Na Li Ruonan Hu Yanan Yu Ke Xu Hongwei Ling Qian Lu Tingting Yang Tao Wang Tao Wang Xiaoxing Yin |
| author_facet | Jinfang Song Jinfang Song Na Li Ruonan Hu Yanan Yu Ke Xu Hongwei Ling Qian Lu Tingting Yang Tao Wang Tao Wang Xiaoxing Yin |
| author_sort | Jinfang Song |
| collection | DOAJ |
| 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). |
| first_indexed | 2024-04-12T06:19:58Z |
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| language | English |
| last_indexed | 2024-04-12T06:19:58Z |
| publishDate | 2022-08-01 |
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| spelling | doaj.art-0c775ad8b1cd435c8a7c6f0e58dcde4a2022-12-22T03:44:21ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922022-08-011310.3389/fendo.2022.949990949990Effects of PPARD gene variants on the therapeutic responses to exenatide in chinese patients with type 2 diabetes mellitusJinfang Song0Jinfang Song1Na Li2Ruonan Hu3Yanan Yu4Ke Xu5Hongwei Ling6Qian Lu7Tingting Yang8Tao Wang9Tao Wang10Xiaoxing Yin11Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, ChinaDepartment of Pharmacy, Affiliated Hospital of Jiangnan University, Wuxi, ChinaJiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, ChinaJiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, ChinaJiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, ChinaJiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, ChinaDepartment of Endocrinology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, ChinaJiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, ChinaJiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, ChinaJiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, ChinaDepartment of Pharmacy, Affiliated Hospital of Xuzhou Medical University, Xuzhou, ChinaJiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, ChinaBackgroundExenatide 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).https://www.frontiersin.org/articles/10.3389/fendo.2022.949990/fullPPARD genegenetic varianttype 2 diabetes mellitusexenatideinsulin resistance |
| spellingShingle | Jinfang Song Jinfang Song Na Li Ruonan Hu Yanan Yu Ke Xu Hongwei Ling Qian Lu Tingting Yang Tao Wang Tao Wang Xiaoxing Yin Effects of PPARD gene variants on the therapeutic responses to exenatide in chinese patients with type 2 diabetes mellitus Frontiers in Endocrinology PPARD gene genetic variant type 2 diabetes mellitus exenatide insulin resistance |
| title | Effects of PPARD gene variants on the therapeutic responses to exenatide in chinese patients with type 2 diabetes mellitus |
| title_full | Effects of PPARD gene variants on the therapeutic responses to exenatide in chinese patients with type 2 diabetes mellitus |
| title_fullStr | Effects of PPARD gene variants on the therapeutic responses to exenatide in chinese patients with type 2 diabetes mellitus |
| title_full_unstemmed | Effects of PPARD gene variants on the therapeutic responses to exenatide in chinese patients with type 2 diabetes mellitus |
| title_short | Effects of PPARD gene variants on the therapeutic responses to exenatide in chinese patients with type 2 diabetes mellitus |
| title_sort | effects of ppard gene variants on the therapeutic responses to exenatide in chinese patients with type 2 diabetes mellitus |
| topic | PPARD gene genetic variant type 2 diabetes mellitus exenatide insulin resistance |
| url | https://www.frontiersin.org/articles/10.3389/fendo.2022.949990/full |
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