Effects of PPARD gene variants on the therapeutic responses to exenatide in chinese patients with type 2 diabetes mellitus
Background 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...
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Published in | Frontiers in endocrinology (Lausanne) Vol. 13; p. 949990 |
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Main Authors | , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Frontiers Media S.A
16.08.2022
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Subjects | |
Online Access | Get full text |
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Summary: | Background
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.
Methods
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.
Results
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.
Conclusion
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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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 This article was submitted to Diabetes: Molecular Mechanisms, a section of the journal Frontiers in Endocrinology Edited by: Jian-Quan Luo, Central South University, China Reviewed by: Qian Ren, Nanjing Normal University, China; Gopal L. Khatik, National Institute of Pharmaceutical Education and Research, India |
ISSN: | 1664-2392 1664-2392 |
DOI: | 10.3389/fendo.2022.949990 |