Skip to main content

Advertisement

SpringerLink
Log in

Association between glucagon-like peptide-1 receptor gene polymorphism and treatment response to GLP1R agonists in Chinese patients with type 2 diabetes: a prospective cohort study

  • Clinical Trial
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Clinical response to glucagon-like peptide-1 receptor agonists (GLP1RAs) varies considerably among patients with type 2 diabetes mellitus (T2DM). The aim of the current study was to examine the potential association between the genetic variants in GLP1R gene polymorphism with the therapeutic efficacy as well as gastrointestinal adverse drug reactions (ADRs) of GLP1RAs in Chinese T2DM patients.

Methods

Adult T2DM patients were eligible to participate in this prospective cohort study. Subjects received 12-week treatment with either exenatide (20 μg/day) or liraglutide (1.2 mg/day). GLP1R rs10305420 and rs3765467 genotyping was performed using the Sanger sequencing method. Clinical response to GLP1RAs was assessed in the patients who completed the 12-week treatment and defined by the change of fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), and body mass index (BMI) from the baseline.

Results

A total of 176 subjects (mean age 50.9 ± 12.7 years, 111 men) were enrolled. The planned 12-week treatment was completed by 156 patients. HbA1c reduction was significantly larger in subjects carrying the rs3765467 GG genotype vs. GA + AA genotypes (1.7% ± 2.4% vs. 0.8% ± 1.8%; P = 0.002). Similarly, the 7.0% target HbA1c attainment rate was significantly higher in subjects carrying the rs3765467 GG genotype vs. GA + AA genotypes (50.9% vs. 23.8%; P = 0.002). Gastrointestinal ADRs did not differ significantly among different genotypes.

Conclusion

GLP1R rs3765467 polymorphism is associated with therapeutic response to GLP1RAs in Chinese T2DM patients. HbA1c reduction is more pronounced in subjects with the GG genotype.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Kirkpatrick A et al (2012) Predicted structure of agonist-bound glucagon-like peptide 1 receptor, a class B G protein-coupled receptor. Proc Natl Acad Sci USA 109(49):19988–19993

    Article  CAS  Google Scholar 

  2. Shaefer CF, Kushner P, Aguilar R (2015) User’s guide to mechanism of action and clinical use of GLP-1 receptor agonists. Postgrad Med 127(8):818–826

    Article  Google Scholar 

  3. Dailey MJ, Moran TH (2013) Glucagon-like peptide 1 and appetite. TRENDS IN ENDOCRINOLOGY AND METABOLISM 24(2):85–91

    Article  CAS  Google Scholar 

  4. Skibicka KP (2013) The central GLP-1: implications for food and drug reward. Front Neurosci 7:181

    Article  Google Scholar 

  5. Egan JM, Clocquet AR, Elahi D (2002) The insulinotropic effect of acute exendin-4 administered to humans: comparison of nondiabetic state to type 2 diabetes. J Clin Endocrinol Metab 87(3):1282–1290

    Article  CAS  Google Scholar 

  6. Amylin Pharmaceuticals Inc. (2008) Patient information. Byetta® (exenatide injection). [cited 2009 Feb 16]; available from: https://www.drugs.com/cons/byetta.html

  7. Agerso H et al (2002) The pharmacokinetics, pharmacodynamics, safety and tolerability of NN2211, a new long-acting GLP-1 derivative, in healthy men. Diabetologia 45(2):195–202

    Article  CAS  Google Scholar 

  8. Anderson SL et al (2003) Determining predictors of response to exenatide in type 2 diabetes. J Am Pharm Assoc 52(4):466–71

  9. Tokuyama Y et al (2004) Five missense mutations in glucagon-like peptide 1 receptor gene in Japanese population. Diabetes Res Clin Pract 66(1):63–69

    Article  CAS  Google Scholar 

  10. Sathananthan A et al (2010) Common genetic variation in GLP1R and insulin secretion in response to exogenous GLP-1 in nondiabetic subjects: a pilot study. Diabetes Care 33(9):2074–2076

    Article  CAS  Google Scholar 

  11. Donnelly D (2012) The structure and function of the glucagon-like peptide-1 receptor and its ligands. Br J Pharmacol 166(1):27–41

    Article  CAS  Google Scholar 

  12. Jensterle M et al (2015) Genetic variability in GLP-1 receptor is associated with inter-individual differences in weight lowering potential of liraglutide in obese women with PCOS: a pilot study. Eur J Clin Pharmacol 71(7):817–824

    Article  CAS  Google Scholar 

  13. Lin CH et al (2015) Polymorphisms of GLP-1 receptor gene and response to GLP-1 analogue in patients with poorly controlled type 2 diabetes. J Diabetes Res 176949

  14. Yu MJ et al (2019) GLP1R variant is associated with response to exenatide in overweight Chinese Type 2 diabetes patients. Pharmacogenomics 20(4):273–278

    Article  CAS  Google Scholar 

  15. Beinborn M et al (2005) A human glucagon-like peptide-1 receptor polymorphism results in reduced agonist responsiveness. Regul Pept 130(1–2):1–6

    Article  CAS  Google Scholar 

  16. Turton MD et al (1996) A role for glucagon-like peptide-1 in the central regulation of feeding. Nature 379(6560):69–72

    Article  CAS  Google Scholar 

  17. Secher A et al (2014) The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss. J Clin Investig 124(10):4473–4488

    Article  CAS  Google Scholar 

  18. Sisley S et al (2014) Neuronal GLP1R mediates liraglutide’s anorectic but not glucose-lowering effect. J Clin Invest 124(6):2456–2463

    Article  CAS  Google Scholar 

  19. van Can J et al (2014) Effects of the once-daily GLP-1 analog liraglutide on gastric emptying, glycemic parameters, appetite and energy metabolism in obese, non-diabetic adults. Int J Obes 38(6):784–793

    Article  Google Scholar 

  20. Naranjo CA et al (1981) A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 30(2):239–245

    Article  CAS  Google Scholar 

  21. Genomes Aggregation Database. [cited 2020 Dec 1]; Available from: http://gnomad.broadinstitute.org

  22. Koole C et al (2011) Polymorphism and ligand dependent changes in human glucagon-like peptide-1 receptor (GLP-1R) function: allosteric rescue of loss of function mutation. Mol Pharmacol 80(3):486–497

    Article  CAS  Google Scholar 

  23. Scrocchi LA et al (1996) Glucose intolerance but normal satiety in mice with a null mutation in the glucagon-like peptide 1 receptor gene. Nat Med 2(11):1254–1258

    Article  CAS  Google Scholar 

  24. Xiang SK et al (2019) Glucagon-like peptide-1 receptor gene polymorphism is associated with fat mass in Chinese nuclear families with male offspring. Acta Biochim Biophys Sin 51(5):545–547

    Article  CAS  Google Scholar 

  25. Kwak SH et al (2018) Nonsynonymous variants in PAX4 and GLP1R are associated with type 2 diabetes in an East Asian population. Diabetes 67(9):1892–1902

    Article  CAS  Google Scholar 

  26. Han E et al (2016) A genetic variant in GLP1R is associated with response to DPP-4 inhibitors in patients with type 2 diabetes. Medicine 95(44):e5155

  27. Yau AMW et al (2018) A pilot study investigating the influence of glucagon-like peptide-1 receptor single nucleotide polymorphisms on gastric emptying rate in Caucasian men. Front Physiol 9:1331

    Article  Google Scholar 

  28. Chedid V et al (2018) Allelic variant in the glucagon-like peptide 1 receptor gene associated with greater effect of liraglutide and exenatide on gastric emptying: a pilot pharmacogenetics study. Neurogastroenterol motility 30(7):e13313

Download references

Funding

This work was supported by the National Key Development Plan for Precision Medicine Research (2017YFC0910004) and Jinan Science Project (201602171).

Author information

Author notes

  1. Ziwan Guan and Yue Du are co-first authors and contributed equally to this work.

Authors and Affiliations

  1. School of Pharmaceutical Sciences, Shandong University, Jinan, China

    Ziwan Guan, Rui Li & Kunrong Wu

  2. School of Pharmaceutical Sciences, Shandong First Medical University, Taian, China

    Yue Du, Shufang Zhang, Ying Yin & Xiaoli Li

  3. Department of Endocrinology, Shandong Provincial Qianfoshan Hospital, the First Hospital Affiliated With Shandong First Medical University, Jinan, China

    Yuedong Xu & Xiaoqian Zhang

  4. Department of Pharmacy, Liaocheng People’s Hospital, Liaocheng, China

    Fan Zhang

  5. Department of Clinical Pharmacy, Shandong Provincial Qianfoshan Hospital, the First Hospital Affiliated With Shandong First Medical University, 16766 Jingshi Road, Jinan, 250014, China

    Yan Li

Authors
  1. Ziwan Guan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yue Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rui Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shufang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yuedong Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xiaoqian Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Fan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ying Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Kunrong Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Xiaoli Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Yan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

YL designed and supervised the study. ZG and YD performed the data analysis and drafted the manuscript. RL, YX, FZ, YY, and XZ participated in the data collection and sample analysis. KW, XL, and SZ participated in the data analysis.

Corresponding author

Correspondence to Yan Li.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Guan, Z., Du, Y., Li, R. et al. Association between glucagon-like peptide-1 receptor gene polymorphism and treatment response to GLP1R agonists in Chinese patients with type 2 diabetes: a prospective cohort study. Eur J Clin Pharmacol 78, 793–799 (2022). https://doi.org/10.1007/s00228-021-03249-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-021-03249-z

Keywords

Search

Navigation