GLP1R and GIPR gene sequencing for glycemic response to DPP-4 inhibitors in T2DM patients

Abstract

Interindividual variability in glycemic response to dipeptidyl peptidase-4 (DPP-4) inhibitors remains a major challenge in the management of type 2 diabetes mellitus (T2DM). DPP-4 inhibitors exert their effects by inhibiting the degradation of incretin hormones. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are among these incretin hormones. Genetic variations in the receptor genes for these incretin hormones can influence both receptor function and incretin sensitivity. In this study, conducted on patients with T2DM receiving DPP-4 inhibitor therapy, we aimed to evaluate the relationship between variants in the relevant genes and glycemic response. Targeted next-generation sequencing (t-NGS) was used to sequence both the exons and the exon-intron boundary regions of the GIPR and GLP1R genes. A total of 42 T2DM patients undergoing DPP-4 inhibitor treatment were included in the study. Patients were divided into two groups based on their HbA1c levels: those with adequate glycemic control (≤7.0%) and those with inadequate glycemic control (>7.0%). Sequencing of the GLP1R and GIPR genes revealed 16 variants, including missense, intronic, synonymous, and non-coding region changes. The intronic variant rs767803082 in the GLP1R gene was classified as a VUS. Analysis of genotype distribution between the groups showed a nominally significant difference only for the GIPR gene variant rs34783010:G>T (p=0.043; BH q=0.172). When comparing the GG and GT genotypes, the GT genotype was predominantly observed in the group with adequate glycemic control, whereas the GG genotype was more frequent among patients with inadequate glycemic control (p=0.047). Our findings suggest that the GIPR rs34783010 variant may contribute to individual variability in the glycemic response to DPP-4 inhibitor therapy.

Keywords

• Genetic variation
• GLP1R
• GIPR
• next-generation sequencing
• single nucleotide polymorphism
• T2DM

Ethical Statement

The study was performed in accordance with the Declaration of Helsinki on medical research consisting of a human study group. The protocol was approved by the Ethics Committee of the Halic University (Approval Number: 2025/288).

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