A missense variant in GLP1R gene is associated with the glycaemic response to treatment with gliptins

Abstract

Gliptins act by increasing endogenous incretin levels. Glucagon-like peptide-1 receptor (GLP1R) and glucose-dependent insulinotropic peptide receptor (GIPR) are their indirect drug targets. Variants of GLP1R and GIPR have previously been associated with the incretin effect. The aim of the present pilot study was to examine associations of the GLP1R and GIPR gene variants with the glycaemic response to gliptins. A total of 140 consecutive patients with type 2 diabetes were followed-up 6 months after initiation of gliptin treatment. GLP1R rs6923761 (Gly168Ser) and GIPR rs10423928 genotyping was performed using real-time PCR, with subsequent high-resolution melting analysis. The main study outcome was reduction in glycated haemoglobin (HbA1c) after treatment. GLP1R Gly168Ser variant was significantly associated with reduction in HbA1c in an additive model (β = -0.33, p = 0.011). The mean reduction in HbA1c in Ser/Ser homozygotes was significantly lower compared with Gly-allele carriers [0.12 ± 0.23% vs. 0.80 ± 0.09% (1.3 ± 2.5 mmol/mol vs. 8.7 ± 1.0 mmol/mol); p = 0.008]. In conclusion, GLP1R missense variant was associated with a reduced response to gliptin treatment. The genotype-related effect size of ∼0.7% (8 mmol/mol) is equal to an average effect of gliptin treatment and makes this variant a candidate for use in precision medicine.

Pharmacogenetics of dipeptidyl peptidase 4 inhibitors in a Taiwanese population with type 2 diabetes

“…Previous studies showed that polymorphism in DPP4 [25, 26] and GLP1R [27, 28], which are directly involved in the mechanism of action of DPP-4 inhibitors, was associated with the glycemic response to DPP-4 inhibitor treatment. Appropriate regulation of insulin secretion may also be related to DPP-4 inhibitor efficacy.…”

“…Thus, genetic variations among different ethnic groups may alter the metabolism and therapeutic response of DPP-4 inhibitors, as previously demonstrated by pharmacogenomic and pharmacogenetic studies [23, 24]. Accordingly, the genetic effects of several genes such as DPP4 [25, 26], GLP1R [27, 28], and TCF7L2 [29] on the therapeutic response of DPP-4 inhibitors in patients with T2D have been investigated in clinical trial and case-control studies with a candidate gene approach. In the present report, we used an assumption-free genome-wide association study (GWAS) to identify the potential genes involved in the therapeutic response to DPP-4 inhibitors among patients with T2D in a Taiwanese population.…”

Pharmacogenetics of type 2 diabetes mellitus, the route toward tailored medicine

“…The risk C allele was also reported to be associated with higher fasting glucose but lower 2‐h postload glucose concentrations during an OGTT . Taken together, these findings suggest that GIPR variants could potentially modulate the response to DPP‐4 inhibitors, nevertheless, to date, this effect has not been revealed by clinical studies …”

“…The polymorphism rs10305493 (Ser333Cys) instead has been proven to preserve peptide response . The SNP rs6923761 (Gly168Ser) was nominally associated with reduced insulin secretion in response to GLP‐1 infusion during a hyperglycemic clamp in nondiabetic American subjects and with a weaker response to the glucose‐lowering effect of DPP‐4 inhibitors in patients with T2DM . On the contrary, the same polymorphism was associated with higher efficacy of liraglutide, and it was shown to increase weight and fat mass loss after liraglutide treatment, different types of diet, or bilio‐pancreatic diversion surgery .…”

“…198,201 Taken together, these findings suggest that GIPR variants could potentially modulate the response to DPP-4 inhibitors, nevertheless, to date, this effect has not been revealed by clinical studies. 194,197,202 The GLP-1 receptor is an important drug target for the treatment of T2DM, and several non-synonymous variants of GLP1R have been carefully characterized: rs367543060 Thr149Met variant, identified in one Japanese diabetic subject, 203 induces a significant loss of function in vitro [204][205][206] and impairs the insulin secretory response to GLP-1 in vivo. 203,206 The polymorphism rs10305493 (Ser333Cys) instead has been proven to preserve peptide response.…”