Response to the dipeptidyl peptidase‐4 inhibitors in Japanese patients with type 2 diabetes might be associated with a diplotype of two single nucleotide polymorphisms on the interleukin‐6 promoter region under a certain level of physical activity

Abstract

Aims/IntroductionMuscle-derived interleukin-6 (IL-6) has been reported to promote glucagon-like peptide-1 (GLP-1) secretion, and we explored the association of single nucleotide polymorphisms (SNPs) in the human IL-6 promoter region with the responsiveness to dipeptidyl peptidase-4 inhibitors (DPP-4Is), drugs that increase circulating GLP-1.Materials and MethodsThe present observational study enrolled Japanese patients with type 2 diabetes who took a DPP-4I over 3 months, and most of the clinical information was collected retrospectively. We defined non-responders as those having less than a 0.2% decrease of the glycated hemoglobin level at 3 or 4 months after starting DPP-4I treatment. Physical activity was retrospectively estimated by the Japanese short version of International Physical Activity Questionnaire.ResultsWe studied 316 patients whose physical activity corresponding to the season of the DPP-4I administration was estimated. The non-responder rate was 29.7%. We analyzed rs1800796 and rs2097677, both are suggested to be functional in Japanese. Multivariate analysis for all patients showed that the adjusted odds ratio for the non-responder risk of the diplotype rs1800796 G/*–rs2097677 A/* against C/C-G/G (OR_G*A*) was 0.445 (P = 0.068). When patients were stratified by the International Physical Activity Questionnaire into low (n = 149) and moderate/high (n = 167) activity groups, however, OR_G*A* in each group was 1.58 (P = 0.615) and 0.153 (P = 0.003), respectively.ConclusionsThe diplotype rs1800796 G/*–rs2097677 A/* might contribute to responsiveness to DPP-4Is in Japanese patients with type 2 diabetes under a certain level of physical activity. However, further investigation is warranted to confirm this.

Pharmacogenetics of Type 2 Diabetes—Progress and Prospects

“…Matsui et al performed a study on the effects of SNPs in the IL6 promoter region on response to DPP4I. The results showed that diplotype rs1800796 allele G and rs2097677 allele A might contribute to DPP4I responsiveness in case the carrier is physically active [ 130 ].…”

A genetic variant in GLP1R is associated with response to DPP-4 inhibitors in patients with type 2 diabetes

“…[ 23 ] On the other hand, an association between interleukin-6 polymorphism and DPP-4 inhibitor response has been reported. [ 24 ] Recent preclinical studies have shown association between DPP-4 inhibitors and incretin receptors. [ 25 , 26 ] Since administration of DPP-4 inhibitor to incretin receptor knockout mice did not improve glycemic parameters, these findings suggest the importance of incretin receptor in glucoregulatory actions of DPP-4 inhibitors.…”

Hepatic Dipeptidyl Peptidase-4 Controls Pharmacokinetics of Vildagliptin In Vivo

“…Because the renal function of these six healthy subjects was normal, the variability of vildagliptin cyano group-hydrolyzing activity might have caused the interindividual variability in C max and AUC of vildagliptin. There are nonresponders to vildagliptin, who do not show any significant decrease of hemoglobin A1c (Nakamura and Terauchi, 2013;Matsui et al, 2015). Additionally, vildagliptin can cause rare but serious adverse reactions, such as liver injury (Deacon, 2011;Kurita et al, 2014), bullous pemphigoid (Béné et al, 2015;Mendonça et al, 2016), and interstitial pneumonia (Kuse et al, 2016), in patients.…”