Journal Article

DPP4 gene variation affects GLP-1 secretion, insulin secretion, and glucose tolerance in humans with high body adiposity

Gallwitz, Baptist, Machicao, Fausto, Holst, Jens Juul, Böhm, Anja, Fritsche, Andreas, Stefan, Norbert, Wagner, Robert, Häring, Hans-Ulrich, Staiger, Harald

2017

Overview

Dipeptidyl-peptidase 4 (DPP-4) cleaves and inactivates the insulinotropic hormones glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide, collectively termed incretins. DPP-4 inhibitors entered clinical practice as approved therapeutics for type-2 diabetes in 2006. However, inter-individual variance in the responsiveness to DPP-4 inhibitors was reported. Thus, we asked whether genetic variation in the DPP4 gene affects incretin levels, insulin secretion, and glucose tolerance in participants of the TÜbingen Family study for type-2 diabetes (TÜF). Fourteen common (minor allele frequencies ≥0.05) DPP4 tagging single nucleotide polymorphisms (SNPs) were genotyped in 1,976 non-diabetic TÜF participants characterized by oral glucose tolerance tests and bioimpedance measurements. In a subgroup of 168 subjects, plasma incretin levels were determined. We identified a variant, i.e., SNP rs6741949, in intron 2 of the DPP4 gene that, after correction for multiple comparisons and appropriate adjustment, revealed a significant genotype-body fat interaction effect on glucose-stimulated plasma GLP-1 levels (p = 0.0021). Notably, no genotype-BMI interaction effects were detected (p = 0.8). After stratification for body fat content, the SNP negatively affected glucose-stimulated GLP-1 levels (p = 0.0229), insulin secretion (p = 0.0061), and glucose tolerance (p = 0.0208) in subjects with high body fat content only. A common variant, i.e., SNP rs6741949, in the DPP4 gene interacts with body adiposity and negatively affects glucose-stimulated GLP-1 levels, insulin secretion, and glucose tolerance. Whether this SNP underlies the reported inter-individual variance in responsiveness to DPP-4 inhibitors, at least in subjects with high body fat content, remains to be shown.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adipose tissue / Adiposity - genetics / Adult / Analysis / Biology and Life Sciences / Blood Glucose - metabolism / Body fat / Body mass / Body mass index / Chromosomes, Human, Pair 2 - genetics / Diabetes / Diabetes mellitus / Dipeptidyl Peptidase 4 - genetics / Dipeptidyl-peptidase IV / Endocrinology / Family studies / Fasting - blood / Female / Gene frequency / Genetic aspects / Genetic Association Studies / Genetic diversity / Genetic Loci / Genetic variation / Genotypes / Glucagon / Glucagon-like peptide 1 / Glucagon-Like Peptide 1 - metabolism / Glucose / Glucose tolerance / Glucose Tolerance Test / Health care / Hormones / Humans / Inhibitors / Insulin / Insulin - metabolism / Insulin resistance / Insulin Secretion / Internal medicine / Male / Medicine / Medicine and Health Sciences / Metabolic disorders / Metabolites / Middle Aged / Nephrology / Obesity / Peptidase / Pharmaceutical industry / Plasma / Polymorphism, Single Nucleotide - genetics / Polypeptides / Proteins / Research design / Rodents / Secretion / Single-nucleotide polymorphism / Subgroups / Type 2 diabetes / Weight control