Abstract
ObjectiveDipeptidyl-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).Research design and methodsFourteen 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.ResultsWe 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.ConclusionsA 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.
Highlights
Dipeptidyl-peptidase 4 (DPP-4, alias CD26) is a ubiquitously expressed single-pass type II transmembrane protein that aggregates in cholesterol-rich lipid rafts and interacts with several other proteins, e.g., caveolin 1, adenosine deaminase, fibroblast activation protein, insulin-like growth factor 2 receptor, receptor-type protein tyrosine phosphatase C, and extracellular matrix proteins [1]
I.e., single nucleotide polymorphisms (SNPs) rs6741949, in intron 2 of the DPP4 gene that, after correction for multiple comparisons and appropriate adjustment, revealed a significant genotypebody fat interaction effect on glucose-stimulated plasma glucagon-like peptide 1 (GLP-1) levels (p = 0.0021)
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
Summary
Dipeptidyl-peptidase 4 (DPP-4, alias CD26) is a ubiquitously expressed single-pass type II transmembrane protein that aggregates in cholesterol-rich lipid rafts and interacts with several other proteins, e.g., caveolin 1, adenosine deaminase, fibroblast activation protein, insulin-like growth factor 2 receptor, receptor-type protein tyrosine phosphatase C, and extracellular matrix proteins [1]. Among its known substrates are chemokines, growth factors, neuropeptides, and peptide hormones, such as the incretins glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) [1,3]. A soluble form of DPP4 is known to be present in human plasma, urine, and seminal fluid and is thought to derive from proteolytic cleavage of the transmembrane protein [5]. The regulation of this process is poorly understood
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