DPP4 gene variation affects GLP-1 secretion, insulin secretion, and glucose tolerance in humans with high body adiposity.
DPP4 gene variation affects GLP-1 secretion, insulin secretion, and glucose tolerance in humans with high body adiposity.
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DOI：
10.1371/journal.pone.0181880
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Staiger H
中科院分区：
文献类型：
--
作者：
Böhm A;Wagner R;Machicao F;Holst JJ;Gallwitz B;Stefan N;Fritsche A;Häring HU;Staiger H
二肽基肽酶 4 (DPP-4) 可裂解促胰岛素激素胰高血糖素样肽 1 (GLP-1) 和抑胃多肽（统称为肠促胰岛素）并使其失活。 DPP-4 抑制剂于 2006 年作为批准的 2 型糖尿病治疗药物进入临床实践。然而，据报道，对 DPP-4 抑制剂的反应存在个体间差异。因此，我们询问 DPP4 基因的遗传变异是否会影响 TÜbingen Family 研究 2 型糖尿病 (TÜF) 参与者的肠促胰岛素水平、胰岛素分泌和葡萄糖耐量。通过口服葡萄糖耐量测试和生物阻抗测量，对 1,976 名非糖尿病 TÜF 参与者进行了 14 个常见（次要等位基因频率≥0.05）DPP4 标记单核苷酸多态性 (SNP) 的基因分型。在 168 名受试者组成的亚组中，测定了血浆肠促胰岛素水平。我们在 DPP4 基因的内含子 2 中发现了一个变异，即 SNP rs6741949，经过多重比较校正和适当调整后，揭示了基因型-体脂肪相互作用对葡萄糖刺激的血浆 GLP-1 水平的显着影响 (p = 0.0021)。值得注意的是，没有检测到基因型-BMI 相互作用的影响（p = 0.8）。对身体脂肪含量进行分层后，仅在身体脂肪含量较高的受试者中，SNP 对葡萄糖刺激的 GLP-1 水平 (p = 0.0229)、胰岛素分泌 (p = 0.0061) 和葡萄糖耐量 (p = 0.0208) 产生负面影响。 DPP4 基因中的一个常见变异，即 SNP rs6741949，与身体肥胖相互作用，并对葡萄糖刺激的 GLP-1 水平、胰岛素分泌和葡萄糖耐量产生负面影响。该 SNP 是否是报道的对 DPP-4 抑制剂反应性的个体间差异的基础，至少在体脂含量高的受试者中，仍有待证实。
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.
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影响因子：
8
作者：
Monami, Matteo;Cremasco, Francesco;Mannucci, Edoardo
通讯作者：
Mannucci, Edoardo
影响因子：
5.8
作者：
Carr, Richard D.;Larsen, Marianne O.;Ahren, Bo
通讯作者：
Ahren, Bo
影响因子：
5.8
作者：
Toft-Nielsen, MB;Damholt, MB;Holst, JJ
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Holst, JJ
影响因子：
2
作者：
Kirino, Yasushi;Sei, Masako;Sato, Youichi
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Sato, Youichi
DOI：
10.1006/bbrc.2001.4999
发表时间：
2001-06-08
影响因子：
3.1
作者：
Nagakura, T;Yasuda, N;Tanaka, I
通讯作者：
Tanaka, I