Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Eberhard Karls University Tübingen, Tübingen, Germany.
Diabetes. 2010 Dec;59(12):3247-52. doi: 10.2337/db10-0674. Epub 2010 Aug 29.
Several single nucleotide polymorphisms (SNPs) in diabetes risk genes reduce glucose- and/or incretin-induced insulin secretion. Here, we investigated interactions between glycemia and such diabetes risk polymorphisms.
Insulin secretion was assessed by insulinogenic index and areas under the curve of C-peptide/glucose in 1,576 subjects using an oral glucose tolerance test (OGTT). Participants were genotyped for 10 diabetes risk SNPs associated with β-cell dysfunction: rs5215 (KCNJ11), rs13266634 (SLC30A8), rs7754840 (CDKAL1), rs10811661 (CDKN2A/2B), rs10830963 (MTNR1B), rs7903146 (TCF7L2), rs10010131 (WFS1), rs7923837 (HHEX), rs151290 (KCNQ1), and rs4402960 (IGF2BP2). Furthermore, the impact of the interaction between genetic variation in TCF7L2 and glycemia on changes in insulin secretion was tested in 315 individuals taking part in a lifestyle intervention study.
For the SNPs in TCF7L2 and WFS1, we found a significant interaction between glucose control and insulin secretion (all P ≤ 0.0018 for glucose × genotype). When plotting insulin secretion against glucose at 120 min OGTT, the compromising SNP effects on insulin secretion are most apparent under high glucose. In the longitudinal study, rs7903146 in TCF7L2 showed a significant interaction with baseline glucose tolerance upon change in insulin secretion (P = 0.0027). Increased glucose levels at baseline predicted an increase in insulin secretion upon improvement of glycemia by lifestyle intervention only in carriers of the risk alleles.
For the diabetes risk genes TCF7L2 and WFS1, which are associated with impaired incretin signaling, the level of glycemia determines SNP effects on insulin secretion. This indicates the increasing relevance of these SNPs during the progression of prediabetes stages toward clinically overt type 2 diabetes.
一些糖尿病风险基因中的单核苷酸多态性（SNPs）可降低葡萄糖和/或肠促胰岛素诱导的胰岛素分泌。在此，我们研究了血糖与这些糖尿病风险 SNPs 之间的相互作用。
通过口服葡萄糖耐量试验（OGTT），对 1576 名受试者的胰岛素原指数和 C-肽/血糖曲线下面积进行胰岛素分泌评估。参与者对与β细胞功能障碍相关的 10 个糖尿病风险 SNPs（KCNJ11 的 rs5215、SLC30A8 的 rs13266634、CDKAL1 的 rs7754840、CDKN2A/2B 的 rs10811661、MTNR1B 的 rs10830963、TCF7L2 的 rs7903146、WFS1 的 rs10010131、HHEX 的 rs7923837、KCNQ1 的 rs151290 和 IGF2BP2 的 rs4402960）进行基因分型。此外，我们在参加生活方式干预研究的 315 名个体中，检测了 TCF7L2 基因遗传变异与血糖之间的相互作用对胰岛素分泌变化的影响。
对于 TCF7L2 和 WFS1 中的 SNPs，我们发现血糖控制与胰岛素分泌之间存在显著的相互作用（所有 P≤0.0018 用于葡萄糖×基因型）。当在 OGTT 120 分钟时将胰岛素分泌与葡萄糖作图时，在高血糖下，SNP 对胰岛素分泌的不利影响最为明显。在纵向研究中，TCF7L2 的 rs7903146 与胰岛素分泌变化时的基线葡萄糖耐量呈显著交互作用（P=0.0027）。仅在风险等位基因携带者中，基线血糖水平升高预示着通过生活方式干预改善血糖时胰岛素分泌增加。
对于与肠促胰岛素信号受损相关的糖尿病风险基因 TCF7L2 和 WFS1，血糖水平决定了 SNP 对胰岛素分泌的影响。这表明这些 SNPs 在从前驱糖尿病阶段向临床显性 2 型糖尿病进展过程中的相关性不断增加。
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