The common SLC30A8 Arg325Trp variant is associated with reduced first-phase insulin release in 846 non-diabetic offspring of type 2 diabetes patients -: the EUGENE2 study
The common SLC30A8 Arg325Trp variant is associated with reduced first-phase insulin release in 846 non-diabetic offspring of type 2 diabetes patients -: the EUGENE2 study
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DOI：
10.1007/s00125-008-0955-6
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发表时间：
2008-05-01
期刊：
影响因子：
8.2
通讯作者：
Hansen, T.
中科院分区：
文献类型：
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作者：
Boesgaard, T. W.;Zilinskaite, J.;Hansen, T.
目的/假设 近期一项全基因组关联研究发现，编码锌转运蛋白8（ZnT - 8）中精氨酸325色氨酸多态性的SLC30A8 rs13266634多态性与2型糖尿病相关。在此，我们研究该多态性是否与2型糖尿病患者的非糖尿病后代在静脉和口服葡萄糖负荷时胰岛素释放的改变有关。
方法 我们对来自5个不同白人种群的846名2型糖尿病患者的非糖尿病后代进行了SLC30A8 rs13266634基因分型：丹麦人（n = 271）、芬兰人（n = 217）、德国人（n = 149）、意大利人（n = 109）和瑞典人（n = 100）。参与者接受了静脉葡萄糖耐量试验（IVGTT）和口服葡萄糖耐量试验（OGTT），并测量了胰岛素敏感性。
结果 在静脉葡萄糖耐量试验期间测量到，2型糖尿病主要风险等位基因C的纯合子携带者第一相胰岛素释放（0 - 10分钟）降低了19%（CC：3624 ± 3197；CT：3763 ± 2674；TT：4478 ± 3032 pmol·l⁻¹·min⁻¹，均值±标准差；p = 0.007）。我们发现该基因型对口服葡萄糖耐量试验期间测量的胰岛素释放或胰岛素敏感性的评估无显著影响。
结论/解释 在欧洲2型糖尿病患者的非糖尿病后代中，46%是ZnT - 8中精氨酸325色氨酸多态性的纯合子携带者，已知该多态性与2型糖尿病相关。这些易患糖尿病的后代的特征是静脉葡萄糖负荷后第一相胰岛素释放降低19%，这表明该变异在胰腺β细胞功能障碍的发病机制中起作用。
Aims/hypothesis A recent genome-wide association study identified the SLC30A8 rs13266634 polymorphism encoding an Arg325Trp polymorphism in the zinc transporter protein member 8 (ZnT-8) to be associated with type 2 diabetes. Here, we investigate whether the polymorphism is related to altered insulin release in response to intravenous and oral glucose loads in non-diabetic offspring of type 2 diabetic patients.Methods We genotyped SLC30A8 rs13266634 in 846 non-diabetic offspring of type 2 diabetic patients from five different white populations: Danish (n=271), Finnish (n=217), German (n=149), Italian (n=109) and Swedish (n=100). Participants were subjected to both IVGTTs and OGTTs, and measurements of insulin sensitivity.Results Homozygous carriers of the major type 2 diabetes C risk-allele showed a 19% decrease in first-phase insulin release (0-10 min) measured during the IVGTT (CC 3,624+/-3,197; CT 3,763+/-2,674; TT 4,478+/-3,032 pmol l(-1) min(-1), mean+/-SD; p=0.007). We found no significant genotype effect on insulin release measured during the OGTT or on estimates of insulin sensitivity.Conclusions/Interpretation Of European non-diabetic offspring of type 2 diabetes patients, 46% are homozygous carriers of the Arg325Trp polymorphism in ZnT-8, which is known to associate with type 2 diabetes. These diabetes-prone offspring are characterised by a 19% decrease in first-phase insulin release following an intravenous glucose load, suggesting a role for this variant in the pathogenesis of pancreatic beta cell dysfunction.