Division of Endocrinology, Diabetology, Angiology, Nephrology, and Clinical Chemistry, Department of Internal Medicine, Eberhard Karls University Tübingen, German Center for Diabetes Research (DZD), Otfried-Müller-Str. 10, 72076, Tübingen, Germany.
J Mol Med (Berl). 2011 Jan;89(1):75-81. doi: 10.1007/s00109-010-0687-1. Epub 2010 Nov 2.
The liver X receptors (LXRs)-α and -β play a crucial role in control of insulin production and secretion in pancreatic β-cells. We hypothesized that common variants in the NR1H2 and NR1H3 genes, encoding LXR-β and -α, respectively, may alter pancreatic β-cell function. One thousand five hundred seventy-four subjects of European ancestry with elevated risk for type 2 diabetes were genotyped for the two NR1H2 single nucleotide polymorphisms (SNPs) rs2248949 and rs1405655 and for the four NR1H3 SNPs rs11039149, rs3758673, rs12221497 and rs2279238, and association studies with metabolic traits were performed. Metabolic characterization comprised an oral glucose tolerance test (OGTT) in all participants and, in addition, a hyperinsulinemic-euglycemic clamp and an intravenous glucose tolerance test (IVGTT) in subsets. One hundred per cent of common genetic variation (minor allele frequency ≥1%) within the NR1H2 and NR1H3 loci (D' = 1.0; r² ≥ 0.8) were covered by the six chosen tagging SNPs. NR1H2 rs2248949 was nominally associated with OGTT-derived first-phase insulin secretion and proinsulin conversion to insulin and significantly associated with the AUC of insulin levels during the IVGTT (p = 0.007) after adjustment for age, gender, BMI and insulin sensitivity in the dominant model, with the minor allele conferring reduced pancreatic β-cell function to the carriers. In subjects of European ancestry at increased risk for type 2 diabetes, common variation within the NR1H2 gene impaired insulin secretion, which may facilitate the development of type 2 diabetes.
肝 X 受体 (LXRs)-α 和 -β 在控制胰腺 β 细胞胰岛素的产生和分泌中起着至关重要的作用。我们假设编码 LXR-β 和 -α 的 NR1H2 和 NR1H3 基因中的常见变体可能会改变胰腺 β 细胞的功能。1574 名具有 2 型糖尿病高发风险的欧洲血统个体对 NR1H2 的两个单核苷酸多态性 (SNP) rs2248949 和 rs1405655 以及 NR1H3 的四个 SNP rs11039149、rs3758673、rs12221497 和 rs2279238 进行了基因分型，并进行了与代谢特征的关联研究。所有参与者都进行了口服葡萄糖耐量试验 (OGTT)，此外，一部分参与者还进行了高胰岛素正葡萄糖钳夹和静脉葡萄糖耐量试验 (IVGTT)。NR1H2 和 NR1H3 基因座内 100%的常见遗传变异 (次要等位基因频率≥1%)（D'=1.0；r²≥0.8）被六个选择的标记 SNP 所覆盖。NR1H2 rs2248949 与 OGTT 衍生的第一时相胰岛素分泌和胰岛素原转化为胰岛素呈名义相关，与 IVGTT 期间胰岛素水平的 AUC 显著相关（p=0.007），在显性模型中，在调整年龄、性别、BMI 和胰岛素敏感性后，携带次要等位基因的个体的胰腺 β 细胞功能降低。在具有 2 型糖尿病高发风险的欧洲血统个体中，NR1H2 基因内的常见变异会损害胰岛素分泌，从而可能促进 2 型糖尿病的发生。
