Division of Endocrinology, Diabetology, Angiology, Nephrology, and Clinical Chemistry, Department of Internal Medicine, University Hospital of Tübingen, Otfried-Müller-Str, 10, 72076 Tübingen, Germany.
BMC Med Genet. 2010 Jun 4;11:84. doi: 10.1186/1471-2350-11-84.
The nuclear receptor NR4A1 is implicated in metabolic regulation in insulin-sensitive tissues, such as liver, adipose tissue, and skeletal muscle. Functional loss of NR4A1 results in insulin resistance and enhanced intramuscular and hepatic lipid content. Therefore, we investigated in a cohort of white European subjects at increased risk for type 2 diabetes whether genetic variation within the NR4A1 gene locus contributes to prediabetic phenotypes, such as insulin resistance, ectopic fat distribution, or beta-cell dysfunction.
We genotyped 1495 subjects (989 women, 506 men) for five single nucleotide polymorphisms (SNPs) tagging 100% of common variants (MAF = 0.05) within the NR4A1 gene locus with an r2 = 0.8. All subjects underwent an oral glucose tolerance test (OGTT), a subset additionally had a hyperinsulinemic-euglycemic clamp (n = 506). Ectopic hepatic (n = 296) and intramyocellular (n = 264) lipids were determined by magnetic resonance spectroscopy. Peak aerobic capacity, a surrogate parameter for oxidative capacity of skeletal muscle, was measured by an incremental exercise test on a motorized treadmill (n = 270).
After appropriate adjustment and Bonferroni correction for multiple comparisons, none of the five SNPs was reliably associated with insulin sensitivity, ectopic fat distribution, peak aerobic capacity, or indices of insulin secretion (all p > or = 0.05).
Our data suggest that common genetic variation within the NR4A1 gene locus may not play a major role in the development of prediabetic phenotypes in our white European population.
核受体 NR4A1 参与胰岛素敏感组织（如肝脏、脂肪组织和骨骼肌）的代谢调节。NR4A1 功能丧失会导致胰岛素抵抗和增强的肌肉内和肝内脂质含量。因此，我们在一组患有 2 型糖尿病风险增加的白种欧洲人群中研究了 NR4A1 基因座内的遗传变异是否导致糖尿病前期表型，如胰岛素抵抗、异位脂肪分布或β细胞功能障碍。
我们对 1495 名受试者（989 名女性，506 名男性）进行了 5 个单核苷酸多态性（SNP）的基因分型，这些 SNP 标记了 NR4A1 基因座内 100%的常见变异（MAF = 0.05），r2 = 0.8。所有受试者均接受口服葡萄糖耐量试验（OGTT），一部分受试者还进行了高胰岛素正葡萄糖钳夹（n = 506）。通过磁共振波谱法测定异位肝（n = 296）和肌内（n = 264）脂质。通过电动跑步机上的递增运动试验测量峰值有氧能力，这是骨骼肌氧化能力的替代参数（n = 270）。
在适当的调整和多重比较的 Bonferroni 校正后，这 5 个 SNP 均与胰岛素敏感性、异位脂肪分布、峰值有氧能力或胰岛素分泌指数无关（均 p > 0.05）。
我们的数据表明，NR4A1 基因座内的常见遗传变异可能在我们的白种欧洲人群中糖尿病前期表型的发展中不起主要作用。
