A functional polymorphism in the promotor of UCP2 enhances obesity risk but reduces type 2 diabetes risk in obese middle aged humans
A functional polymorphism in the promotor of UCP2 enhances obesity risk but reduces type 2 diabetes risk in obese middle aged humans
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DOI：
10.2337/diabetes.51.11.3331
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发表时间：
2002-11-01
期刊：
影响因子：
7.7
通讯作者：
Patsch, W
中科院分区：
文献类型：
--
作者：
Krempler, F;Esterbauer, H;Patsch, W
2型糖尿病是一种常见的糖尿病。我们先前观察到解偶联蛋白2（UCP 2）启动子的功能性G/A多态性与肥胖症的关联。野生型G等位基因与体内脂肪组织mRNA表达降低、体外转录活性降低和肥胖风险增加相关。另一方面，在动物和细胞培养模型中的研究确定胰腺β-细胞UCP ′ 2表达是对葡萄糖的胰岛素分泌反应的主要决定因素。因此，我们确定了-866G/A多态性与β细胞功能和肥胖糖尿病风险的相关性。我们在这里表明，胰腺转录因子PAX 6优先结合，并更有效地反式激活的变体比野生型UCP 2启动子等位基因在β细胞系INS 1-E。通过研究39名肥胖非糖尿病患者，我们观察到β细胞功能的基因型差异;野生型受试者显示出比变异等位基因受试者更大的倾向指数（胰岛素敏感性和急性胰岛素对葡萄糖反应的乘积）（P < 0.03）。通过比较肥胖受试者与非2型糖尿病，我们观察到糖尿病患病率的基因型相关差异，这转化为野生型受试者的两倍年龄调整风险降低。因此，更常见的UCP 2启动子G等位基因虽然有助于肥胖，但对2型糖尿病提供了相对保护。
Obesity is frequently associated with type 2 diabetes. We previously observed an association of a functional G/A polymorphism in the uncoupling protein 2 (UCP2) promoter with obesity. The wild-type G allele was associated with reduced adipose tissue mRNA expression in vivo, reduced transcriptional activity in vitro, and increased risk of obesity. On the other hand, studies in animal and cell culture models identified pancreatic beta-cell UCP'2 expression as a main determinant of the insulin secretory response to glucose. We therefore ascertained associations of the -866G/A polymorphism with beta-cell function and diabetes risk in obesity. We show here that the pancreatic transcription factor PAX6 preferentially binds to and more effectively trans activates the variant than the wild-type UCP2 promoter allele in the beta-cell line INS1-E. By studying 39 obese nondiabetic humans, we observed genotype differences in beta-cell function; wild-type subjects displayed a greater disposition index (the product of insulin sensitivity and acute insulin response to glucose) than subjects with the variant allele (P < 0.03). By comparing obese subjects with and without type 2 diabetes, we observed genotype-associated differences in diabetes prevalence that translated into a twofold age-adjusted risk reduction in wild-type subjects. Thus, the more common UCP2 promoter G allele, while being conducive for obesity, affords relative protection against type 2 diabetes.