Smith Steve R, Bai Fulu, Charbonneau Chantal, Janderová Lenka, Argyropoulos George
Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808, USA.
Diabetes. 2003 Jul;52(7):1611-8. doi: 10.2337/diabetes.52.7.1611.
Insulin resistance is a component of type 2 diabetes and often precedes pancreatic beta-cell failure. Contributing factors include obesity and a central pattern of fat accumulation with a strong genetic component. The adipocyte secreted hormone resistin has been proposed as a link between the adipocyte and insulin resistance by inhibition of insulin-stimulated glucose uptake and/or blocking adipocyte differentiation. Here we report that the G/G genotype of a single nucleotide polymorphism (SNP) in the promoter of the human resistin gene, -180C>G, had significantly increased basal promoter activity in adipocytes. These data were recapitulated in vivo, where G/G homozygotes had significantly higher resistin mRNA levels in human abdominal subcutaneous fat. A significant interaction was also found between the -180C>G SNP, a marker of oxidative stress (NAD[P]H quinone oxidoreductase mRNA) and homeostasis model assessment of insulin resistance. In addition, resistin mRNA was positively and independently correlated with insulin resistance and hepatic fat as measured by liver X-ray attenuation. These data implicate resistin in the pathophysiology of the human insulin resistance syndrome, an effect mediated by the -180C>G promoter SNP and potentially cellular oxidative stress.
胰岛素抵抗是2型糖尿病的一个组成部分，且常常先于胰腺β细胞功能衰竭出现。促成因素包括肥胖以及具有强大遗传成分的脂肪堆积的中心模式。脂肪细胞分泌的抵抗素已被提出是通过抑制胰岛素刺激的葡萄糖摄取和/或阻断脂肪细胞分化，在脂肪细胞与胰岛素抵抗之间建立联系。在此我们报告，人类抵抗素基因启动子中一个单核苷酸多态性（SNP）-180C>G的G/G基因型，在脂肪细胞中显著增加了基础启动子活性。这些数据在体内得到了重现，在体内G/G纯合子在人类腹部皮下脂肪中具有显著更高的抵抗素mRNA水平。还发现-180C>G SNP（氧化应激标志物（NAD[P]H醌氧化还原酶mRNA））与胰岛素抵抗的稳态模型评估之间存在显著相互作用。此外，抵抗素mRNA与通过肝脏X线衰减测量的胰岛素抵抗和肝脏脂肪呈正相关且独立相关。这些数据表明抵抗素参与了人类胰岛素抵抗综合征的病理生理过程，这种作用由-180C>G启动子SNP介导，并可能与细胞氧化应激有关。
