Kovacs Peter, Hanson Robert L, Lee Yong-Ho, Yang Xiaolin, Kobes Sayuko, Permana Paska A, Bogardus Clifton, Baier Leslie J
Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona 85016, USA.
Diabetes. 2003 Dec;52(12):3005-9. doi: 10.2337/diabetes.52.12.3005.
The insulin receptor substrate-1 (IRS1) is a critical element in insulin-signaling pathways, and mutations in the IRS1 gene have been reported to have a role in determining susceptibility to traits related to type 2 diabetes. In gene expression studies of tissue biopsies from nondiabetic Pima Indians, IRS1 mRNA levels were reduced in adipocytes from obese subjects compared with lean subjects, and IRS1 mRNA levels were also reduced in skeletal muscle from insulin-resistant subjects compared with insulin-sensitive subjects (all P < 0.05). Based on these expression differences and the known physiologic role of IRS1, this gene was investigated as a candidate gene for susceptibility to type 2 diabetes in Pima Indians, a population with an extremely high incidence and prevalence of type 2 diabetes. Thirteen variants were identified, and among these variants, several were in complete linkage disequilibrium. Four genotypically unique variants were further genotyped in 937 DNA samples from full-heritage Pima Indians. Three of the variants were modestly associated with type 2 diabetes (P < 0.05), one of which was additionally associated with 2-h plasma insulin and glucose as well as insulin action at physiologic and maximally stimulating insulin concentrations (all P < 0.05). The association of variants in IRS1 with type 2 diabetes and type 2 diabetes-related phenotypes and the differential expression of IRS1 in adipocytes and skeletal muscle suggest a role of this gene in the pathogenesis of type 2 diabetes in Pima Indians.
胰岛素受体底物-1（IRS1）是胰岛素信号通路中的关键元件，据报道，IRS1基因突变在决定2型糖尿病相关性状易感性方面发挥作用。在对非糖尿病皮马印第安人组织活检的基因表达研究中，与瘦人相比，肥胖受试者脂肪细胞中的IRS1 mRNA水平降低，与胰岛素敏感受试者相比，胰岛素抵抗受试者骨骼肌中的IRS1 mRNA水平也降低（所有P<0.05）。基于这些表达差异以及IRS1已知的生理作用，该基因作为皮马印第安人2型糖尿病易感性的候选基因进行了研究，皮马印第安人是2型糖尿病发病率和患病率极高的人群。共鉴定出13个变异体，其中几个变异体处于完全连锁不平衡状态。在来自纯血统皮马印第安人的937份DNA样本中，对4个基因型独特的变异体进行了进一步基因分型。其中3个变异体与2型糖尿病存在适度关联（P<0.05），其中一个变异体还与2小时血浆胰岛素和葡萄糖以及生理和最大刺激胰岛素浓度下的胰岛素作用相关（所有P<0.05）。IRS1变异体与2型糖尿病及2型糖尿病相关表型的关联以及IRS1在脂肪细胞和骨骼肌中的差异表达表明该基因在皮马印第安人2型糖尿病发病机制中起作用。
