Day C P, Grove J, Daly A K, Stewart M W, Avery P J, Walker M
Department of Medicine, University of Newcastle upon Tyne, UK.
Diabetologia. 1998 Apr;41(4):430-4. doi: 10.1007/s001250050926.
Insulin resistance is a feature of non-diabetic relatives of non-insulin-dependent diabetic (NIDDM) families. Tumour necrosis factor-alpha (TNF alpha) expression is linked with insulin resistance, and is under strong genetic control. We examined the relationship between insulin resistance and two polymorphisms of the TNF alpha promoter region (positions -238 and -308). Non-diabetic relatives (n = 123) of NIDDM families and control subjects (n = 126) with no family history of diabetes were studied. Insulin resistance was determined by homeostasis model assessment (HOMA) and short insulin tolerance test (ITT), and genotyping was by restriction digest. The -238 polymorphism (TNFA-A allele) was carried by 14 relatives and 11 control subjects, and all were heterozygotes. To examine the relationship between the -238 polymorphism and insulin resistance independent of potentially confounding factors, the relatives with the TNFA-A allele were individually pair-matched for age, sex, waist-hip ratio, body mass index, and glucose tolerance with relatives homozygous for the wild-type allele. Relatives with the TNFA-A allele had decreased insulin resistance (HOMA index: 2.0, 3.6 +/- 2.1 [means +/- SD of differences], p = 0.03), and this was true for comparable pair-matched control subjects (HOMA index: 1.1, 1.9 +/- 0.8, p = 0.01). Combining relative (n = 7) and control (n = 4) pairs that had undergone an ITT, subjects with the TNFA-A allele had an increased K(ITT) (3.8, 3.0 +/- 1.0%/min, p = 0.04) similarly indicating decreased insulin resistance. There was no significant relationship between the -308 polymorphism and insulin resistance. We conclude that the TNFA-A allele is associated with decreased insulin resistance as assessed by two independent methods, and may protect against the future development of NIDDM in susceptible individuals.
胰岛素抵抗是非胰岛素依赖型糖尿病（NIDDM）家族非糖尿病亲属的一个特征。肿瘤坏死因子-α（TNFα）的表达与胰岛素抵抗相关，且受强遗传控制。我们研究了胰岛素抵抗与TNFα启动子区域两个多态性位点（-238和-308位）之间的关系。对NIDDM家族的非糖尿病亲属（n = 123）和无糖尿病家族史的对照受试者（n = 126）进行了研究。通过稳态模型评估（HOMA）和短胰岛素耐量试验（ITT）测定胰岛素抵抗，通过限制性酶切进行基因分型。14名亲属和11名对照受试者携带-238多态性（TNFA-A等位基因），且均为杂合子。为了研究-238多态性与胰岛素抵抗之间独立于潜在混杂因素的关系，将携带TNFA-A等位基因的亲属与野生型等位基因纯合的亲属按年龄、性别、腰臀比、体重指数和糖耐量进行个体配对。携带TNFA-A等位基因的亲属胰岛素抵抗降低（HOMA指数：2.0，差异均值±标准差为3.6±2.1，p = 0.03），可比的配对对照受试者也是如此（HOMA指数：1.1，1.9±0.8，p = 0.01）。将进行了ITT的亲属（n = 7）和对照（n = 4）配对组合，携带TNFA-A等位基因的受试者K(ITT)升高（3.8，3.0±1.0%/分钟，p = 0.04），同样表明胰岛素抵抗降低。-308多态性与胰岛素抵抗之间无显著关系。我们得出结论，通过两种独立方法评估，TNFA-A等位基因与降低的胰岛素抵抗相关，可能对易感个体未来发生NIDDM具有保护作用。
