Fontaine-Bisson Bénédicte, Wolever Thomas M S, Chiasson Jean-Louis, Rabasa-Lhoret Rémi, Maheux Pierre, Josse Robert G, Leiter Lawrence A, Rodger N Wilson, Ryan Edmond A, El-Sohemy Ahmed
Department of Nutritional Sciences, University of Toronto, Toronto, Canada.
Metabolism. 2007 May;56(5):649-55. doi: 10.1016/j.metabol.2006.12.013.
Tumor necrosis factor alpha (TNF-alpha) is a proinflammatory cytokine that impairs insulin action and alters lipid metabolism. We investigated the effects of genetic polymorphisms of TNF-alpha on circulating biomarkers of insulin resistance and lipid metabolism during an 8-hour metabolic profile test and a 2-hour oral glucose tolerance test in subjects with type 2 diabetes mellitus. Subjects (N = 123) recruited were type 2 diabetic men (n = 56) and women (n = 67) aged 36 to 75 years with a body mass index of at least 25 kg/m(2). Blood samples were collected to determine postprandial changes in circulating lipid levels and biomarkers of insulin resistance. Subjects were genotyped by polymerase chain reaction-restriction fragment length polymorphism for the TNF-alpha -238G>A, -308G>A, and -863C>A polymorphisms. Compared with subjects who were homozygous for the -238G allele, carriers of the -238A allele had an altered ability to suppress postprandial free fatty acids as shown by an increased net incremental area under the curve (0.26 +/- 2.44 vs -1.33 +/- 2.71 mEq h(-1) L(-1), P = .002) during the 8-hour metabolic profile test. This effect was observed in obese (1.04 +/- 2.42 vs -1.68 +/- 2.70 mEq h(-1) L(-1), P = .0004) but not in non-obese (-0.63 +/- 2.20 vs -0.95 +/- 2.71 mEq h(-1) L(-1), P = .6) individuals. Among obese subjects, carriers of the -308A allele had greater insulin resistance as estimated by the homeostasis model assessment of insulin resistance index (4.36 +/- 2.83 vs 2.85 +/- 1.75, P = .01), but no differences were observed among non-obese subjects (2.19 +/- 1.24 vs 1.97 +/- 0.90, P = .6). Our findings suggest that the -238G>A and -308G>A polymorphisms of TNF-alpha alter circulating free fatty acids and insulin resistance in obese subjects with type 2 diabetes mellitus.
肿瘤坏死因子α（TNF-α）是一种促炎细胞因子，会损害胰岛素作用并改变脂质代谢。我们在2型糖尿病患者的8小时代谢谱测试和2小时口服葡萄糖耐量测试中，研究了TNF-α基因多态性对胰岛素抵抗和脂质代谢循环生物标志物的影响。招募的受试者（N = 123）为年龄在36至75岁、体重指数至少为25kg/m²的2型糖尿病男性（n = 56）和女性（n = 67）。采集血样以测定餐后循环脂质水平和胰岛素抵抗生物标志物的变化。通过聚合酶链反应-限制性片段长度多态性对受试者进行TNF-α -238G>A、-308G>A和-863C>A多态性基因分型。与-238G等位基因纯合子受试者相比，-238A等位基因携带者在8小时代谢谱测试中抑制餐后游离脂肪酸的能力发生改变，曲线下净增量面积增加（0.26±2.44 vs -1.33±2.71mEq h⁻¹L⁻¹，P = 0.002）。在肥胖个体中观察到这种效应（1.04±2.42 vs -1.68±2.70mEq h⁻¹L⁻¹，P = 0.0004），但在非肥胖个体中未观察到（-0.63±2.20 vs -0.95±2.71mEq h⁻¹L⁻¹，P = 0.6）。在肥胖受试者中，通过胰岛素抵抗指数的稳态模型评估估计，-308A等位基因携带者具有更高的胰岛素抵抗（4.36±2.83 vs 2.85±1.75，P = 0.01），但在非肥胖受试者中未观察到差异（2.19±1.24 vs 1.97±0.90，P = 0.6）。我们的研究结果表明，TNF-α的-238G>A和-308G>A多态性改变了2型糖尿病肥胖受试者的循环游离脂肪酸和胰岛素抵抗。
