肿瘤坏死因子α基因启动子区变异与胰岛素抵抗的相关研究

目的研究肿瘤坏死因子α（ＴＮＦα）基因启动子区３０８ｂｐＧ→Ａ变异与中国人群的体脂、胰岛素分泌与作用、糖脂水平的关系，探讨ＴＮＦα参与胰岛素抵抗的可能机制。方法以３５９例中国人为对象。用聚合酶链反应（ＰＣＲ）／ＮｃｏＩ酶解法检测ＴＮＦα－３０８ｂｐＧ→Ａ（ＴＮＦαＰ）变异，测定空腹血脂谱及葡萄糖负荷０、１／２、１、２及３小时血浆葡萄糖（ＰＧ）、胰岛素（ＩＮＳ）、Ｃ肽（ＣＰ）及游离脂肪酸（ＦＦＡ）的水平。结果（１）ＴＮＦαＰ变异基因型频率与糖尿病及肥胖均无相关性；（２）非糖尿病者糖兴奋后２小时ＦＦＡ亚组及ＦＦＡ总面积亚组中下降少者ＧＡ杂合子频率显著增高（Ｆｉｓｈｅｒ检验Ｐ＝０００２及００４１）；（３）非糖尿病ＧＡ杂合子者糖兴奋后ＦＦＡ曲线各时值高于ＧＧ纯合子者，其中２小时及３小时ＦＦＡ水平差异有显著意义（Ｐ分别为０．０２９及０．０３０）。糖尿病者基因型比较中亦有此种趋势。结论ＴＮＦα致胰岛素抵抗的发生机制之一是脂肪分解增强，ＦＦＡ释放增多。该基因变异所导致的脂肪分解差异可能是群体中胰岛素抵抗程度变异的机制之一。

The mechanism of tumor necrosis factoralpha (TNFalpha)induced insulin resistance by variation in promoter region of TNFalpha gene

Objective To investigate the relationship between the G to A variant at the -308bp of the promoter region of tumor necrosis factoralpha gene (TNFP) and the body adiposity, the insulin secretion and action,and the glucose and lipid levels in Chinese population. Method 359 Chinese were genotyped for the TNFP by using PCR/Nco digestion.Fasting blood lipid profile and the levels of plasma glucose (PG),insulin (INS),cpeptide (CP) and the free fatty acids (FFA) at 0,1/2, 1, 2 and 3 hours after glucose challenge were measured. Results Genotype frequencies of TNFP were not associated with diabetes and obesity. The genotype frequency of the G/A heterozygotes was significantly increased in nondiabetic subgroups with less decreased levels of 2hFFAand AUCFFA after glucose challenge(Fisher exact P=0.002 and 0.041 respectively). The FFA levels in nondiabetics with G/A heterozygotes were higher than those with G/G homozygotes,especially in the comparisons of the 2h and 3h FFA levels after glucose challenge (P=0.029 and 0.030 respectively).Similar tendency was also observed in diabetics. Conclusion circulation FFA level reflects the degree of lipolysis in adipose tissue. The difference in the degree of lipolysis led by the variant of the promoter region of TNFalpha may be one of the mechanisms for the variation in the degree of insulin resistance in general population.