The TNF-alpha gene Nco I polymorphism influences the relationship among insulin resistance, percent body fat, and increased serum leptin levels

Abstract

Tumor necrosis factor-alpha (TNF-alpha), acting as a modulator of gene expression in adipocytes, is implicated in the development of insulin resistance and obesity. The aim of this study was to investigate whether the Nco I polymorphism of the TNF-alpha gene influences the relationship among insulin resistance, percent body fat, and serum leptin levels. A sample of 38 subjects (19 men, mean age 36.2 +/- 1.9 years, BMI 28.8 +/- 1.2 kg/m2, range 22.2-35.7; and 19 women, age 34.9 +/- 1.4 years, BMI 28.1 +/- 0.8 kg/m2, range 19-37.9) was divided into two groups on the basis of the Nco I genotype. Twenty-three subjects were (+/+) homozygotes for the presence of the Nco I restriction site that is associated with a guanine at position -308 of the TNF-alpha promoter. Of the other subjects, 12 were (+/-) heterozygotes and 3 (-/-) homozygotes for the absence of the restriction site, resulting from a guanine-to-adenine substitution at position -308 of the TNF-alpha promoter. This substitution (termed TNF-2) leads to higher rate of transcription of TNF-alpha than the wild-type allele TNF-1 in vitro. TNF-1 (+/+) and TNF-2 (+/- and -/-) groups of subjects were comparable in sex, age, BMI, waist-to-hip ratio, and several skinfold measurements. Basal serum insulin was greater (14.2 +/- 2 vs. 9.2 +/- 0.9 mU/l, P = 0.041) in the TNF-2 group in the presence of comparable serum glucose concentration. The integrated area under the curve of serum insulin concentrations, measured in response to a 75-g oral glucose challenge, and the percent body fat, measured by bioelectric impedance, were significantly increased in TNF-2 subjects (226.8 +/- 33 vs. 139.4 +/- 17.8 mU/l, P = 0.032; 33.6 +/- 2.8 vs. 24.9 +/- 2%, P = 0.01). TNF-2 subjects also showed a decreased insulin sensitivity index, as determined by the frequently sampled intravenous glucose tolerance test with minimal model analysis (1.9 +/- 0.4 vs. 3.05 +/- 0.3 min(-1) x mU(-1) x l(-1), P = 0.03). These differences were more marked among women. Paralleling the known relationship between insulin and leptin levels, serum leptin concentration was clearly increased in the TNF-2 group (19.6 +/- 3.4 vs. 11.1 +/- 1.5 ng/ml, P = 0.03). Therefore, (+/-) heterozygotes and (-/-) homozygotes may be more susceptible to developing insulin resistance and increased percent body fat. Results of the present study suggest that TNF-alphaNco I polymorphism may exacerbate the alterations in leptin levels normally found among insulin-resistant subjects.