Tumor necrosis factor-α (TNF-α), 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-a 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-a 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-a promoter. This substitution (termed TNF-2) leads to higher rate of transcription of TNF-a 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 mlM, 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 · mU−1 · 1−1 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-αNco I polymorphism may exacerbate the alterations in leptin levels normally found among insulin-resistant subjects.
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September 01 1997
The TNF-α Gene Neo I Polymorphism Influences the Relationship Among Insulin Resistance, Percent Body Fat, and Increased Serum Leptin Levels
J M Fernández-Real;
J M Fernández-Real
Department of Endocrinology, University Hospital of Girona “Dr. Josep Trueta,”
Girona
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C Gutierrez;
C Gutierrez
Department of Endocrinology, University Hospital of Tarragona Joan XXIII
Tarragona
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W Ricart;
W Ricart
Department of Endocrinology, University Hospital of Girona “Dr. Josep Trueta,”
Girona
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R Casamitjana;
R Casamitjana
Hormonal Laboratory, University Hospital Clínic, University Hospital of Bellvitge
Barcelona, Spain
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M Fernández-Castañer;
M Fernández-Castañer
Department of Endocrinology, University Hospital of Bellvitge
Barcelona, Spain
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J Vendrell;
J Vendrell
Department of Endocrinology, University Hospital of Tarragona Joan XXIII
Tarragona
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C Richart;
C Richart
Department of Endocrinology, University Hospital of Tarragona Joan XXIII
Tarragona
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J Soler
J Soler
Department of Endocrinology, University Hospital of Bellvitge
Barcelona, Spain
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Address correspondence and reprint requests to Dr. J.M. Fernández-Real, Department of Endocrinology, Hospital de Girona, Ctra. Franca s/n, 17007 Girona, Spain.
Diabetes 1997;46(9):1468–1472
Article history
Received:
November 19 1996
Revision Received:
April 28 1997
Accepted:
April 28 1997
PubMed:
9287048
Citation
J M Fernández-Real, C Gutierrez, W Ricart, R Casamitjana, M Fernández-Castañer, J Vendrell, C Richart, J Soler; The TNF-α Gene Neo I Polymorphism Influences the Relationship Among Insulin Resistance, Percent Body Fat, and Increased Serum Leptin Levels. Diabetes 1 September 1997; 46 (9): 1468–1472. https://doi.org/10.2337/diab.46.9.1468
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