Lower rate of tumor necrosis factor-alpha -863A allele and higher concentration of tumor necrosis factor-alpha receptor 2 in first-degree relatives of subjects with type 2 diabetes.
Allelic variants of the tumor necrosis factor-alpha (TNF-alpha) gene seem to contribute to insulin resistance increasing the transcription rate of TNF-alpha. The TNF-alpha -863A allele is associated with a lower expression of TNF-alpha gene and less secretion of the cytokine. To investigate whether an abnormal TNF-alpha system regulation may contribute to early impairment of insulin action in first-degree relatives of patients with type 2 diabetes mellitus (DM), we studied the TNF-alpha -863C/A polymorphism and the soluble fraction of TNF-alpha receptor-2 (sTNFR2) concentration in these subjects in comparison to a control group. A total of 52% of subjects in the relatives' group showed an abnormal oral glucose tolerance (either as impaired glucose tolerance [IGT] or diabetes) and had more features of the insulin resistance syndrome, despite showing similar body composition as controls. The plasma concentration of the sTNFR2 was higher and insulin sensitivity (%S) was lower in the relatives' group than in the controls. Likewise, the TNF-alpha -863A allele was more commonly detected in the control group (10 of 41) than in the relative's group (2 of 36, P =.029). In a multivariate linear regression analysis, neither TNF-alpha -863A allele nor sTNFR2 independently determined %S. Only body mass index (BMI) and the presence of a positive family history of DM were independent determinants of insulin resistance. In summary, our study showed a lower rate of TNF-alpha -863A allele and higher concentrations of sTNFR2 in first-degree relatives of DM subjects. These findings could be included among the genetic, metabolic, and clinical heterogeneity that characterizes the pathophysiology of DM. The presence of abnormalities in the TNF-alpha pathway could predispose to the development of DM in subjects at risk for the disease.
Costa
A
A
Endocrinology Unit, Hospital Clínic i Universitari de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
Fernández-Real
J M
JM
Vendrell
J
J
Broch
M
M
Casamitjana
R
R
Ricart
W
W
Conget
I
I
D000328:Adult; D000368:Aged; D000483:Alleles; D015703:Antigens, CD / Q000235:genetics* / Q000378:metabolism*; D001786:Blood Glucose / Q000378:metabolism; D015992:Body Mass Index; D002784:Cholesterol / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D005951:Glucose Tolerance Test; D006801:Humans; D020738:Leptin / Q000097:blood; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics* / Q000378:metabolism*; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D015703:Antigens, CD; D001786:Blood Glucose; D020738:Leptin; D018124:Receptors, Tumor Necrosis Factor; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D002784:Cholesterol