The effect of the -308A allele of the TNF-alpha gene on insulin action is dependent on obesity.

Objective: Promoter polymorphisms of the tumor necrosis factor alpha (TNF-alpha) gene are associated with insulin sensitivity and BMI. We investigated whether the effect of the G-308A polymorphism of the TNF-alpha gene on insulin action depends on BMI.

Research Methods And Procedures: The effects of the G-308A polymorphism on the rates of glucose and lipid oxidation and free fatty acid (FFA) levels were studied using the hyperinsulinemic euglycemic clamp combined with indirect calorimetry in 129 healthy subjects.

Results: The -308A allele of the TNF-alpha gene was associated with high rates of glucose oxidation (p = 0.008 adjusted for age, gender, and BMI) and lipid synthesis (p = 0.037) and suppression of FFA levels (p = 0.023) during hyperinsulinemia. In normal weight subjects (BMI < 26 kg/m(2)), the -308 allele was associated with high rates of glucose oxidation (p = 0.036) during the clamp but not with high rates of lipid synthesis (p = 0.896) or FFA suppression (p = 0.464). In overweight subjects (BMI >or= 26 kg/m(2)), high rates of lipid synthesis and FFA suppression (p = 0.010 and p = 0.042, respectively) but not the rates of glucose oxidation during the clamp (p = 0.193) were associated with the -308A allele.

Discussion: The -308A allele of the promoter of the TNF-alpha gene is associated with high rates of glucose oxidation in normal weight subjects and with effective lipid storage in overweight subjects. These findings suggest an interaction of the polymorphism with obesity.