The Effect of the −308A Allele of the TNF‐α Gene on Insulin Action Is Dependent on Obesity

Abstract

PIHLAJAMÄ KI, JUSSI, MARI YLINEN, PAULI KARHAPÄ Ä , ILKKA VAUHKONEN, AND MARKKU LAAKSO. The effect of the Ϫ308A allele of the TNF-␣ gene on insulin action is dependent on obesity. Obes Res. 2003;11:912-917. Objective: Promoter polymorphisms of the tumor necrosis factor alpha (TNF-␣) gene are associated with insulin sensitivity and BMI. We investigated whether the effect of the G-308A polymorphism of the TNF-␣ 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 Ϫ308A allele of the TNF-␣ gene was associated with high rates of glucose oxidation (p ϭ 0.008 adjusted for age, gender, and BMI) and lipid synthesis (p ϭ 0.037) and suppression of FFA levels (p ϭ 0.023) during hyperinsulinemia. In normal weight subjects (BMI Ͻ 26 kg/m 2 ), the Ϫ308 allele was associated with high rates of glucose oxidation (p ϭ 0.036) during the clamp but not with high rates of lipid synthesis (p ϭ 0.896) or FFA suppression (p ϭ 0.464). In overweight subjects (BMI Ն 26 kg/m 2 ), high rates of lipid synthesis and FFA suppression (p ϭ 0.010 and p ϭ 0.042, respectively) but not the rates of glucose oxidation during the clamp (p ϭ 0.193) were associated with the Ϫ308A allele. Discussion: The Ϫ308A allele of the promoter of the TNF-␣ 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.

Inter-Ethnic Variations in Association of TNF-Alpha G308a Single Nucleotide Polymorphism with Type 2 Diabetes Mellitus - A Review

“…The probable explanation of higher BMI is the association of presence of TNF-α G308A polymorphism with higher rates of lipid synthesis, and suppression of FFA levels in obese persons but not in non-obese healthy persons. Interestingly, TNF-α A allele was associated with augmented glucose oxidation in non-obese healthy subjects but not in obese subjects [53]. This indicates the differential effect of TNF-α -308 A allele on lipid and glucose metabolism in obese and non-obese subjects.…”

“…The association between TNF-α -308 heterozygous GA with higher S. FFA levels as compared to GG genotype has been found in Chinese non-diabetics [33], although in another study, A allele was associated with higher lipid synthesis and suppressed FFA levels in over-weight Finnish subjects though, the same allele was associated with higher glucose oxidation but not with higher lipid synthesis or suppressed FFA levels in non-obese healthy Finnish subjects [53]. Percent body fat was found to be increased in the presence of A allele in obese Spanish population [42] whereas Obese Chinese with GG genotype had lower HDL cholesterol than carriers of GA or AA genotype [39].…”

Asociación del polimorfi smo TNF-alpha -308 G/A con los cambios metabólicos secundarios a una dieta hipocalórica rica en proteínas/baja en hidratos de carbono versus una dieta hipocalórica estándar

“…Further, our design also shows an improvement in insulin concentrations and HOMA-R after weight loss secondary to a high protein/low carbohydrate hypocaloric diet only in subjects with -308 GG genotype. Some previous studies have proposed that the effects of the -308 GA promoter variant of the TNF-alpha gene on insulin action may depend on body weight (24). The A allele was associated with high RQ (resting quotient), indicating high rates of glucose oxidation and lipid synthesis, depending of BMI (24).…”

“…Some previous studies have proposed that the effects of the -308 GA promoter variant of the TNF-alpha gene on insulin action may depend on body weight (24). The A allele was associated with high RQ (resting quotient), indicating high rates of glucose oxidation and lipid synthesis, depending of BMI (24). On the other hand, the promoter variant at position -308 leads to a higher rate of TNF alpha gene transcription, followed by raised TNF-alpha concentrations and decreased insulin resistance (25).…”

Pharmacogenetics of antipsychotic-induced weight gain

“…Among those, the TNFα-308 G/A promoter polymorphism has shown significant correlations the most with obesity (Brand et al 2001) and fat and glucose metabolism in Caucasians (Kubaszek et al 2003;Pihlajamaki et al 2003), with subcutaneous fat accumulation, insulin resistance and leptin levels (Fernandez-Real et al 1997), and obesity and insulin resistance (Hoffstedt et al 2000;Wybranska et al 2003), as well as fat percentage (Dalziel et al 2002) in women.…”