Tumor necrosis factor α −238G>A genotype alters postprandial plasma levels of free fatty acids in obese individuals with type 2 diabetes mellitus

Abstract Tumor necrosis factor α (TNF- α ) is a proinflammatory cytokine that impairs insulin action and alters lipid metabolism. We investigated the effects of genetic polymorphisms of TNF- α on circulating biomarkers of insulin resistance and lipid metabolism during an 8-hour metabolic profile test and a 2-hour oral glucose tolerance test in subjects with type 2 diabetes mellitus. Subjects (N = 123) recruited were type 2 diabetic men (n = 56) and women (n = 67) aged 36 to 75 years with a body mass index of at least 25 kg/m 2 . Blood samples were collected to determine postprandial changes in circulating lipid levels and biomarkers of insulin resistance. Subjects were genotyped by polymerase chain reaction-restriction fragment length polymorphism for the TNF- α −238G>A, −308G>A, and −863C>A polymorphisms. Compared with subjects who were homozygous for the −238G allele, carriers of the −238A allele had an altered ability to suppress postprandial free fatty acids as shown by an increased net incremental area under the curve (0.26 ± 2.44 vs −1.33 ± 2.71 mEq h −1 L −1 , P = .002) during the 8-hour metabolic profile test. This effect was observed in obese (1.04 ± 2.42 vs −1.68 ± 2.70 mEq h −1 L −1 , P = .0004) but not in non-obese (−0.63 ± 2.20 vs −0.95 ± 2.71 mEq h −1 L −1 , P = .6) individuals. Among obese subjects, carriers of the −308A allele had greater insulin resistance as estimated by the homeostasis model assessment of insulin resistance index (4.36 ± 2.83 vs 2.85 ± 1.75, P = .01), but no differences were observed among non-obese subjects (2.19 ± 1.24 vs 1.97 ± 0.90, P = .6). Our findings suggest that the −238G>A and −308G>A polymorphisms of TNF- α alter circulating free fatty acids and insulin resistance in obese subjects with type 2 diabetes mellitus.