Tumor necrosis factor a À238G N A genotype alters postprandial plasma levels of free fatty acids in obese individuals with type 2 diabetes mellitus Be ´ne ´dicte Fontaine-Bisson a , Thomas M.S. Wolever a,f , Jean-Louis Chiasson b,d , Re ´mi Rabasa-Lhoret c,d , Pierre Maheux e , Robert G. Josse a,f , Lawrence A. Leiter a,i , N. Wilson Rodger g , Edmond A. Ryan h , Ahmed El-Sohemy a, 4 a Department of Nutritional Sciences, University of Toronto, Toronto, Canada H3C 3J7 b Department of Medicine, Universite ´ de Montre ´al, Montre ´al, Montre ´al, Canada H3T 1A8 c Department of Nutrition, Universite ´ de Montre ´al, Montre ´al, Montre ´al, Canada H2W 1T7 d Research Center, Centre Hospitalier de l’Universite ´ de Montre ´al (CHUM), Montre ´al, Canada H2W 1T7 e Department of Medicine, Division of Endocrinology and Metabolism, Universite ´ de Sherbrooke, Sherbrooke, Canada J1H 5N4 f Osteoporosis Centre, St Michael’s Hospital, Toronto, Canada M5C 2T2 g Division of Endocrinology, University of Western Ontario, St. Joseph’s Hospital, London, Canada N6A 4V2 h Department of Medicine, University of Alberta, Edmonton, Canada T6G 2S2 i Division of Endocrinology and Metabolism, St. Michael’s Hospital, Toronto, Canada M5C 2T2 Received 9 March 2006; accepted 11 December 2006 Abstract Tumor necrosis factor a (TNF-a ) is a proinflammatory cytokine that impairs insulin action and alters lipid metabolism. We investigated the effects of genetic polymorphisms of TNF-a 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-a À238G N A, À308G N A, and À863C N A polymorphisms. Compared with subjects who were homozygous for the À238G allele, carriers of the À238A allele had an altered ability to suppress postprandial free fatty acids as shown by an increased net incremental area under the curve (0.26 F 2.44 vs À1.33 F 2.71 mEq h À1 L À1 , P = .002) during the 8-hour metabolic profile test. This effect was observed in obese (1.04 F 2.42 vs À1.68 F 2.70 mEq h À1 L À1 , P = .0004) but not in non-obese (À0.63 F 2.20 vs À0.95 F 2.71 mEq h À1 L À1 , P = .6) individuals. Among obese subjects, carriers of the À308A allele had greater insulin resistance as estimated by the homeostasis model assessment of insulin resistance index (4.36 F 2.83 vs 2.85 F 1.75, P = .01), but no differences were observed among non-obese subjects (2.19 F 1.24 vs 1.97 F 0.90, P = .6). Our findings suggest that the À238G N A and À308G N A polymorphisms of TNF-a alter circulating free fatty acids and insulin resistance in obese subjects with type 2 diabetes mellitus. D 2007 Published by Elsevier Inc. 1. Introduction The metabolic syndrome is characterized by abdominal obesity, increased fasting blood glucose, dyslipidemia, and hypertension, and is associated with an increased risk of type 2 diabetes mellitus and cardiovascular disease [1]. There is growing evidence that chronic inflammation is also an important feature of the metabolic syndrome [1]. Obese and diabetic individuals have elevated plasma levels of tumor necrosis factor a (TNF-a ), a multifunctional regulatory cytokine involved in the inflammatory response [2,3]. TNF-a is highly expressed in adipocytes [4] and inhibits insulin-signaling pathways [5], impairs peripheral 0026-0495/$ – see front matter D 2007 Published by Elsevier Inc. doi:10.1016/j.metabol.2006.12.013 4 Corresponding author. Tel.: +1 416 946 5776; fax: +1 416 978 5882. E-mail address: a.el.sohemy@utoronto.ca (A. El-Sohemy). Metabolism Clinical and Experimental 56 (2007) 649 – 655 www.elsevier.com/locate/metabol