PHYSIOLOGICAL RESEARCH  ISSN 0862-8408 (print)  ISSN 1802-9973 (online) © 2008 Institute of Physiology v.v.i., Academy of Sciences of the Czech Republic, Prague, Czech Republic Fax +420 241 062 164, e-mail: physres@biomed.cas.cz, www.biomed.cas.cz/physiolres Physiol. Res. 57 (Suppl. 1): S77-S90, 2008 PPARγ2 Pro12Ala Polymorphism in Relation to Free Fatty Acids Concentration and Composition in Lean Healthy Czech Individuals with and without Family History of Diabetes Type 2 B. BENDLOVÁ, D. VEJRAŽKOVÁ, J. VČELÁK, P. LUKÁŠOVÁ, D. BURKOŇOVÁ, M. KUNEŠOVÁ, J. VRBÍKOVÁ, K. DVOŘÁKOVÁ, K. VONDRA, M. VAŇKOVÁ Institute of Endocrinology, Prague, Czech Republic Received November 12, 2007 Accepted January 17, 2008 On-line February 13, 2008 Summary Free fatty acids (FFAs) are natural ligands of the PPARγ2 receptor. FFA plasma concentration and composition may represent one of the factors accounting for high heterogeneity of conclusions concerning the effect of the Pro12Ala on BMI, insulin sensitivity or diabetes type 2 (DM2) susceptibility. Our objective was to investigate the relation and possible interactions between the Pro12Ala polymorphism and FFA status, metabolic markers, and body composition in 324 lean nondiabetic subjects (M/F: 99/225; age 32±11 years; BMI 23.9±4.0 kg/m 2 ) with and without family history of DM2. Family history of DM2 was associated with lower % PUFA and slightly higher % MUFA. The presence of Pro12Ala polymorphism was not associated with fasting plasma FFA concentration or composition, anthropometric or metabolic markers of glucose and lipid metabolism in tested population. However, the interaction of carriership status with FFA levels influenced the basal glucose levels, insulin sensitivity and disposition indices, triglycerides, HDL-cholesterol and leptin levels, especially in women. The metabolic effects of 12Ala carriership were influenced by FFA levels – the beneficial role of 12Ala was seen only in the presence of low concentration of plasma FFA. Surprisingly, a high PUFA/SFA ratio was associated with lower insulin sensitivity, the protective effect of 12Ala allele was apparent in subjects with family history of DM2. On the basis of our findings and published data we recommend the genotyping of diabetic patients for Pro12Ala polymorphism of the PPARγ2 gene before treatment with thiazolidinediones and education of subjects regarding diet and physical activity, which modulate metabolic outcomes. Key words PPARγ2 Pro12Ala polymorphism • Free fatty acids concentration • Free fatty acids • Composition • Polyunsaturated fatty acids • Insulin sensitivity • Offspring • Diabetes type 2 Corresponding author B. Bendlová, Institute of Endocrinology, Národní třída 8, 116 94 Prague 1, Czech Republic. E-mail: bbendlova@endo.cz Introduction The prevalence of obesity and diabetes mellitus type 2 (DM2) has been increasing dramatically throughout the entire world in the last decades. There is growing evidence that the interaction between genetic factors and environmental factors such as dietary habits, physical activity, stress, chemical toxins etc. plays a crucial role in the pathogenesis of these multifactorial diseases (Barroso 2005, Uusitupa 2005, Cocozza 2007). In spite of intensive study, the pathogenetic mechanisms for this are still not completely understood. It is suggested that the major metabolic defect is the impaired fat metabolism, which is associated with the development of insulin resistance, the key feature of metabolic syndrome (McGarry 2002, Cahová et al. 2007). Free fatty acids are one of the major dietetic factors, which influence insulin sensitivity and beta-cell function (Keller 2006). Numerous studies over the past 25 years have demonstrated that saturated (SFA), monounsaturated (MUFA), and polyunsaturated fatty acids (PUFA) do not regulate glucose and lipid metabolism in the same way or with the same outcomes (Storlien et al. 1991, McGarry 2002). Dietary polyunsaturated fatty acids (PUFAs), particularly the long-chain n-3 fatty acids of fish oils, improve the anomalies in glucose and lipid metabolism associated with fat ingestion. PUFAs rich in long chain n-3 fatty acids markedly reduce hepatic TG