Conjugated linoleic acid and the metabolic syndrome : Clinical and metabolic studies with special reference to insulin resistance, oxidative stress and inflammation

Sammanfattning: The aim of this thesis was to investigate the metabolic effects of conjugated linoleic acid (CLA) in middle-aged men with the metabolic syndrome, a high-risk group for type 2 diabetes. CLA is a group of fatty acid isomers with antiobesity and antidiabetogenic effects in animals, and CLA is therefore used as a supplement in humans. The t10c12CLA isomer seems to mediate these actions, but effects in humans are unknown. In two randomized, double-blind, controlled studies, abdominally obese men were randomized to a t10c12CLA concentrate, an isomer mixture (CLA) or placebo in a dose of ~ 1 % of energy intake. Insulin sensitivity (euglycemic clamp), sagittal abdominal diameter, lipid peroxidation (isoprostanes), plasma inflammation markers (C-reactive protein, TNFa, IL-6), serum IGF-1 and leptin were assessed before and after 1-3 months. CLA had no favorable metabolic effects, despite a slight decrease in sagittal abdominal diameter. In contrast, CLA elevated lipid peroxidation and reduced HDL cholesterol. Unexpectedly, t10c12CLA caused isomer-specific insulin resistance, dyslipidemia, oxidative stress and signs of inflammation, independent of hyperglycemia. Interestingly, induced insulin resistance was related to oxidative stress, and plasma tocopherol levels were related to increased oxidative stress indicating a compensatory mechanism. There are important differences between humans and animals in metabolic response to CLA. In contrast to the hypothesis, t10c12CLA emerged as a unique model of induced metabolic syndrome. Commercial CLA have no beneficial effects in prediabetic men. In contrast, the t10c12CLA content (~40%) in CLA supplements might be diabetogenic and proatherogenic in predisposed subjects. In conclusion, this study reveals clinically relevant isomer-specific insulin resistance of CLA in prediabetic men, possibly via a free-radical linked mechanism. The results provide new physiological insights of the role of specific fatty acids as potent modulators of insulin resistance and inflammation in man with relevance for type 2 diabetes and cardiovascular disease.