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Tetradecylthioacetic acid attenuates dyslipidaemia in male patients with type 2 diabetes mellitus, possibly by dual PPAR‐α/δ activation and increased mitochondrial fatty acid oxidation
Author(s) -
Løvås K.,
Røst T. H.,
Skorve J.,
Ulvik R. J.,
Gudbrandsen O. A.,
Bohov P.,
Wensaas A. J.,
Rustan A. C.,
Berge R. K.,
Husebye E. S.
Publication year - 2009
Publication title -
diabetes, obesity and metabolism
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.445
H-Index - 128
eISSN - 1463-1326
pISSN - 1462-8902
DOI - 10.1111/j.1463-1326.2008.00958.x
Subject(s) - medicine , endocrinology , docosahexaenoic acid , beta oxidation , fatty acid , eicosapentaenoic acid , type 2 diabetes , fatty acid metabolism , lipid metabolism , carbohydrate metabolism , peroxisome proliferator activated receptor , polyunsaturated fatty acid , type 2 diabetes mellitus , chemistry , metabolism , biology , diabetes mellitus , biochemistry , receptor
Aim: We previously demonstrated that a modified fatty acid, tetradecylthioacetic acid (TTA), improves transport and utilization of lipids and increases mitochondrial fatty acid oxidation in animal and cell studies. We conducted an exploratory study of safety and effects of this novel drug in patients with type 2 diabetes mellitus and investigated the mechanism of action in human cell lines. Methods: Sixteen male patients with type 2 diabetes mellitus received 1 g TTA daily for 28 days in an open‐labelled study, with measurement of parameters of lipid metabolism, glucose metabolism and safety (ClinicalTrials.gov NCT00605787). The mechanism of action was further investigated in a human liver cell line (HepG2) and in cultured human skeletal muscle cells (myotubes). Results: Mean LDL cholesterol level declined from 4.2 to 3.7 mmol/l (p < 0.001), accompanied by increased levels of the HDL apolipoproteins A1 and A2, and a decline in LDL/HDL ratio from 4.00 to 3.66 (p = 0.008). Total fatty acid levels declined, especially the fraction of the polyunsaturated n‐3 fatty acids docosahexaenoic acid (−13%, p = 0.002) and eicosapentaenoic acid (−10%, p = 0.07). Glucose metabolism was not altered and the drug was well tolerated. In cultured liver cells, TTA acted as a pan‐PPAR agonist with predominant PPAR‐α and PPAR‐δ activation at low TTA concentrations. In myotubes, TTA and a PPAR‐δ agonist, but not the PPAR‐α or PPAR‐γ agonists, increased the fatty acid oxidation. Conclusions: We demonstrate for the first time that TTA attenuates dyslipidaemia in patients with type 2 diabetes mellitus. These effects may occur through mechanisms involving PPAR‐α and PPAR‐δ activation, resulting in increased mitochondrial fatty acid oxidation.