Tetradecylthioacetic Acid Attenuates Dyslipidaemia in Male Patients With Type 2 Diabetes Mellitus, Possibly by Dual PPAR-alpha/delta Activation and Increased Mitochondrial Fatty Acid Oxidation

Diabetes Obes Metab. 2009 Apr;11(4):304-14. doi: 10.1111/j.1463-1326.2008.00958.x.

Abstract

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-alpha and PPAR-delta activation at low TTA concentrations. In myotubes, TTA and a PPAR-delta agonist, but not the PPAR-alpha or PPAR-gamma 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-alpha and PPAR-delta activation, resulting in increased mitochondrial fatty acid oxidation.

Publication types

  • Clinical Trial, Phase II
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Blood Glucose / metabolism
  • Blood Pressure / drug effects
  • Body Weight / drug effects
  • Cells, Cultured
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Dyslipidemias / blood
  • Dyslipidemias / drug therapy*
  • Fatty Acids / blood
  • Humans
  • Hypolipidemic Agents / therapeutic use*
  • Lipid Metabolism / drug effects
  • Lipids / blood
  • Lipoproteins / blood
  • Male
  • Middle Aged
  • Muscle Fibers, Skeletal / drug effects
  • Muscle Fibers, Skeletal / metabolism
  • PPAR alpha / agonists
  • PPAR alpha / metabolism
  • PPAR delta / agonists
  • PPAR delta / metabolism
  • Sulfides / therapeutic use*
  • Tumor Cells, Cultured

Substances

  • Blood Glucose
  • Fatty Acids
  • Hypolipidemic Agents
  • Lipids
  • Lipoproteins
  • PPAR alpha
  • PPAR delta
  • Sulfides
  • 1-(carboxymethylthio)tetradecane

Associated data

  • ClinicalTrials.gov/NCT00605787