Fatty Acid Incubation of Myotubues from Humans with Type 2 Diabetes Leads to Enhanced Release of Beta Oxidation Products Due to Impaired Fatty Acid Oxidation: Effects of Tetradecylthioacetic Acid and Eicosapentaenoic Acid

Abstract

Objective: Increased availability of fatty acids is important for accumulation of intracellular lipids and development of insulin resistance in human myotubes. It is unknown whether different types of fatty acids like eicosapentaenoic acid (EPA) or tetradecylthioacetic acid (TTA) influence these processes.

Research Design and Methods: We examined fatty acid and glucose metabolism, and gene expression in cultured human skeletal muscle cells from control and T2D individuals after four days preincubation with EPA or TTA.

Results: T2D myotubes exhibited reduced formation of CO₂ from palmitic acid (PA), whereas release of β-oxidation products was unchanged at baseline, but significantly increased with respect to control myotubes after preincubation with TTA and EPA. Preincubation with TTA enhanced both complete (CO₂) and β-oxidation of PA, whereas EPA increased only β-oxidation significantly. EPA markedly enhanced TAG accumulation in myotubes, more pronounced in T2D cells. TAG accumulation and fatty acid oxidation were inversely correlated only after EPA preincubation, and total level of acyl-CoA was reduced. Glucose oxidation (CO₂ formation) was enhanced and lactate production decreased after chronic exposure to EPA and TTA, whereas glucose uptake and storage were unchanged. Both EPA and especially TTA increased the expression of genes involved in fatty acid uptake, activation, accumulation and oxidation.

Conclusion: Our results suggest: a) mitochondrial dysfunction in diabetic myotubes is caused by disturbances downstream of fatty acid β-oxidation; b) EPA promoted accumulation of TAG, enhanced β-oxidation and increased glucose oxidation; c) TTA improved complete PA oxidation in diabetic myotubes, opposed increased lipid accumulation and increased glucose oxidation.