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Fatty Acid Incubation of Myotubes From Humans With Type 2 Diabetes Leads to Enhanced Release of ��-Oxidation Products Because of Impaired Fatty Acid Oxidation: Effects of Tetradecylthioacetic Acid and Eicosapentaenoic Acid

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 type 2 diabetic individuals after 4 days of preincubation with EPA or TTA.RESULTS—Type 2 diabetes 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 palmitic acid, whereas EPA increased only β-oxidation significantly. EPA markedly enhanced triacylglycerol (TAG) accumulation in myotubes, more pronounced in type 2 diabetes 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. EPA and especially TTA increased the expression of genes involved in fatty acid uptake, activation, accumulation, and oxidation.CONCLUSIONS—Our results suggest that 1) mitochondrial dysfunction in diabetic myotubes is caused by disturbances downstream of fatty acid β-oxidation; 2) EPA promoted accumulation of TAG, enhanced β-oxidation, and increased glucose oxidation; and 3) TTA improved complete palmitic acid oxidation in diabetic myotubes, opposed increased lipid accumulation, and increased glucose oxidation.Type 2 diabetes is characterized by hyperglycemia, reduced ability to oxidize fat, and accumulation of triacylglycerol (TAG) in skeletal muscle fibers. The increased deposition of intramyocellular TAG (imTAG) has received special interest, because several studies have demonstrated a positive association between insulin resistance and imTAG storage (1,2). Accumulation of imTAG depends on the availability and uptake of fatty acids, the rate of fatty acid oxidation, and the rate of synthesis and hydrolysis of TAG. Increased availability of plasma free fatty acid (FFA) during lipid infusion or high-fat feeding is associated with development of insulin resistance and accumulation of imTAG in vivo (3). Moreover, studies have shown impaired capacity for fatty acid oxidation in skeletal muscle from insulin-resistant/type 2 diabetic individuals (4,5), and reduced mitochondrial fatty acid oxidation in skeletal muscle and myotubes is associated with increased deposition of imTAG (6–8). Fatty acids may promote insulin resistance via intracellular intermediates such as acyl-CoA, diacylglycerol (DAG), and ceramides, interfering with insulin signaling and glucose metabolism (9).Previous studies have demonstrated positive effects on skeletal muscle insulin sensitivity of mono- and polyunsaturated fatty acids (PUFAs) compared with saturated fatty acids (10–12). Very long–chain ω-3 fatty acids, including eicosapentaenoic acid (EPA), may protect against skeletal muscle insulin resistance caused by high-fat feeding in vivo (1,13). PUFAs may also promote increased TAG accumulation without impairing insulin-stimulated glucose uptake in myotubes (10,11). The sulfur-substituted fatty acid analog tetradecylthioacetic acid (TTA) is a pan–peroxisome proliferator–activated receptor (pan-PPAR) activator that reduces plasma lipids and enhances hepatic fatty acid oxidation in rodents (14). Dual and pan-PPAR agonists are currently being developed for treatment of type 2 diabetes (15), and TTA has been shown to improve glucose metabolism in insulin-resistant rats (16) and to stimulate mitochondrial proliferation in rat skeletal muscle (17). We have recently demonstrated that TTA may increase fatty acid oxidation in human myotubes similar to the PPARδ-specific agonist {"type":"entrez-nucleotide","attrs":{"text":"GW501516","term_id":"289075981","term_text":"GW501516"}}GW501516 (18).Skeletal muscle metabolism is influenced by physical activity, hormonal status, and muscle fiber type, rendering it difficult to determine the impact of EPA and TTA on basal and insulin-stimulated intermediary metabolism. Cultured human myotubes display the morphological, metabolic, and biochemical properties of adult skeletal muscle (19) and offer a unique model to distinguish between genetic and environmental factors in the etiology of insulin resistance (20). We and others have reported several potential intrinsic deficiencies in myotubes from individuals with type 2 diabetes, including lower basal palmitate oxidation (21) and impaired insulin-stimulated glucose metabolism (20,22). It is unknown whether EPA or TTA may improve insulin resistance or other characteristics of type 2 diabetes, such as decreased lipid oxidation in myotubes.To identify the potential effects of EPA and TTA on the intermediary energy metabolism and insulin resistance, we compared the effect of TTA, EPA, and oleic acid in myotubes established from obese individuals with type 2 diabetes and obese healthy subjects.     

Clostridium difficile toxins A and B directly stimulate human mast cells

Clostridium difficile toxins A and B (TcdA and TcdB) are the causative agents of antibiotic-associated pseudomembranous colitis. Mucosal mast cells play a crucial role in the inflammatory processes underlying this disease. We studied the direct effects of TcdA and TcdB on the human mast cell line HMC-1 with respect to degranulation, cytokine release, and the activation of proinflammatory signal pathways. TcdA and TcdB inactivate Rho GTPases, the master regulators of the actin cytoskeleton. The inactivation of Rho GTPases induced a reorganization of the actin cytoskeleton accompanied by morphological changes of cells. The TcdB-induced reorganization of the actin cytoskeleton in HMC-1 cells reduced the number of electron-dense mast cell-specific granules. Accordingly, TcdB induced the release of hexosaminidase, a marker for degranulation, in HMC-1 cells. The actin rearrangement was found to be responsible for degranulation since latrunculin B induced a comparable hexosaminidase release. In addition, TcdB as well as latrunculin B induced the activation of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase 1/2 and also resulted in a p38 MAPK-dependent increased formation of prostaglandins D(2) and E(2). The autocrine stimulation of HMC-1 cells by prostaglandins partially contributed to the degranulation. Interestingly, TcdB-treated HMC-1 cells, but not latrunculin B-treated HMC-1 cells, showed a strong p38 MAPK-dependent increase in interleukin-8 release. Differences in the mast cell responses to TcdB and latrunculin B are probably due to the presence of functionally inactive Rho GTPases in toxin-treated cells. Thus, the HMC-1 cell line is a promising model for studying the direct effects of C. difficile toxins on mast cells independently of the tissue context.