title: Abnormal metabolism flexibility in response to high palmitate concentrations in myotubes derived from obese type 2 diabetic patients.
abstract: Insulin resistance in type 2 diabetes (T2D) is associated with intramuscular lipid (IMCL) accumulation. To determine whether impaired lipid oxidation is involved in IMCL accumulation, we measured expression of genes involved in mitochondrial oxidative metabolism or biogenesis, mitochondrial content and palmitate beta-oxidation before and after palmitate overload (600μM for 16h), in myotubes derived from healthy subjects and obese T2D patients. Mitochondrial gene expression, content and network were not different between groups. Basal palmitate beta-oxidation was not affected in T2D myotubes, whereas after 16h of palmitate pre-treatment, T2D myotubes in contrast to control myotubes, showed an inability to increase palmitate beta-oxidation (p<0.05). Interestingly, acetyl-CoA carboxylase (ACC) phosphorylation was increased with a tendency for statistical significance after palmitate pre-treatment in control myotubes (p=0.06) but not in T2D myotubes which can explain their inability to increase palmitate beta-oxidation after palmitate overload. To determine whether the activation of the AMP activated protein kinase (AMPK)-ACC pathway was able to decrease lipid content in T2D myotubes, cells were treated with AICAR and metformin. These AMPK activators had no effect on ACC and AMPK phosphorylation in T2D myotubes as well as on lipid content, whereas AICAR, but not metformin, increased AMPK phosphorylation in control myotubes. Interestingly, metformin treatment and mitochondrial inhibition by antimycin induced increased lipid content in control myotubes. We conclude that T2D myotubes display an impaired capacity to respond to metabolic stimuli.
authors.affiliation: INSERM, ESPRI25 Muscle et pathologies, Montpellier, F-34295, France.
authors.forename: Magali
authors.initials: M
authors.lastname: Kitzmann
authors.forename: Louise
authors.initials: L
authors.lastname: Lantier
authors.forename: Sophie
authors.initials: S
authors.lastname: Hébrard
authors.forename: Jacques
authors.initials: J
authors.lastname: Mercier
authors.forename: Marc
authors.initials: M
authors.lastname: Foretz
authors.forename: Celine
authors.initials: C
authors.lastname: Aguer
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D050356:Lipid Metabolism / Q000187:drug effects; D008687:Metformin / Q000494:pharmacology; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009765:Obesity / Q000378:metabolism*; D010084:Oxidation-Reduction; D010168:Palmitates / Q000378:metabolism*; D010766:Phosphorylation; D052097:Quadriceps Muscle / Q000378:metabolism / Q000473:pathology; D012265:Ribonucleotides / Q000494:pharmacology
chemical_list: D007004:Hypoglycemic Agents; D010168:Palmitates; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D008687:Metformin; D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase; C031143:AICA ribonucleotide