title: Chronic hyperglycemia reduces substrate oxidation and impairs metabolic switching of human myotubes.
abstract: Skeletal muscle of insulin resistant individuals is characterized by lower fasting lipid oxidation and reduced ability to switch between lipid and glucose oxidation. The purpose of the present study was to examine if chronic hyperglycemia would impair metabolic switching of myotubes. Human myotubes were treated with or without chronic hyperglycemia (20mmol/l glucose for 4 days), and metabolism of [(14)C]oleic acid (OA) and [(14)C]glucose was studied. Myotubes exposed to chronic hyperglycemia showed a significantly reduced OA uptake and oxidation to CO(2), whereas acid-soluble metabolites were increased compared to normoglycemic cells (5.5mmol/l glucose). Glucose suppressibility, the ability of acute glucose (5mmol/l) to suppress lipid oxidation, was 50% in normoglycemic cells and reduced to 21% by hyperglycemia. Adaptability, the capacity to increase lipid oxidation with increasing fatty acid availability, was not affected by hyperglycemia. Glucose uptake and oxidation were reduced by about 40% after hyperglycemia, and oxidation of glucose in presence of mitochondrial uncouplers showed that net and maximal oxidative capacities were significantly reduced. Hyperglycemia also abolished insulin-stimulated glucose uptake. Moreover, ATP concentration was reduced by 25% after hyperglycemia. However, none of the measured mitochondrial genes were downregulated nor was mitochondrial DNA content. Microarray and real-time RT-PCR showed that no genes were significantly regulated by chronic hyperglycemia. Addition of chronic lactate reduced both glucose and OA oxidation to the same extent as hyperglycemia. In conclusion, chronic hyperglycemia reduced substrate oxidation in skeletal muscle cells and impaired metabolic switching. The effect is most likely due to an induced mitochondrial dysfunction.
authors.affiliation: Faculty of Health Sciences, Oslo University College, Oslo, Norway. vigdis.aas@hf.hio.no
authors.forename: Vigdis
authors.initials: V
authors.lastname: Aas
authors.forename: Nina P
authors.initials: NP
authors.lastname: Hessvik
authors.forename: Marianne
authors.initials: M
authors.lastname: Wettergreen
authors.forename: Andreas W
authors.initials: AW
authors.lastname: Hvammen
authors.forename: Stefan
authors.initials: S
authors.lastname: Hallén
authors.forename: G Hege
authors.initials: GH
authors.lastname: Thoresen
authors.forename: Arild C
authors.initials: AC
authors.lastname: Rustan
mesh_terms: D019297:2,4-Dinitrophenol / Q000494:pharmacology; D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000328:Adult; D002478:Cells, Cultured; D004272:DNA, Mitochondrial / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D018628:Gene Dosage; D020869:Gene Expression Profiling; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D015151:Immunoblotting; D007773:Lactates / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D019301:Oleic Acid / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010084:Oxidation-Reduction / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014475:Uncoupling Agents / Q000494:pharmacology
chemical_list: D004272:DNA, Mitochondrial; D007773:Lactates; D014475:Uncoupling Agents; D019301:Oleic Acid; D000255:Adenosine Triphosphate; D055372:AMP-Activated Protein Kinases; D005947:Glucose; D019297:2,4-Dinitrophenol