title: The effect of muraglitazar on adiponectin signalling, mitochondrial function and fat oxidation genes in human skeletal muscle in vivo.
abstract: OBJECTIVE
  The molecular mechanisms by which muraglitazar (peroxisome proliferator-activated receptor γ/α agonist) improves insulin sensitivity in Type 2 diabetes mellitus are not fully understood. We hypothesized that muraglitazar would increase expression of 5'-monophosphate-activated protein kinase and genes involved in adiponectin signalling, free fatty acid oxidation and mitochondrial function in skeletal muscle.
  
  
  METHODS
  Sixteen participants with Type 2 diabetes received muraglitazar, 5 mg/day (n = 12) or placebo (n = 4). Before and after 16 weeks, participants had vastus lateralis muscle biopsy followed by 180 min euglycaemic hyperinsulinaemic clamp.
  
  
  RESULTS
  Muraglitazar increased plasma adiponectin (9.0 ± 1.1 to 17.8 ± 1.5 μg/ml, P < 0.05), while no significant change was observed with placebo. After 16 weeks with muraglitazar, fasting plasma glucose declined by 31%, fasting plasma insulin decreased by 44%, insulin-stimulated glucose disposal increased by 81%, HbA1c decreased by 21% and plasma triglyceride decreased by 39% (all P < 0.05). Muraglitazar increased mRNA levels of 5'-monophosphate-activated protein kinase, adiponectin receptor 1, adiponectin receptor 2, peroxisome proliferator-activated receptor gamma coactivator-1 alpha and multiple genes involved in mitochondrial function and fat oxidation. In the placebo group, there were no significant changes in expression of these genes.
  
  
  CONCLUSIONS
  Muraglitazar increases plasma adiponectin, stimulates muscle 5'-monophosphate-activated protein kinase expression and increases expression of genes involved in adiponectin signalling, mitochondrial function and fat oxidation. These changes represent important cellular mechanisms by which dual peroxisome proliferator-activated receptor agonists improve skeletal muscle insulin sensitivity.
authors.affiliation: Mayo Clinic in Arizona, Scottsdale; School of Life Sciences, Arizona State University, Tempe; Department of Basic Medical Sciences, University of Arizona College of Medicine - Phoenix.
authors.forename: D K
authors.initials: DK
authors.lastname: Coletta
authors.forename: M
authors.initials: M
authors.lastname: Fernandez
authors.forename: E
authors.initials: E
authors.lastname: Cersosimo
authors.forename: A
authors.initials: A
authors.lastname: Gastaldelli
authors.forename: N
authors.initials: N
authors.lastname: Musi
authors.forename: R A
authors.initials: RA
authors.lastname: DeFronzo
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000502:physiology; D052242:Adiponectin / Q000097:blood / Q000502:physiology*; D001706:Biopsy; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology; D008297:Male; D008875:Middle Aged; D008931:Mitochondria, Muscle / Q000187:drug effects* / Q000502:physiology; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010080:Oxazoles / Q000494:pharmacology* / Q000627:therapeutic use; D010084:Oxidation-Reduction; D047493:PPAR alpha / Q000819:agonists; D047495:PPAR gamma / Q000819:agonists; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D014280:Triglycerides / Q000097:blood
chemical_list: D052242:Adiponectin; D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D010080:Oxazoles; D047493:PPAR alpha; D047495:PPAR gamma; D014280:Triglycerides; D055372:AMP-Activated Protein Kinases; D005998:Glycine; C500085:muraglitazar