title: Improved skeletal muscle oxidative enzyme activity and restoration of PGC-1 alpha and PPAR beta/delta gene expression upon rosiglitazone treatment in obese patients with type 2 diabetes mellitus.
abstract: OBJECTIVE
  To examine whether rosiglitazone alters gene expression of some key genes involved in mitochondrial biogenesis and oxidative capacity in skeletal muscle of type 2 diabetic patients, and whether this is associated with alterations in skeletal muscle oxidative capacity and lipid content.
  
  
  METHODS
  measured in muscle biopsies obtained from diabetic patients, before and after 8 weeks of rosiglitazone treatment, and matched controls. Furthermore, whole-body insulin sensitivity and substrate utilization were assessed.
  
  
  METHODS
  Ten obese type 2 diabetic patients and 10 obese normoglycemic controls matched for age and BMI.
  
  
  METHODS
  Gene expression and mitochondrial protein content of complexes I-V of the respiratory chain were measured by quantitative polymerase chain reaction and Western blotting, respectively. Histochemical staining was used to quantify lipid accumulation and complex II succinate dehydrogenase (SDH) activity. Insulin sensitivity and substrate utilization were measured during a hyperinsulinemic-euglycemic clamp with indirect calorimetry.
  
  
  RESULTS
  Skeletal-muscle mRNA of PGC-1 alpha and PPAR beta/delta--but not of other genes involved in glucose, fat and oxidative metabolism--was significantly lower in diabetic patients (P<0.01). Rosiglitazone significantly increased PGC-1 alpha ( approximately 2.2-fold, P<0.01) and PPAR beta/delta ( approximately 2.6-fold, P<0.01), in parallel with an increase in insulin sensitivity, SDH activity and metabolic flexibility (P<0.01). Surprisingly, none of the measured mitochondrial proteins was reduced in type 2 diabetic patients, nor affected by rosiglitazone treatment. No alterations were seen in muscular fat accumulation upon treatment.
  
  
  CONCLUSIONS
  These results suggest that the insulin-sensitizing effect of rosiglitazone may involve an effect on muscular oxidative capacity, via PGC-1 alpha and PPAR beta/delta, independent of mitochondrial protein content and/or changes in intramyocellular lipid.
authors.affiliation: Department of Human Biology, Nutrition and Toxicology Research Institute Maastricht (NUTRIM), Maastricht University, Maastricht, The Netherlands. m.mensink@hb.unimaas.nl
authors.forename: M
authors.initials: M
authors.lastname: Mensink
authors.forename: M K C
authors.initials: MK
authors.lastname: Hesselink
authors.forename: A P
authors.initials: AP
authors.lastname: Russell
authors.forename: G
authors.initials: G
authors.lastname: Schaart
authors.forename: J-P
authors.initials: JP
authors.lastname: Sels
authors.forename: P
authors.initials: P
authors.lastname: Schrauwen
mesh_terms: D001706:Biopsy; D001786:Blood Glucose / Q000378:metabolism; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D007333:Insulin Resistance / Q000502:physiology; D050356:Lipid Metabolism / Q000187:drug effects / Q000502:physiology; D008297:Male; D008875:Middle Aged; D008931:Mitochondria, Muscle / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D009765:Obesity / Q000150:complications / Q000378:metabolism*; D048068:PPAR-beta / Q000235:genetics / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D006360:Heat-Shock Proteins; D007004:Hypoglycemic Agents; D024101:Mitochondrial Proteins; D048068:PPAR-beta; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077154:Rosiglitazone