title: Pioglitazone treatment restores in vivo muscle oxidative capacity in a rat model of diabetes.
abstract: OBJECTIVE
  To determine the effect of pioglitazone treatment on in vivo and ex vivo muscle mitochondrial function in a rat model of diabetes.
  
  
  METHODS
  Both the lean, healthy rats and the obese, diabetic rats are Zucker Diabetic Fatty (ZDF) rats. The homozygous fa/fa ZDF rats are obese and diabetic. The heterozygous fa/+ ZDF rats are lean and healthy. Diabetic Zucker Diabetic Fatty rats were treated with either pioglitazone (30 mg/kg/day) or water as a control (n = 6 per group), for 2 weeks. In vivo ¹H and ³¹P magnetic resonance spectroscopy was performed on skeletal muscle to assess intramyocellular lipid (IMCL) content and muscle oxidative capacity, respectively. Ex vivo muscle mitochondrial respiratory capacity was evaluated using high-resolution respirometry. In addition, several markers of mitochondrial content were determined.
  
  
  RESULTS
  IMCL content was 14-fold higher and in vivo muscle oxidative capacity was 26% lower in diabetic rats compared with lean rats, which was, however, not caused by impairments of ex vivo mitochondrial respiratory capacity or a lower mitochondrial content. Pioglitazone treatment restored in vivo muscle oxidative capacity in diabetic rats to the level of lean controls. This amelioration was not accompanied by an increase in mitochondrial content or ex vivo mitochondrial respiratory capacity, but rather was paralleled by an improvement in lipid homeostasis, that is lowering of plasma triglycerides and muscle lipid and long-chain acylcarnitine content.
  
  
  CONCLUSIONS
  Diminished in vivo muscle oxidative capacity in diabetic rats results from mitochondrial lipid overload and can be alleviated by redirecting the lipids from the muscle into adipose tissue using pioglitazone treatment.
authors.affiliation: Department of Biomedical Engineering, Biomedical NMR, Eindhoven University of Technology, Eindhoven, the Netherlands.
authors.forename: B
authors.initials: B
authors.lastname: Wessels
authors.forename: J
authors.initials: J
authors.lastname: Ciapaite
authors.forename: N M A
authors.initials: NM
authors.lastname: van den Broek
authors.forename: S M
authors.initials: SM
authors.lastname: Houten
authors.forename: K
authors.initials: K
authors.lastname: Nicolay
authors.forename: J J
authors.initials: JJ
authors.lastname: Prompers
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002331:Carnitine / Q000031:analogs & derivatives / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D015228:Hypertriglyceridemia / Q000150:complications / Q000517:prevention & control; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D000960:Hypolipidemic Agents / Q000627:therapeutic use; D050356:Lipid Metabolism / Q000187:drug effects*; D008297:Male; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000150:complications / Q000517:prevention & control*; D063269:Mitochondrial Turnover / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D009765:Obesity / Q000150:complications; D010085:Oxidative Phosphorylation / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D047495:PPAR gamma / Q000037:antagonists & inhibitors; D000077205:Pioglitazone; D011924:Rats, Zucker; D045162:Thiazolidinediones / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D015415:Biomarkers; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; C116917:acylcarnitine; D002331:Carnitine; D000077205:Pioglitazone
keywords: PPAR-gamma agonist; Zucker Diabetic Fatty rat; antidiabetic drug; energy regulation; lipid-lowering therapy; thiazolidinediones