title: Pioglitazone-induced improvements in insulin sensitivity occur without concomitant changes in muscle mitochondrial function.
abstract: OBJECTIVE
  Pioglitazone (Pio) is known to improve insulin sensitivity in skeletal muscle. However, the role of Pio in skeletal muscle lipid metabolism and skeletal muscle oxidative capacity is not clear. The aim of this study was to determine the effects of chronic Pio treatment on skeletal muscle mitochondrial activity in individuals with type 2 diabetes (T2D).
  
  
  METHODS
  Twenty-four participants with T2D (13M/11F 53.38±2.1years; BMI 36.47±1.1kg/m2) were randomized to either a placebo (CON, n=8) or a pioglitazone (PIO, n=16) group. Following 12weeks of treatment, we measured insulin sensitivity by hyperinsulinemic-euglycemic clamp (clamp), metabolic flexibility by calculating the change in respiratory quotient (ΔRQ) during the steady state of the clamp, intra- and extra-myocellular lipid content (IMCL and EMCL, respectively) by1H magnetic resonance spectroscopy (1H-MRS) and muscle maximal ATP synthetic capacity (ATPmax) by31P-MRS.
  
  
  RESULTS
  Following 12weeks of PIO treatment, insulin sensitivity (p<0.0005 vs. baseline) and metabolic flexibility (p<0.05 vs. CON) significantly increased. PIO treatment significantly decreased IMCL content and increased EMCL content in gastrocnemius, soleus and tibialis anterior muscles. ATPmax was unaffected by PIO treatment.
  
  
  CONCLUSIONS
  These results suggest that 12weeks of pioglitazone treatment improves insulin sensitivity, metabolic flexibility and myocellular lipid distribution without any effect on maximal ATP synthetic capacity in skeletal muscle. Consequently, pioglitazone-induced enhancements in insulin responsiveness and fuel utilization are independent of mitochondrial function.
authors.affiliation: Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA 70808, USA; Department of Kinesiology, University of Texas in El Paso, 500 University Ave, El Paso, TX 79968, USA.
authors.forename: Sudip
authors.initials: S
authors.lastname: Bajpeyi
authors.affiliation: Translational Research Institute for Metabolism and Diabetes, Florida Hospital, Orlando, FL 32804, USA.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Pasarica
authors.affiliation: Department of Radiology, University of Washington Medical Center, 1959 NE Pacific St, Seattle, WA 98195, USA.
authors.forename: Kevin E
authors.initials: KE
authors.lastname: Conley
authors.affiliation: Department of Clinical and Diagnostic Sciences, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Bradley R
authors.initials: BR
authors.lastname: Newcomer
authors.affiliation: Department of Radiology, University of Washington Medical Center, 1959 NE Pacific St, Seattle, WA 98195, USA.
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Jubrias
authors.affiliation: Department of Kinesiology, University of Texas in El Paso, 500 University Ave, El Paso, TX 79968, USA.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Gamboa
authors.affiliation: Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA 70808, USA.
authors.forename: Kori
authors.initials: K
authors.lastname: Murray
authors.affiliation: Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA 70808, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Sereda
authors.affiliation: Translational Research Institute for Metabolism and Diabetes, Florida Hospital, Orlando, FL 32804, USA; Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL 32827, USA.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Sparks
authors.affiliation: Translational Research Institute for Metabolism and Diabetes, Florida Hospital, Orlando, FL 32804, USA; Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL 32827, USA. Electronic address: Steven.R.Smith.MD@flhosp.org.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Smith
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000328:Adult; D001823:Body Composition; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D004311:Double-Blind Method; D005260:Female; D015309:Glucose Clamp Technique; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D007333:Insulin Resistance; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008931:Mitochondria, Muscle / Q000187:drug effects* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D000255:Adenosine Triphosphate; D000077205:Pioglitazone
keywords: ATPmax; Diabetes; IMCL; Muscle; Pioglitazone