Opposite effects of pioglitazone and rosiglitazone on mitochondrial respiration in skeletal muscle of patients with type 2 diabetes.
OBJECTIVE
Skeletal muscle insulin resistance has been linked to mitochondrial dysfunction. We examined how improvements in muscular insulin sensitivity following rosiglitazone (ROSI) or pioglitazone (PIO) treatment would affect muscle mitochondrial function in patients with type 2 diabetes mellitus (T2DM).


METHODS
Muscle biopsies were obtained from 21 patients with T2DM before and after 12 weeks on either ROSI (4 mg once daily) [n = 12; age, 59.2 +/- 2.2 years; body mass index (BMI), 29.6 +/- 0.7 kg/m(2)] or PIO (30 mg once daily) (n = 9; age, 56.3 +/- 2.4 years; BMI, 29.5 +/- 1.5 kg/m(2)). An age- and BMI-matched control group was also included (n = 8; age, 61.8 +/- 2.3 years; BMI, 28.4 +/- 0.6 kg/m(2)). Insulin sensitivity, citrate synthase- and beta-hydroxyacyl-CoA-dehydrogenase (HAD) activity, intramuscular triglyceride (IMTG) and protein content of complexes I-IV were measured, while mitochondrial respiration per milligram muscle was measured in saponin-treated skinned muscle fibres using high-resolution respirometry.


RESULTS
Mitochondrial respiration per milligram muscle was lower in T2DM compared to controls at baseline and decreased during ROSI treatment but increased during PIO treatment. Citrate synthase activity and average protein content of complexes I-IV were unchanged in the ROSI group, but protein content of complexes II and III increased during PIO treatment. Insulin sensitivity improved in all patients, but IMTG levels were unchanged.


CONCLUSIONS
We show opposite effects of ROSI and PIO on mitochondrial respiration, and also show that insulin sensitivity can be improved independently of changes in mitochondrial respiration. We confirm that mitochondrial respiration is reduced in T2DM compared to age- and BMI-matched control subjects.
Rabøl
R
R
Center for Healthy Aging, Department of Biomedical Sciences, University of Copenhagen, Denmark. rasmus.rabol@yale.edu
Boushel
R
R
Almdal
T
T
Hansen
C N
CN
Ploug
T
T
Haugaard
S B
SB
Prats
C
C
Madsbad
S
S
Dela
F
F
D015992:Body Mass Index; D019069:Cell Respiration / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007150:Immunohistochemistry; D007333:Insulin Resistance; D008297:Male; D008875:Middle Aged; D008931:Mitochondria, Muscle / Q000187:drug effects* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D000077205:Pioglitazone; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*
D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D000077205:Pioglitazone; D000077154:Rosiglitazone; D045162:Thiazolidinediones