Reduced skeletal muscle uncoupling protein-3 content in prediabetic subjects and type 2 diabetic patients: restoration by rosiglitazone treatment.
BACKGROUND
The mitochondrial uncoupling protein-3 (UCP3) has been implicated in the protection of the mitochondrial matrix against lipid-induced mitochondrial damage. Recent evidence points toward mitochondrial aberrations as a major contributor to the development of insulin resistance and diabetes, and UCP3 is reduced in diabetes.


OBJECTIVE
We compared skeletal muscle UCP3 protein levels in prediabetic subjects [i.e. impaired glucose tolerance (IGT)], diabetic patients, and healthy controls and examined whether rosiglitazone treatment was able to restore UCP3. PATIENTS, DESIGN, INTERVENTION: Ten middle-aged obese men with type 2 diabetes mellitus [age, 61.4 +/- 3.1 yr; body mass index (BMI), 29.8 +/- 2.9 kg/m(2)], nine IGT subjects (age, 59.0 +/- 6.6 yr; BMI, 29.7 +/- 3.0 kg/m(2)), and 10 age- and BMI-matched healthy controls (age, 57.3 +/- 7.4 yr; BMI, 30.1 +/- 3.9 kg/m(2)) participated in this study. After baseline comparisons, diabetic patients received rosiglitazone (2 x 4 mg/d) for 8 wk.


METHODS
Muscle biopsies were sampled to determine UCP3 and mitochondrial protein (complex I-V) content.


RESULTS
UCP3 protein content was significantly lower in prediabetic IGT subjects and in diabetic patients compared with healthy controls (39.0 +/- 28.5, 47.2 +/- 24.7, and 72.0 +/- 23.7 arbitrary units, respectively; P < 0.05), whereas the levels of the mitochondrial protein complex I-V were similar between groups. Rosiglitazone treatment for 8 wk significantly increased insulin sensitivity and muscle UCP3 content (from 53.2 +/- 29.9 to 66.3 +/- 30.9 arbitrary units; P < 0.05).


CONCLUSIONS
We show that UCP3 protein content is reduced in prediabetic subjects and type 2 diabetic patients. Eight weeks of rosiglitazone treatment restores skeletal muscle UCP3 protein in diabetic patients.
Schrauwen
Patrick
P
Nutrition and Toxicology Research Institute Maastricht, Department of Human Biology, Maastricht University, P.O. Box 616, NL-6200 MD Maastricht, The Netherlands. p.schrauwen@hb.unimaas.nl
Mensink
Marco
M
Schaart
Gert
G
Moonen-Kornips
Esther
E
Sels
Jean-Pierre
JP
Blaak
Ellen E
EE
Russell
Aaron P
AP
Hesselink
Matthijs K C
MK
D000368:Aged; D001786:Blood Glucose / Q000378:metabolism; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism*; D015309:Glucose Clamp Technique; D018149:Glucose Intolerance / Q000188:drug therapy; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007333:Insulin Resistance / Q000502:physiology; D007473:Ion Channels; D008297:Male; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism; D011236:Prediabetic State / Q000188:drug therapy / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology* / Q000627:therapeutic use; D000071247:Uncoupling Protein 3
D001786:Blood Glucose; D002352:Carrier Proteins; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007473:Ion Channels; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; D000077154:Rosiglitazone; D045162:Thiazolidinediones; D000071247:Uncoupling Protein 3; C000604392:UCP3 protein, human