Reduced skeletal muscle uncoupling protein-3 content in prediabetic subjects and type 2 diabetic patients: restoration by rosiglitazone treatment

J Clin Endocrinol Metab. 2006 Apr;91(4):1520-5. doi: 10.1210/jc.2005-1572. Epub 2005 Dec 29.

Abstract

Context: 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.

Main outcome measures: 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).

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Blood Glucose / metabolism
  • Carrier Proteins / biosynthesis*
  • Carrier Proteins / genetics
  • Diabetes Mellitus, Type 2 / drug therapy
  • Diabetes Mellitus, Type 2 / metabolism*
  • Glucose Clamp Technique
  • Glucose Intolerance / drug therapy
  • Glycated Hemoglobin / metabolism
  • Humans
  • Hypoglycemic Agents / pharmacology*
  • Hypoglycemic Agents / therapeutic use
  • Insulin Resistance / physiology
  • Ion Channels
  • Male
  • Middle Aged
  • Mitochondrial Proteins / metabolism
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism*
  • Obesity / metabolism
  • Prediabetic State / drug therapy
  • Prediabetic State / metabolism*
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Rosiglitazone
  • Thiazolidinediones / pharmacology*
  • Thiazolidinediones / therapeutic use
  • Uncoupling Protein 3

Substances

  • Blood Glucose
  • Carrier Proteins
  • Glycated Hemoglobin A
  • Hypoglycemic Agents
  • Ion Channels
  • Mitochondrial Proteins
  • RNA, Messenger
  • Thiazolidinediones
  • UCP3 protein, human
  • Uncoupling Protein 3
  • Rosiglitazone