Thiazolidinediones, Like Metformin, Inhibit Respiratory Complex I

A Common Mechanism Contributing to Their Antidiabetic Actions?

  1. Barbara Brunmair1,
  2. Katrin Staniek2,
  3. Florian Gras1,
  4. Nicole Scharf1,
  5. Aleksandra Althaym1,
  6. Renate Clara1,
  7. Michael Roden1,
  8. Erich Gnaiger3,
  9. Hans Nohl2,
  10. Werner Waldhäusl1 and
  11. Clemens Fürnsinn1
  1. 1Department of Medicine III, Division of Endocrinology & Metabolism, University of Vienna, Vienna, Austria
  2. 2Basic Research in Pharmacology and Toxicology, Veterinary University Vienna, Vienna, Austria
  3. 3Department of Transplant Surgery, Clinical and Interdisciplinary Bioenergetics, University of Innsbruck, Innsbruck, Austria
  1. Address correspondence and reprint requests to Clemens Fürnsinn, PhD, Department of Medicine III, Division of Endocrinology & Metabolism, Währinger Gürtel 18-20, A-1090 Vienna, Austria. E-mail: clemens.fuernsinn{at}akh-wien.ac.at

Abstract

Metformin and thiazolidinediones (TZDs) are believed to exert their antidiabetic effects via different mechanisms. As evidence suggests that both impair cell respiration in vitro, this study compared their effects on mitochondrial functions. The activity of complex I of the respiratory chain, which is known to be affected by metformin, was measured in tissue homogenates that contained disrupted mitochondria. In homogenates of skeletal muscle, metformin and TZDs reduced the activity of complex I (30 mmol/l metformin, −15 ± 2%; 100 μmol/l rosiglitazone, −54 ± 7; and 100 μmol/l pioglitazone, −12 ± 4; P < 0.05 each). Inhibition of complex I was confirmed by reduced state 3 respiration of isolated mitochondria consuming glutamate + malate as substrates for complex I (30 mmol/l metformin, −77 ± 1%; 100 μmol/l rosiglitazone, −24 ± 4; and 100 μmol/l pioglitazone, −18 ± 5; P < 0.05 each), whereas respiration with succinate feeding into complex II was unaffected. In line with inhibition of complex I, 24-h exposure of isolated rat soleus muscle to metformin or TZDs reduced cell respiration and increased anaerobic glycolysis (glucose oxidation: 270 μmol/l metformin, −30 ± 9%; 9 μmol/l rosiglitazone, −25 ± 8; and 9 μmol/l pioglitazone, −45 ± 3; lactate release: 270 μmol/l metformin, +84 ± 12; 9 μmol/l rosiglitazone, +38 ± 6; and 9 μmol/l pioglitazone, +64 ± 11; P < 0.05 each). As both metformin and TZDs inhibit complex I activity and cell respiration in vitro, similar mitochondrial actions could contribute to their antidiabetic effects.

Footnotes

    • Accepted December 23, 2003.
    • Received October 14, 2003.
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