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Diabetes 53:1052-1059, 2004
© 2004 by the American Diabetes Association, Inc.

Thiazolidinediones, Like Metformin, Inhibit Respiratory Complex I

A Common Mechanism Contributing to Their Antidiabetic Actions?

Barbara Brunmair1, Katrin Staniek2, Florian Gras1, Nicole Scharf1, Aleksandra Althaym1, Renate Clara1, Michael Roden1, Erich Gnaiger3, Hans Nohl2, Werner Waldhäusl1, and Clemens Fürnsinn1

1 Department of Medicine III, Division of Endocrinology & Metabolism, University of Vienna, Vienna, Austria
2 Basic Research in Pharmacology and Toxicology, Veterinary University Vienna, Vienna, Austria
3 Department of Transplant Surgery, Clinical and Interdisciplinary Bioenergetics, University of Innsbruck, Innsbruck, Austria

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.

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


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Copyright © 2004 by the American Diabetes Association.