title: Thiazolidinediones, like metformin, inhibit respiratory complex I: a common mechanism contributing to their antidiabetic actions?
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 micromol/l rosiglitazone, -54 +/- 7; and 100 micromol/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 micromol/l rosiglitazone, -24 +/- 4; and 100 micromol/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 micromol/l metformin, -30 +/- 9%; 9 micromol/l rosiglitazone, -25 +/- 8; and 9 micromol/l pioglitazone, -45 +/- 3; lactate release: 270 micromol/l metformin, +84 +/- 12; 9 micromol/l rosiglitazone, +38 +/- 6; and 9 micromol/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.
authors.affiliation: Department of Medicine III, Division of Endocrinology & Metabolism, University of Vienna, Vienna, Austria.
authors.forename: Barbara
authors.initials: B
authors.lastname: Brunmair
authors.forename: Katrin
authors.initials: K
authors.lastname: Staniek
authors.forename: Florian
authors.initials: F
authors.lastname: Gras
authors.forename: Nicole
authors.initials: N
authors.lastname: Scharf
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Althaym
authors.forename: Renate
authors.initials: R
authors.lastname: Clara
authors.forename: Michael
authors.initials: M
authors.lastname: Roden
authors.forename: Erich
authors.initials: E
authors.lastname: Gnaiger
authors.forename: Hans
authors.initials: H
authors.lastname: Nohl
authors.forename: Werner
authors.initials: W
authors.lastname: Waldhäusl
authors.forename: Clemens
authors.initials: C
authors.lastname: Fürnsinn
mesh_terms: D000818:Animals; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D000077205:Pioglitazone; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077154:Rosiglitazone; D012402:Rotenone / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology
chemical_list: D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D012402:Rotenone; D000077154:Rosiglitazone; D011189:Potassium Chloride; D008687:Metformin; D042967:Electron Transport Complex I; D000077205:Pioglitazone