Thiazolidinediones, Like Metformin, Inhibit Respiratory Complex I
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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.
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The clinically used drugs with known PGC-1α-modulating activity, such as fibrates, thiazolidinediones, metformin, and statins, display neurotoxicity and a limited ability to cross the blood-brain barrier.
“The clinically used drugs with known PGC-1α-modulating activity, such as fibrates, thiazolidinediones, metformin, and statins, display neurotoxicity and a limited ability to cross the blood–brain barrier (BBB) [35,36,37,38].”
From Protective Effects of PGC-1α Activators on Ischemic Stroke in a Rat Model of Photochemically Induced Thrombosis (2021) · cites this paper as [36]
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- Authors
- Brunmair, B., Staniek, K., Gras, F., Scharf, N., Althaym, A., Clara, R., Roden, M., Gnaiger, E., Nohl, H., Waldhäusl, W., & Fürnsinn, C.
- Affiliations
- University of Vienna (AT)
- University of Veterinary Medicine Vienna (AT)
- Universität Innsbruck (AT)
- Department of Medicine III, Division of Endocrinology & Metabolism, University of Vienna, Vienna, Austria
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2004-04-01
- Volume
- 53
- Issue
- 4
- Pages
- 1052-1059
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2403578638
- Cited by
- 521
- References
- 39
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 15 · 2023: 10 · 2022: 14 · 2021: 15 · 2020: 33 · 2019: 25 · 2018: 16 · 2017: 27 · 2016: 37 · 2015: 30 · 2014: 40 · 2013: 33 · 2012: 29
- FWCI
- 7.64
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Pfizer
- Austrian Science Fund
- Universität Wien
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- thiazolidinediones, metformin, mitochondrial complex I, mitochondrial respiration, rosiglitazone, pioglitazone, skeletal muscle, anaerobic glycolysis, glucose oxidation, lactate release, antidiabetic mechanism, type 2 diabetes
- MeSH terms
- Rosiglitazone, Pioglitazone, Animals, Energy Metabolism, Hypoglycemic Agents, Male, Metformin, Mitochondria, Oxygen Consumption, Potassium Chloride, Rotenone, Rats, Sprague-Dawley, Muscle, Skeletal, Electron Transport Complex I, Thiazolidinediones, Rats
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