Metformin delays the manifestation of diabetes and vascular dysfunction in Goto–Kakizaki rats by reduction of mitochondrial oxidative stress
Abstract
BACKGROUND AND AIM: This study was undertaken to test the hypothesis that hyperglycaemia induces the generation of reactive oxygen species (ROS) by mitochondria and that the oxidative stress thereby exerted is diminished by treatment with metformin. As a parameter of mitochondrial ROS formation, the activity of mitochondrial aconitase activity was determined using Goto-Kakizaki (GK) rats as model of type 2 diabetes. METHODS: In parallel with the development of diabetes (glucose, insulin), the generation of oxidative stress was determined in aortic tissue, heart and kidney of GK rats by measurement of lipid peroxides, oxidized proteins (carbonyl activity) and mitochondrial aconitase activity. Vascular activity was determined in aortae by measuring the endothelium-dependent vasodilatation in response to acetylcholine, and vasoconstriction in response to phenylephrine. RESULTS: At the age of 12-14 weeks, blood glucose levels rose dramatically from 7.5 up to 16.2 mM, indicating the manifestation of an overt diabetes. In addition, the glucose tolerance was impaired. The increase in blood glucose was not accompanied by changes in plasma insulin. Whereas the lipid peroxides in plasma only showed a tendency to increase, the amount of oxidized proteins (carbonyl moieties) increased from 4.6 to 10.9 micromol/mg protein (2.4 fold). In addition, the lipid peroxides in tissue were increased. Mitochondrial aconitase activity was reduced in the aorta and kidney, but not in the heart of diabetic animals. Treatment with metformin nearly normalized the hyperglycaemia and prevented the rise in carbonyl, tissue lipid peroxides and the fall in aconitase activity. Whereas the endothelium-dependent vasodilatation was not affected by the diabetes, the reaction of aortae in response to phenylephrine was strongly enhanced, changes which were prevented by treatment with metformin. CONCLUSIONS: These observations provide in vivo evidence that the generation of ROS plays an important role in the onset of diabetes and the development of vascular dysfunction in GK rats with type 2 diabetes.
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Mitochondrial ROS are implicated in renal pathology in the Goto-Kakizaki rat, a rodent model of type 2 diabetes.
“Mitochondrial ROS also were implicated in renal pathology in the Goto-Kakizaki rat, a rodent model of type 2 diabetes (275).”
From Mitochondrial Dysfunction in Diabetes: From Molecular Mechanisms to Functional Significance and Therapeutic Opportunities (2010) · cites this paper as [275]
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- Authors
- Rösen, P., & Wiernsperger, N. F.
- Affiliations
- Inserm (FR)
- Venue
- Diabetes/Metabolism Research and Reviews
- Publisher
- Wiley
- Published
- 2006
- Volume
- 22
- Issue
- 4
- Pages
- 323-330
- ISSN
- 1520-7552 (ISSN-L)
- 1520-7560
- OpenAlex
- W2027419462
- Cited by
- 102
- References
- 47
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 3 · 2023: 3 · 2022: 3 · 2021: 7 · 2020: 4 · 2019: 5 · 2018: 3 · 2017: 7 · 2016: 4 · 2015: 5 · 2014: 5 · 2013: 11 · 2012: 1
- FWCI
- 3.51
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Diabetes/Metabolism Research and Reviews (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- metformin, type 2 diabetes, Goto-Kakizaki rats, mitochondrial oxidative stress, reactive oxygen species, hyperglycemia, mitochondrial aconitase, lipid peroxidation, protein carbonylation, vascular dysfunction, endothelium-dependent vasodilation, vasoconstriction, glucose tolerance, insulin resistance
- MeSH terms
- Animals, Aorta, Thoracic, Blood Glucose, Diabetes Mellitus, Type 2, Diabetic Angiopathies, Disease Models, Animal, Hypoglycemic Agents, Male, Metformin, Mitochondria, Rats, Inbred Strains, Rats, Wistar, Oxidative Stress, Rats, In Vitro Techniques
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