Cited by 102Metabolism, Diabetes, and CancerNitric Oxide and Endothelin EffectsMitochondrial Function and Pathology

Metformin delays the manifestation of diabetes and vascular dysfunction in Goto–Kakizaki rats by reduction of mitochondrial oxidative stress

Rösen, Peter, Wiernsperger, Nicolas F.·2006·Diabetes/Metabolism Research and Reviews

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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Crossref · 10.1002/dmrr.623

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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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