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Cited by 95Metabolism, Diabetes, and CancerAdvanced Glycation End Products researchNitric Oxide and Endothelin Effects

Metformin Prevents Glucose-Induced Protein Kinase C-β2 Activation in Human Umbilical Vein Endothelial Cells Through an Antioxidant Mechanism

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Gallo, Alessandra, Ceolotto, Giulio, Pinton, Paolo, Iori, Elisabetta, Murphy, Ellen, Rutter, Guy A., Rizzuto, Rosario, Semplicini, Andrea +1 more·2005·Diabetes
DOI 10.2337/diabetes.54.4.1123
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Abstract

Hyperglycemia determines the vascular complications of diabetes through different mechanisms: one of these is excessive activation of the isoform beta2 of protein kinase C (PKC-beta2). Metformin, a widely used antidiabetic agent, is associated with decreased cardiovascular mortality in obese type 2 diabetic patients. Therefore, we assessed the role of metformin in glucose-induced activation of PKC-beta2 and determined the mechanism of its effect in human umbilical venous endothelial cells grown to either normo- (5 mmol/l) or hyperglycemia (10 mmol/l) and moderately and acutely exposed to 25 mmol/l glucose. We studied PKC-beta2 activation by developing adenovirally expressed chimeras encoding fusion protein between green fluorescent protein (GFP) and conventional beta2 isoform (PKC-beta2-GFP). Glucose (25 mmol/l) induced the translocation of PKC-beta2-GFP from the cytosol to the membrane in cells grown to hyperglycemia but not in those grown in normal glucose medium. Metformin (20 micromol/l) prevented hyperglycemia-induced PKC-beta2-GFP translocation. We also assessed oxidative stress under the same conditions with a 4-((9-acridine-carbonyl)amino)-2,2,6,6-tetramethylpiperidin-oxyl,free radical (TEMPO-9-AC) fluorescent probe. We observed significantly increased radical oxygen species production in cells grown in hyperglycemia medium, and this effect was abolished by metformin. We show that in endothelial cells, metformin inhibits hyperglycemia-induced PKC-beta2 translocation because of a direct antioxidant effect. Our data substantiate the findings of previous large intervention studies on the beneficial effect of this drug in type 2 diabetic patients.

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  • Metformin and other drugs used for T2DM, like SGLT2 inhibitors, may also reduce hyperglycemia-induced elevated endothelial ROS, independent of negative effects on complex 1, such as via inhibition of NADPH oxidase or blocking entry of glucose into the endothelium.

    “Metformin and other drugs used for T2DM, like the SGLT2 inhibitors, may also reduce hyperglycemia-induced elevated endothelial ROS, independent of negative effects on complex 1, such as via inhibition of NADPH oxidase or blocking the entry of glucose into the endothelium (32, 107–109, 187, 188)”

    From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [187]

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Authors
Gallo, A., Ceolotto, G., Pinton, P., Iori, E., Murphy, E., Rutter, G. A., Rizzuto, R., Semplicini, A., & Avogaro, A.
Affiliations
  • University of Padua (IT)
  • University of Ferrara (IT)
  • University of Bristol (GB)
ORCID
Venue
Diabetes
Publisher
American Diabetes Association
Published
2005-04-01
Volume
54
Issue
4
Pages
1123-1131
ISSN
  • 0012-1797 (ISSN-L)
  • 1939-327X
DOI
10.2337/diabetes.54.4.1123
OpenAlex
W2156913795
Cited by
95
References
33
Citations by year
2025: 2 · 2024: 1 · 2023: 3 · 2022: 2 · 2021: 3 · 2020: 6 · 2019: 2 · 2018: 6 · 2017: 3 · 2016: 5 · 2015: 5 · 2014: 1 · 2013: 9 · 2012: 5
FWCI
3.40
Type
journal article
Language
en
Open access
Locations
  • Diabetes (publishedVersion)
  • PubMed (publishedVersion)
  • Institutional Research Information System University of Ferrara (University of Ferrara) (submittedVersion)
  • Padua Research Archive (University of Padova) (submittedVersion)
  • INFM-OAR (INFN Catania) (submittedVersion, other-oa)
Funders
  • Juvenile Diabetes Research Foundation International
  • Ministero dell’Istruzione, dell’Università e della Ricerca
  • Associazione Italiana per la Ricerca sul Cancro
  • Medical Research Council
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
Keywords
metformin, hyperglycemia, endothelial cells, oxidative stress, antioxidant defense, PKC translocation, type 2 diabetes, diabetic vascular complications, reactive oxygen species
MeSH terms
Cells, Cultured, Endothelium, Vascular, Glucose, Humans, Hyperglycemia, Hypoglycemic Agents, Metformin, Protein Kinase C, Umbilical Veins, Reactive Oxygen Species, Protein Kinase C beta

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