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Cited by 97Nitric Oxide and Endothelin EffectsDiabetes Treatment and ManagementMetabolism, Diabetes, and Cancer

The DOI matches its Crossref record; 241 of the 242 references it cites were found in a registry or an index.

Can Metformin Exert as an Active Drug on Endothelial Dysfunction in Diabetic Subjects

Open access
Salvatore, Teresa, Pafundi, Pia Clara, Galiero, Raffaele, Rinaldi, Luca, Caturano, Alfredo, Vetrano, Erica, Aprea, Concetta, Albanese, Gaetana, Di Martino, Anna, Ricozzi, Carmen, Imbriani, Simona, Sasso, Ferdinando Carlo·2020·Biomedicines
DOI 10.3390/biomedicines9010003PMC PMC7822116
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Abstract

Cardiovascular mortality is a major cause of death among in type 2 diabetes (T2DM). Endothelial dysfunction (ED) is a well-known important risk factor for the development of diabetes cardiovascular complications. Therefore, the prevention of diabetic macroangiopathies by preserving endothelial function represents a major therapeutic concern for all National Health Systems. Several complex mechanisms support ED in diabetic patients, frequently cross-talking each other: uncoupling of eNOS with impaired endothelium-dependent vascular response, increased ROS production, mitochondrial dysfunction, activation of polyol pathway, generation of advanced glycation end-products (AGEs), activation of protein kinase C (PKC), endothelial inflammation, endothelial apoptosis and senescence, and dysregulation of microRNAs (miRNAs). Metformin is a milestone in T2DM treatment. To date, according to most recent EASD/ADA guidelines, it still represents the first-choice drug in these patients. Intriguingly, several extraglycemic effects of metformin have been recently observed, among which large preclinical and clinical evidence support metformin's efficacy against ED in T2DM. Metformin seems effective thanks to its favorable action on all the aforementioned pathophysiological ED mechanisms. AMPK pharmacological activation plays a key role, with metformin inhibiting inflammation and improving ED. Therefore, aim of this review is to assess metformin's beneficial effects on endothelial dysfunction in T2DM, which could preempt development of atherosclerosis.

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Crossref · 10.3390/biomedicines9010003

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Figures

Figure 1 Main mechanisms of high glucose-induced endothelial dysfunction (direct arrows indicate the direction of the pathway, whilst double arrow stands for bidirectional pathway).
Figure 1 Main mechanisms of high glucose-induced endothelial dysfunction (direct arrows indicate the direction of the pathway, whilst double arrow stands for bidirectional pathway).CC BY · PubMed Central
Figure 2 Mechanisms by which metformin promotes NO production (direct arrows indicate the direction of the pathway).
Figure 2 Mechanisms by which metformin promotes NO production (direct arrows indicate the direction of the pathway).CC BY · PubMed Central
Figure 3 Schematic picture of the mechanisms by which metformin exerts a protective action against oxidative stress and endothelial dysfunction (direct arrows indicate the direction of the pathway, whilst blocked arrows stands for inhibition of that specific pathway. Double arrow stands instead for a bidirectional reaction).
Figure 3 Schematic picture of the mechanisms by which metformin exerts a protective action against oxidative stress and endothelial dysfunction (direct arrows indicate the direction of the pathway, whilst blocked arrows stands for inhibition of that specific pathway. Double arrow stands instead for a bidirectional reaction).CC BY · PubMed Central
Figure 4 Mechanisms by which Metformin protect Endothelial Cells from apoptosis, senescence, and death (direct arrows indicate the direction of the pathway, whilst blocked arrows stands for inhibition of that specific pathway).
Figure 4 Mechanisms by which Metformin protect Endothelial Cells from apoptosis, senescence, and death (direct arrows indicate the direction of the pathway, whilst blocked arrows stands for inhibition of that specific pathway).CC BY · PubMed Central

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Citations

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Metadata

Authors
Salvatore, T., Pafundi, P. C., Galiero, R., Rinaldi, L., Caturano, A., Vetrano, E., Aprea, C., Albanese, G., Di Martino, A., Ricozzi, C., Imbriani, S., & Sasso, F. C.
Affiliations
  • University of Campania "Luigi Vanvitelli" (IT)
  • Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Piazza Luigi Miraglia 2, I-80138 Naples, Italy
Corresponding author
Sasso, Ferdinando Carlo
ORCID
Venue
Biomedicines
Publisher
MDPI AG
Published
2020-12-22
Volume
9
Issue
1
Pages
3
ISSN
2227-9059 (ISSN-L)
DOI
10.3390/biomedicines9010003
PMC
PMC7822116
OpenAlex
W3113948922
Cited by
97
References
242
Citations by year
2026: 5 · 2025: 8 · 2024: 22 · 2023: 13 · 2022: 32 · 2021: 17
FWCI
1.98
Type
journal article
Language
en
Open access
Licence
Locations
  • Biomedicines (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Archivio Istituzionale della Ricerca - Università degli Studi della Campania "Luigi Vanvitelli" (submittedVersion)
  • Archivio Istituzionale della Ricerca - Università degli Studi del Molise (submittedVersion)
Topics
  • Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords
metformin, endothelial dysfunction, type 2 diabetes, AMPK activation, diabetic macroangiopathy, cardiovascular complications, endothelial inflammation, oxidative stress, advanced glycation end products, polyol pathway, protein kinase C, endothelial cell apoptosis, microRNA, atherosclerosis prevention

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