Why the endothelium? The endothelium as a target to reduce diabetes-associated vascular disease
Open accessAbstract
Over the past 66 years, our knowledge of the role of the endothelium in the regulation of cardiovascular function and dysfunction has advanced from the assumption that it is a single layer of cells that serves as a barrier between the blood stream and vascular smooth muscle to an understanding of its role as an essential endocrine-like organ. In terms of historical contributions, we pay particular credit to (1) the Canadian scientist Dr. Rudolf Altschul who, based on pathological changes in the appearance of the endothelium, advanced the argument in 1954 that "one is only as old as one's endothelium" and (2) the American scientist Dr. Robert Furchgott, a 1998 Nobel Prize winner in Physiology or Medicine, who identified the importance of the endothelium in the regulation of blood flow. This review provides a brief history of how our knowledge of endothelial function has advanced and now recognize that the endothelium produces a plethora of signaling molecules possessing paracrine, autocrine, and, arguably, systemic hormone functions. In addition, the endothelium is a therapeutic target for the anti-diabetic drugs metformin, glucagon-like peptide I (GLP-1) receptor agonists, and inhibitors of the sodium-glucose cotransporter 2 (SGLT2) that offset the vascular disease associated with diabetes.
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Based on evidence from both clinical and pre-clinical studies, metformin, independent of its anti-hyperglycemic actions, directly protects the endothelium.
“Based on evidence from both clinical and pre-clinical studies metformin, independent of its anti-hyperglycemic actions, directly protects the endothelium (33–35).”
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 [34]
With a plasma half-life of approximately 3 to 5 hours and subject to dosing schedule, it is unlikely that other than in gut enterocytes a significant cellular accumulation of metformin occurs when used for T2DM.
“However, with a plasma half-life of approximately 3 to 5 hours, and subject to the schedule of dosing, it is unlikely, that other than in gut enterocytes, a significant cellular accumulation of metformin occurs when the drug is used for the treatment of T2DM (34, 155, 156, 159, 160).”
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 [34]
When prescribed in the usual oral dosage range of 250 to ~2550 mg/day for T2DM and in the absence of reduced renal function, peak plasma levels of metformin are unlikely to exceed 15-20 μM, with trough levels between 1-5 μM, and a plasma half-life of approximately 3 to 5 hours.
“When prescribed in the usual oral dosage range of 250 to ~2550 mg/day for the treatment of T2DM and in the absence of reduced renal function, it is unlikely that peak plasma levels of metformin would exceed 15-20 μM, with trough levels of between 1-5 μM, and a plasma half-life of approximately 3 to 5 hours.”
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 [34]
Based on critical reviews of the literature, the answer appears to be yes that metformin exerts a direct anti-aging effect on the endothelium, although clinical data could be interpreted as secondary to metformin's actions to enhance insulin sensitivity and lower blood glucose.
“Based on critical reviews of the literature, the answer appears to be “yes”, although the clinical data could be interpreted as secondary to metformin’s actions to enhance insulin sensitivity and lower blood glucose levels (34, 106, 173).”
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 [34]
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References 235 · Cited by 49
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- Authors
- Triggle, C. R., Ding, H., Marei, I., Anderson, T. J., & Hollenberg, M. D.
- Affiliations
- Weill Cornell Medical College in Qatar (QA)
- University of Calgary (CA)
- Corresponding author
- Triggle, Chris R.
- Venue
- Canadian Journal of Physiology and Pharmacology
- Publisher
- Canadian Science Publishing
- Published
- 2020-07
- Volume
- 98
- Issue
- 7
- Pages
- 415-430
- ISSN
- 0008-4212 (ISSN-L)
- 1205-7541
- OpenAlex
- W3011757834
- Cited by
- 49
- References
- 235
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 6 · 2023: 5 · 2022: 15 · 2021: 11 · 2020: 5
- FWCI
- 1.15
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Canadian Journal of Physiology and Pharmacology (publishedVersion, cc-by)
- PubMed (publishedVersion)
- TSpace (University of Toronto) (acceptedVersion)
- Funders
- Qatar Foundation
- Qatar National Research Fund
- Canadian Institutes of Health Research
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
- Keywords
- endothelium, endothelial dysfunction, metformin, GLP-1 receptor agonists, SGLT2 inhibitors, antidiabetic drugs, vascular disease
- MeSH terms
- Blood Circulation, Diabetic Angiopathies, Endothelium, Vascular, Humans, Hypoglycemic Agents, Muscle, Smooth, Vascular, Physiology, Vasoconstriction, Vasodilation, History, 20th Century
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